JP4786147B2 - Cannabinoid receptor modulator - Google Patents

Description

  The present invention relates to a benzene ring condensed 5-membered heterocyclic compound, particularly a benzofuran derivative, and a pharmaceutical composition containing the same as a cannabinoid receptor modulator.

  The cannabinoid receptor belongs to a G protein-coupled receptor having a 7-transmembrane domain. Among these, CB1 receptors mainly distributed in the central nervous system are clarified by Non-Patent Document 1, while CB2 receptors mainly distributed in peripheral tissues and cells in the immune system are non-Patent Document 2. It was discovered by CB1 receptor and CB2 receptor show 48% homology, and CB1 receptor has 97-99% amino acid sequence in rat, mouse and human.

  In the brain, CB1 receptors are more abundant in the hippocampus, striatum, substantia nigra, basal forebrain, olfactory bulb, and cerebellum, and less in the brain stem, medulla, and thalamus. The CB1 receptor is thought to localize in the presynaptic region and to suppress the release of neurotransmitters in a suppressive manner (Non-patent Document 3). As for CB1 receptor, there are four types of agonists, ie, tetrahydrocannabinol (THC) derivative classical cannabinoids with dibenzopyran ring, bicyclic and tricyclic derivatives in which the pyran ring of THC structure is cleaved. -Arachidonic acid derivatives such as classical cannabinoids, aminoalkylindoles, and anandamide (Non-patent Document 4) known as an endogenous agonist are widely known.

  WIN55,212-2, a cannabinoid receptor agonist, has been reported to suppress neuronal cell death based on cerebral ischemia (Non-patent Document 5), and its action is that of the CB1 receptor at the glutamate neuronal presynapse. It is thought that glutamate release is suppressed through activation. In addition, it has been reported that anandamide, an endogenous ligand, exhibits a neuronal cell death inhibitory effect after brain injury (Non-patent Document 6). Baker et al. Also reported that cannabinoid receptor agonists WIN55, 212-2, JWH-133, THC and metaamandaamide improve tremor and spasm in an animal model of multiple sclerosis. (Non-Patent Document 7).

  Cerebrovascular disorder is the second most common cause of death in Japan, the United States, and Europe, and is the leading cause of severe sequelae. Currently, some patients with cerebral embolism and cerebral thrombosis are undergoing active cause treatment (such as tPA). However, due to limited treatment time window, the target is limited to a few percent of the total patient. Yes. In most cases, maintenance therapy is only performed for the purpose of anti-cerebral edema and suppression of recurrence / expansion (antithrombotic drugs), and there is no effective drug for the purpose of curative or brain protection. To date, many development products having various mechanisms of action (eg, glutamate antagonists, calcium antagonists, antioxidants, etc.) have been tried, but most of them have failed clinical trials.

  There is cerebral cryotherapy as a brain protection therapy whose effectiveness has been reviewed clinically with the enhancement of the intensive care system for stroke patients. Brain hypothermia is a therapy that lowers and maintains the brain temperature (brain temperature) to 32-33 ° C., and has a remarkable brain protective effect. For this reason, it has gradually attracted attention. However, this therapy requires intensive care facilities and 24-hour intensive management of multiple medical staff, making it difficult to spread as a general treatment.

By the way, the following compounds have been reported as compounds having an aminoacyl group in a benzene ring of a bicyclic heterocyclic ring in which benzene is condensed to a 5-membered heterocyclic ring.
1) General formula having analgesic action

［式中、R³はアシルアミノ基などを示す。］で表される化合物（特許文献１）。
２）幹細胞・神経前駆細胞の増殖・分化作用を有する、一般式

[Wherein R ³ represents an acylamino group or the like. ] The compound represented by (patent document 1).
2) General formula with proliferation / differentiation of stem cells and neural progenitor cells

［式中、Ｗはアシルアミノ基などを示す。］で表される化合物（特許文献２）。
３）ナトリウムチャンネル調節作用を有する式

[Wherein W represents an acylamino group or the like. ] The compound represented by (patent document 2).
3) Formula with sodium channel regulating action

［式中、基ＮＲ^１Ｒ^２はアミノアシル基等を示す。］で表される化合物（特許文献３）。

[Wherein, the group NR ¹ R ² represents an aminoacyl group or the like. ] (Patent document 3) represented by this.

International Publication WO02 / 085866 Pamphlet JP 2002-348239 A International Publication WO98 / 08842 Pamphlet Devane W A et al. (Molecular Pharmacology, 34, 605-613 (1988)) Munro S et al. (Nature, 365, 61-65 (1993)) Trends Pharmacological Sciences, 22, 565-572 (2001) Science, 258, 1946-1949 (1992) Journal of Neuroscience, 19, 2987-2995 (1999) Nature, 413, 527-531 (2001) Nature, 404, 84 (2000)

  Cerebrovascular disorders are roughly classified into cerebral infarction, cerebral hemorrhage, and subarachnoid hemorrhage. It is necessary to wait for a definitive diagnosis of the disease type by X-ray CT or MRI imaging, which limits the treatment time window. However, since the cannabinoid receptor agonist does not select a disease type, it does not require a definitive diagnosis and can solve the problem of treatment time window. It is also expected to be effective for prophylactic / therapeutic agents and diagnostic agents for cerebrovascular disorders such as cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, head trauma, and various inflammatory diseases. Furthermore, it can be expected that the intensive care system required by the hypothermia therapy and the intensive management system by the medical staff are not required, and that the brain protection effect equivalent to the hypothermia therapy is exhibited.

  Accordingly, an object of the present invention is to provide a benzene ring condensed 5-membered heterocyclic compound having a cannabinoid receptor function regulating action.

As a result of diligent search, the present inventors have unexpectedly found that the compounds represented by the above formulas (I ₀ ), (I), (I ′) and (I ″) having an aminoacyl group in a benzene-fused 5-membered heterocyclic ring are unexpectedly produced. Has been found to have an excellent cannabinoid receptor function regulating action, and as a result of further research, the present invention has been completed.

  That is, the present invention

(1) Formula (I ₀ )

［式中、Ｘは酸素原子、置換されていてもよい硫黄原子、または置換されていてもよいイミノ基を示し、Ｒ^０は置換されていてもよいアシルアミノ基を示し、環Ａ^０はＲ^０以外に更に置換基を有していてもよいベンゼン環を示し、環Ｂは置換されていてもよい５員複素環を示す。］で表される化合物またはその塩あるいはそのプロドラッグを含有するカンナビノイド受容体調節剤、
（２）式（Ｉ_０）で表される化合物またはその塩あるいはそのプロドラッグが、式（Ｉ）

[Wherein, X represents an oxygen atom, an optionally substituted sulfur atom, or an optionally substituted imino group, R ⁰ represents an optionally substituted acylamino group, and ring A ⁰ represents R ⁰ In addition to these, an optionally substituted benzene ring is shown, and ring B is an optionally substituted 5-membered heterocyclic ring. Or a salt thereof or a prodrug thereof, a cannabinoid receptor modulator,
(2) The compound represented by the formula (I ₀ ) or a salt thereof or a prodrug thereof is represented by the formula (I)

［式中、Ｘは酸素原子、置換されていてもよい硫黄原子、または置換されていてもよいイミノ基を示し、Ｒ¹、Ｒ^２、Ｒ^３およびＲ^４は、それぞれ独立して、水素原子、置換されていてもよい炭化水素基、置換されていてもよい複素環基、置換されていてもよいヒドロキシ基、置換されていてもよいメルカプト基、または置換されていてもよいアミノ基を示すか、あるいはＲ^２とＲ^３は一緒になって結合を形成してもよく、またはＲ^１とＲ^２は隣接する炭素原子と一緒になって置換されていてもよい環を形成してもよく、Ｙは−ＣＯ−、−ＳＯ−、または−ＳＯ_２−を示し、Ｒ^５は水素原子または置換されていてもよい炭化水素基を示し、Ｒ^６は水素原子、置換されていてもよい炭化水素基、置換されていてもよいヒドロキシ基、または置換されていてもよいアミノ基を示すか、あるいはＲ^５とＲ^６は隣接する炭素原子または硫黄原子および窒素原子と一緒になって置換されていてもよい環を形成してもよく、環Ａは式

[Wherein, X represents an oxygen atom, an optionally substituted sulfur atom, or an optionally substituted imino group, and R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom , An optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted mercapto group, or an optionally substituted amino group; Or R ² and R ³ may be combined to form a bond, or R ¹ and R ² may be combined with an adjacent carbon atom to form an optionally substituted ring. , Y represents —CO—, —SO—, or —SO ₂ —, R ⁵ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ⁶ represents a hydrogen atom or an optionally substituted carbon. A hydrogen group, an optionally substituted hydroxy group, or Whether represents an amino group which may be substituted, or R ⁵ and R ⁶ may form a substituted together with the adjacent carbon atom or a sulfur atom and a nitrogen atom ring, ring A is an expression

（式中、各記号は前記と同意義を示す）で示される基以外に更に置換基を有していてもよいベンゼン環を示す。］で表される化合物またはその塩あるいはそのプロドラッグである前記（１）記載の剤、
（３）Ｒ¹およびＲ^２が水素原子である前記（２）記載の剤、
（４）Ｒ¹およびＲ^２がそれぞれ水素原子またはＣ_１−４アルキル基である（但し、Ｒ¹およびＲ^２は同時に水素原子にはならない）である前記（２）記載の剤、
（５）式（I_０）で表される化合物またはその塩がカンナビノイド受容体アゴニストである前記（１）記載の剤、
（６）カンナビノイド受容体がカンナビノイド・タイプ１受容体である前記（５）記載の剤、
（７）式（I_０）で表される化合物またはその塩がカンナビノイド受容体アンタゴニストである前記（１）記載の剤、
（８）カンナビノイド受容体がカンナビノイド・タイプ１受容体である前記（７）記載の剤、
（９）式（I_０）で表される化合物またはその塩がカンナビノイド・タイプ２受容体アゴニストである前記（１）記載の剤、
（１０）脳血管障害急性期、脊髄損傷、頭部外傷、多発性硬化症、緑内障、うつ病、嘔吐、関節炎または喘息の予防・治療剤あるいは鎮痛剤である前記（１）に記載の剤、
（１１）記憶障害、精神疾患、肥満、精神病、不安、うつ病、薬物依存症、アルツハイマー病、またはパーキンソン病の予防・治療剤あるいは禁煙補助剤である前記（１）記載の剤、
（１２）多発性硬化症、神経変性疾患、過敏性腸炎、クローン病、逆流性食道炎、COPD、乾癬、自己免疫疾患、移植片拒絶反応、アレルギー性疾患、神経因性疼痛、肝炎ウイルス、または高血圧の予防・治療剤、あるいは免疫調整剤である前記（１）記載の剤、
（１３）式（Ｉ’）

(Wherein each symbol is as defined above) represents a benzene ring which may further have a substituent. Or a salt thereof or a prodrug thereof, the agent according to the above (1),
(3) The agent according to the above (2), wherein R ¹ and R ² are hydrogen atoms,
(4) The agent according to the above (2), wherein R ¹ and R ² are each a hydrogen atom or a C _1-4 alkyl group (provided that R ¹ and R ² do not simultaneously become a hydrogen atom),
(5) The agent according to the above (1), wherein the compound represented by the formula (I ₀ ) or a salt thereof is a cannabinoid receptor agonist,
(6) The agent according to the above (5), wherein the cannabinoid receptor is a cannabinoid type 1 receptor,
(7) The agent according to (1), wherein the compound represented by the formula (I ₀ ) or a salt thereof is a cannabinoid receptor antagonist,
(8) The agent according to the above (7), wherein the cannabinoid receptor is a cannabinoid type 1 receptor,
(9) The agent according to the above (1), wherein the compound represented by the formula (I ₀ ) or a salt thereof is a cannabinoid type 2 receptor agonist,
(10) The agent according to (1) above, which is a prophylactic / therapeutic agent or analgesic agent for cerebrovascular disorder acute phase, spinal cord injury, head injury, multiple sclerosis, glaucoma, depression, vomiting, arthritis or asthma,
(11) The agent according to the above (1), which is a prophylactic / therapeutic agent or adjuvant for smoking cessation for memory impairment, mental illness, obesity, psychosis, anxiety, depression, drug dependence, Alzheimer's disease or Parkinson's disease
(12) Multiple sclerosis, neurodegenerative disease, irritable enteritis, Crohn's disease, reflux esophagitis, COPD, psoriasis, autoimmune disease, graft rejection, allergic disease, neuropathic pain, hepatitis virus, or The agent according to (1) above, which is a prophylactic / therapeutic agent for hypertension, or an immunomodulator,
(13) Formula (I ′)

[式中、Ｘは酸素原子、置換されていてもよい硫黄原子、または置換されていてもよいイミノ基を示し、Ｒ¹およびＲ^２は、それぞれ独立して、水素原子、置換されていてもよい炭化水素基、置換されていてもよい複素環基、置換されていてもよいヒドロキシ基、置換されていてもよいメルカプト基、または置換されていてもよいアミノ基を示すか、あるいはＲ^１とＲ^２は隣接する炭素原子と一緒になって置換されていてもよい環を形成してもよく、Ｒ^3’は水素原子、置換されていてもよい炭化水素基、置換されていてもよいヒドロキシ基、置換されていてもよいメルカプト基、または置換されていてもよいアミノ基を示し、Ｒ^4’は水素原子、置換されていてもよいアルキル基、置換されていてもよいアリール基、または置換されていてもよい複素環基を示し、Ｙは−ＣＯ−、−ＳＯ−、または−ＳＯ_２−を示し、Ｒ^５は水素原子または置換されていてもよい炭化水素基を示し、Ｒ^６’は置換されていてもよい炭化水素基（但し、Ｒ^１およびＲ^２の両方が水素原子ではない場合、Ｒ^６’はベンゼン環を有さない）、置換されていてもよいヒドロキシ基、または置換されていてもよいアミノ基を示し、環Ａ’は式

[Wherein, X represents an oxygen atom, an optionally substituted sulfur atom, or an optionally substituted imino group, and R ¹ and R ² each independently represents a hydrogen atom or an optionally substituted Represents a good hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted mercapto group, or an optionally substituted amino group, or R ¹ R ² may form an optionally substituted ring together with the adjacent carbon atom, R ^{3 ′} may be a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy A group, an optionally substituted mercapto group, or an optionally substituted amino group, wherein R ^{4 ′} is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, or a substituted group; May have been Indicates a heterocyclic group, Y is -CO -, - SO-, or -SO 2 _- indicates, R ⁵ represents a hydrogen atom or an optionally substituted hydrocarbon group, R 6 ^'is optionally substituted May be a hydrocarbon group (provided that when R ¹ and R ² are not hydrogen atoms, R ^{6 ′} does not have a benzene ring), an optionally substituted hydroxy group, or an optionally substituted Represents an amino group, and ring A ′ is represented by the formula

（式中、各記号は前記と同意義を示す）で示される基以外に更に置換基を有していてもよいベンゼン環を示す。］
で表される化合物またはその塩、
（１４）Ｒ¹およびＲ^２がそれぞれ独立して、水素原子、置換されていてもよい炭化水素基、または置換されていてもよい複素環基、置換されていてもよいヒドロキシ基、置換されていてもよいメルカプト基、または置換されていてもよいアミノ基である前記（１３）記載の化合物、
（１５）Ｒ¹およびＲ^２が水素原子である前記（１３）記載の化合物、
（１６）Ｒ¹およびＲ^２がそれぞれ水素原子またはＣ_１−４アルキル基である（但し、Ｒ¹およびＲ^２は同時に水素原子にはならない）前記（１３）記載の化合物、
（１７）Ｒ^３’が水素原子である前記（１３）記載の化合物、
（１８）Ｒ^４’が置換されていてもよいＣ_６−１４アリール基、または置換されていてもよい５〜１４員複素環基である前記（１３）記載の化合物、
（１９）Ｒ^４’が置換されていてもよいフェニル基である前記（１３）記載の化合物、
（２０）Ｒ^４’が置換されていてもよいＣ_１−４アルキル基または置換されていてもよいＣ_１−４アルコキシ基で置換されていてもよいフェニル基である前記（１９）記載の化合物、
（２１）Ｙが−ＣＯ−である前記（１３）記載の化合物、

(Wherein each symbol is as defined above) represents a benzene ring which may further have a substituent. ]
Or a salt thereof,
(14) R ¹ and R ² are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, or a substituted The compound according to the above (13), which may be a mercapto group which may be substituted, or an amino group which may be substituted;
(15) The compound according to the above (13), wherein R ¹ and R ² are hydrogen atoms,
(16) The compound according to the above (13), wherein R ¹ and R ² are each a hydrogen atom or a C _1-4 alkyl group (provided that R ¹ and R ² do not simultaneously become a hydrogen atom)
(17) The compound according to the above (13), wherein R ^{3 ′} is a hydrogen atom,
(18) The compound according to (13) above, wherein R ^{4 ′} is an optionally substituted C _6-14 aryl group, or an optionally substituted 5-14 membered heterocyclic group,
(19) The compound according to the above (13), wherein R ^{4 ′} is an optionally substituted phenyl group,
(20) The compound described in (19) above, wherein R ^{4 ′} is a C _1-4 alkyl group which may be substituted or a phenyl group which may be substituted with a C _1-4 alkoxy group which may be substituted. ,
(21) The compound according to the above (13), wherein Y is -CO-.

(22) The compound according to the above (13), wherein R ⁵ is a hydrogen atom,
(23) The compound according to (13), wherein X is an oxygen atom,
(24) Formula

（式中、各記号は前記と同意義を示す）で示される基が式（Ｉ’）中に示す縮合複素環の５位に置換している前記（１３）記載の化合物、
（２５）置換されていてもよいＣ_６−１４アリール−Ｃ_１−４アルキル基が式（Ｉ’）中に示す縮合複素環の７位に更に置換している前記（２４）記載の化合物、
（２６）置換されていてもよいＣ_６−１４アリール−Ｃ_１−４アルキル基が置換されていてもよいベンジル基である前記（２５）記載の化合物、
（２７）環Ａ’が、式

(Wherein each symbol is as defined above), the compound according to the above (13), wherein the fused heterocyclic ring represented by formula (I ′) is substituted at the 5-position;
(25) The compound according to the above (24), wherein an _optionally substituted C _6-14 aryl-C _1-4 alkyl group is further substituted at the 7-position of the condensed heterocyclic ring shown in the formula (I ′),
(26) The compound according to the above (25), wherein the optionally substituted C _6-14 aryl-C _1-4 alkyl group is an _optionally substituted benzyl group,
(27) Ring A ′ is represented by the formula

（式中、各記号は前記と同意義を示す）で示される基以外に、置換されていてもよいＣ_１−６アルキル基、置換されていてもよいC_６−１２アリール基、置換されていてもよい5または6員の複素環基、およびアシル基から選択される１〜３個の置換基を更に有しているベンゼン環である前記（１３）記載の化合物、
（２８）式（Ｉ_０）中に示す縮合複素環の７位に、置換されていてもよいC_１−４アルキル基、置換されていてもよいC_６−１２アリール基、置換されていてもよい5または6員の複素環基、またはアシル基が置換している前記（２７）記載の化合物、
（２９）式（Ｉ_０）中に示す縮合複素環の７位に、それぞれ置換されていてもよいフェニル基、フラニル基、チエニル基、ピリジル基、アセチル基、プロピオニル基、ブチリル基、またはベンゾイル基が置換している前記（２７）記載の化合物、
（３０）Ｎ−（３−（４−イソプロピルフェニル）−４，６，７−トリメチル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）−３，３−ジメチルブタンアミド、
（＋）−Ｎ−（（３Ｒ）−３−（４−イソプロピルフェニル）−４，６，７−トリメチル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）−３，３−ジメチルブタンアミド、
Ｎ−（７−アセチル−３−（４−イソプロピルフェニル）−４，６−ジメチル−２，３−ジヒドロ−1−ベンゾフラン−５−イル）−３，３−ジメチルブタンアミド、
Ｎ−（３−（４−イソプロピルフェニル）−７−メトキシ−４，６−ジメチル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）−３，３−ジメチルブタンアミド、
（＋）−Ｎ−（（３Ｒ）−７−アセチル−３−（４−イソプロピルフェニル）−４，６−ジメチル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）−３，３−ジメチルブタンアミド、
（＋）−Ｎ−（ｔｅｒｔ−ブチル）−Ｎ’−（（３Ｒ）−３−（４−イソプロピルフェニル）−４，６，７−トリメチル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）ウレア、
Ｎ−（３−（４−イソプロピルフェニル）−４，６−ジメチル−７−フェニル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）−３，３−ジメチルブタンアミド、
Ｎ−（７−（３−ジメチルアミノフェニル）−３−（４−イソプロピルフェニル）−４，６−ジメチル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）−３，３−ジメチルブタンアミド、
Ｎ−（３−ヒドロキシプロピル）−Ｎ’−（３−（４−イソプロピルフェニル）−４，６，７−トリメチル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）ウレア、
Ｎ−（（４−イソプロピル−３−（２−メトキシエトキシ）フェニル）−４，６，７−トリメチル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）−３，３−ジメチルブタンアミド、
Ｎ−（７−（４−イソプロピルベンジル）−３，４，６−トリメチル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）−３，３−ジメチルブタンアミド、
Ｎ−（３−（４−ｔｅｒｔ−ブチルフェニル）−２，２，４，６，７−ペンタメチル−２，３−ジヒドロ−１−ベンゾフラン−５−イル）−３，３−ジメチルブタンアミド、または
Ｎ−（３−（４−イソプロピルフェニル）−４，６，７−トリメチル−３Ｈ−スピロ（１−ベンゾフラン−２，１’−シクロペンタン）−５−イル）−３，３−ジメチルブタンアミド、
（３１）前記（１３）記載の化合物のプロドラッグ、
（３２）前記（１３）記載の化合物またはそのプロドラッグからなる医薬、
（３３）脳血管障害急性期、脊髄損傷、頭部外傷、多発性硬化症、緑内障、うつ病、嘔吐、関節炎または喘息の予防または治療方法あるいは鎮痛方法であって、これらを必要とする対象に式（Ｉ_０）

(Wherein each symbol is as defined above), a C _1-6 alkyl group which may be substituted, a C _6-12 aryl group which may be substituted, a substituent The 5- or 6-membered heterocyclic group which may be, and the benzene ring further having 1 to 3 substituents selected from an acyl group,
(28) A C _1-4 alkyl group which may be substituted, a C _6-12 aryl group which may be substituted, or a substituent at the 7-position of the condensed heterocyclic ring represented by the formula (I ₀ ) A suitable 5- or 6-membered heterocyclic group, or a compound according to (27), wherein the acyl group is substituted;
(29) A phenyl group, a furanyl group, a thienyl group, a pyridyl group, an acetyl group, a propionyl group, a butyryl group, or a benzoyl group each optionally substituted at the 7-position of the condensed heterocyclic ring represented by the formula (I ₀ ) Wherein the compound is substituted,
(30) N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
(+)-N-((3R) -3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide ,
N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
N- (3- (4-Isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
(+)-N-((3R) -7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide,
(+)-N- (tert-butyl) -N ′-((3R) -3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl ) Urea,
N- (3- (4-isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
N- (7- (3-dimethylaminophenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide ,
N- (3-hydroxypropyl) -N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) urea,
N - ((4-Isopropyl-3- (2-methoxyethoxy) off Eniru) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) - 3,3-dimethylbutanamide ,
N- (7- (4-isopropylbenzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
N- (3- (4-tert-butylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide, or N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-3H-spiro (1-benzofuran-2,1′-cyclopentane) -5-yl) -3,3-dimethylbutanamide,
(31) A prodrug of the compound according to (13),
(32) A pharmaceutical comprising the compound according to (13) or a prodrug thereof,
(33) Cerebrovascular disorder acute phase, spinal cord injury, head trauma, multiple sclerosis, glaucoma, depression, vomiting, arthritis or asthma prophylaxis or treatment method or analgesic method for subjects requiring these Formula (I ₀ )

［式中、Ｘは酸素原子、置換されていてもよい硫黄原子、または置換されていてもよいイミノ基を示し、Ｒ^０はアシルアミノ基を示し、環Ａ^０はＲ^０以外に更に置換基を有していてもよいベンゼン環を示し、環Ｂは置換されていてもよい５員複素環を示す。］で表される化合物またはその塩あるいはそのプロドラッグの有効量を投与することを特徴とする方法、
（３４）記憶障害、精神疾患、肥満、精神病、不安、うつ病、薬物依存症、アルツハイマー病、またはパーキンソン病の予防または治療方法、あるいは禁煙の補助方法であって、これらを必要とする対象に式（Ｉ_０）

[Wherein, X represents an oxygen atom, an optionally substituted sulfur atom, or an optionally substituted imino group, R ⁰ represents an acylamino group, and ring A ⁰ represents a substituent other than R ^0. The benzene ring which may have is shown, the ring B shows the 5-membered heterocyclic ring which may be substituted. Or a salt thereof or a prodrug thereof in an effective amount,
(34) A method for the prevention or treatment of memory impairment, mental illness, obesity, psychosis, anxiety, depression, drug addiction, Alzheimer's disease, or Parkinson's disease, or an auxiliary method for smoking cessation. Formula (I ₀ )

［式中、Ｘは酸素原子、置換されていてもよい硫黄原子、または置換されていてもよいイミノ基を示し、Ｒ^０はアシルアミノ基を示し、環Ａ^０はＲ^０以外に更に置換基を有していてもよいベンゼン環を示し、環Ｂは置換されていてもよい５員複素環を示す。］で表される化合物またはその塩あるいはそのプロドラッグの有効量を投与することを特徴とする方法、

[Wherein, X represents an oxygen atom, an optionally substituted sulfur atom, or an optionally substituted imino group, R ⁰ represents an acylamino group, and ring A ⁰ represents a substituent other than R ^0. The benzene ring which may have is shown, the ring B shows the 5-membered heterocyclic ring which may be substituted. Or a salt thereof or a prodrug thereof in an effective amount,

(35) Multiple sclerosis, neurodegenerative disease, irritable enteritis, Crohn's disease, reflux esophagitis, COPD, psoriasis, autoimmune disease, graft rejection, allergic disease, neuropathic pain, hepatitis virus, or A method of preventing or treating hypertension, or a method of immunomodulation, wherein the subject is in need of formula (I ₀ )

［式中、Ｘは酸素原子、置換されていてもよい硫黄原子、または置換されていてもよいイミノ基を示し、Ｒ^０はアシルアミノ基を示し、環Ａ^０はＲ^０以外に更に置換基を有していてもよいベンゼン環を示し、環Ｂは置換されていてもよい５員複素環を示す。］で表される化合物またはその塩あるいはそのプロドラッグの有効量を投与することを特徴とする方法、

[Wherein, X represents an oxygen atom, an optionally substituted sulfur atom, or an optionally substituted imino group, R ⁰ represents an acylamino group, and ring A ⁰ represents a substituent other than R ^0. The benzene ring which may have is shown, the ring B shows the 5-membered heterocyclic ring which may be substituted. Or a salt thereof or a prodrug thereof in an effective amount,

(36) Formula (I ₀ ) for producing a prophylactic / therapeutic agent or analgesic agent for acute stage of cerebrovascular disorder, spinal cord injury, head trauma, multiple sclerosis, glaucoma, depression, vomiting, arthritis or asthma

［式中、Ｘは酸素原子、置換されていてもよい硫黄原子、または置換されていてもよいイミノ基を示し、Ｒ^０はアシルアミノ基を示し、環Ａ^０はＲ^０以外に更に置換基を有していてもよいベンゼン環を示し、環Ｂは置換されていてもよい５員複素環を示す。］で表される化合物またはその塩あるいはそのプロドラッグの使用、
（３７）記憶障害、精神疾患、肥満、精神病、不安、うつ病、薬物依存症、アルツハイマー病、またはパーキンソン病の予防・治療剤あるいは禁煙補助剤を製造するための式（Ｉ_０）

[Wherein, X represents an oxygen atom, an optionally substituted sulfur atom, or an optionally substituted imino group, R ⁰ represents an acylamino group, and ring A ⁰ represents a substituent other than R ^0. The benzene ring which may have is shown, the ring B shows the 5-membered heterocyclic ring which may be substituted. Or a salt thereof or a prodrug thereof,
(37) Formula (I ₀ ) for producing a prophylactic / therapeutic agent or smoking cessation aid for memory impairment, mental illness, obesity, psychosis, anxiety, depression, drug dependence, Alzheimer's disease, or Parkinson's disease

［式中、Ｘは酸素原子、置換されていてもよい硫黄原子、または置換されていてもよいイミノ基を示し、Ｒ^０はアシルアミノ基を示し、環Ａ^０はＲ^０以外に更に置換基を有していてもよいベンゼン環を示し、環Ｂは置換されていてもよい５員複素環を示す。］で表される化合物またはその塩あるいはそのプロドラッグの使用、
（３８）多発性硬化症、神経変性疾患、過敏性腸炎、クローン病、逆流性食道炎、COPD、乾癬、自己免疫疾患、移植片拒絶反応、アレルギー性疾患、神経因性疼痛、肝炎ウイルス、または高血圧の予防・治療剤、あるいは免疫調整剤を製造するための式（Ｉ_０）

[Wherein, X represents an oxygen atom, an optionally substituted sulfur atom, or an optionally substituted imino group, R ⁰ represents an acylamino group, and ring A ⁰ represents a substituent other than R ^0. The benzene ring which may have is shown, the ring B shows the 5-membered heterocyclic ring which may be substituted. Or a salt thereof or a prodrug thereof,
(38) Multiple sclerosis, neurodegenerative disease, irritable enteritis, Crohn's disease, reflux esophagitis, COPD, psoriasis, autoimmune disease, graft rejection, allergic disease, neuropathic pain, hepatitis virus, or Formula (I ₀ ) for producing a prophylactic / therapeutic agent for hypertension or an immunomodulator

［式中、Ｘは酸素原子、置換されていてもよい硫黄原子、または置換されていてもよいイミノ基を示し、Ｒ^０はアシルアミノ基を示し、環Ａ^０はＲ^０以外に更に置換基を有していてもよいベンゼン環を示し、環Ｂは置換されていてもよい５員複素環を示す。］で表される化合物またはその塩あるいはそのプロドラッグの使用、
（３９）式

[Wherein, X represents an oxygen atom, an optionally substituted sulfur atom, or an optionally substituted imino group, R ⁰ represents an acylamino group, and ring A ⁰ represents a substituent other than R ^0. The benzene ring which may have is shown, the ring B shows the 5-membered heterocyclic ring which may be substituted. Or a salt thereof or a prodrug thereof,
(39) Formula

［式中、Ｘは酸素原子、置換されていてもよい硫黄原子、または置換されていてもよいイミノ基を示し、
Ｒ¹、Ｒ^２、Ｒ^３およびＲ^４は、それぞれ独立して、水素原子、置換されていてもよい炭化水素基、置換されていてもよい複素環基、置換されていてもよいヒドロキシ基、置換されていてもよいメルカプト基、または置換されていてもよいアミノ基を示すか、あるいはＲ^２とＲ^３は一緒になって結合を形成してもよく、またはＲ^１とＲ^２は隣接する炭素原子と一緒になって置換されていてもよい環を形成してもよく、
Ｒ^５は水素原子または置換されていてもよい炭化水素基を示し、Ｒ^６は水素原子、置換されていてもよい炭化水素基、置換されていてもよいヒドロキシ基、または置換されていてもよいアミノ基を示すか、あるいはＲ^５とＲ^６は隣接する炭素原子または硫黄原子および窒素原子と一緒になって置換されていてもよい環を形成してもよく、
環Ａは式−ＮＨＲ^５で（式中、各記号は前記と同意義を示す）で示される基以外に更に置換基を有していてもよいベンゼン環を示す。］で表される化合物またはその塩を、
Ｒ^６ＹＬ、（Ｒ^６Ｙ）_２ＯまたはＲ^６Ｎ＝Ｙ（式中、Ｌは脱離基を、Ｙは−ＣＯ−、−ＳＯ−、または−ＳＯ_２−を示す）と反応させることを含む
式

[Wherein, X represents an oxygen atom, an optionally substituted sulfur atom, or an optionally substituted imino group;
R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, Represents an optionally substituted mercapto group, or an optionally substituted amino group, or R ² and R ³ together may form a bond, or R ¹ and R ² are adjacent Together with the carbon atom may form an optionally substituted ring,
R ⁵ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ⁶ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, or an optionally substituted hydrocarbon group. Represents an amino group, or R ⁵ and R ⁶ together with adjacent carbon or sulfur and nitrogen atoms may form an optionally substituted ring;
Ring A represents a benzene ring which may further have a substituent other than the group represented by the formula —NHR ⁵ (wherein each symbol is as defined above). Or a salt thereof,
Reacting with R ⁶ YL, (R ⁶ Y) ₂ O or R ⁶ N = Y (wherein L represents a leaving group, Y represents —CO—, —SO—, or —SO ₂ —). An expression containing

で表される化合物（式中、各記号は前記と同意義を示す）またはその塩の製造方法、等を提供するものである。

(Wherein each symbol is as defined above) or a salt production method thereof, and the like.

Moreover, this invention is another aspect,
(1 ′) a cannabinoid receptor modulator comprising a compound represented by the formula (I ₀ ) or a salt thereof or a prodrug thereof,
(2 ′) The agent according to the above (1 ′), wherein the compound represented by the formula (I ₀ ) or a salt thereof or a prodrug thereof is the compound represented by the formula (I) or a salt thereof or a prodrug thereof;
(3 ′) the agent according to the above (2 ′), wherein R ¹ and R ² are each a hydrogen atom,
(4 ′) the agent according to the above (2 ′), wherein R ¹ and R ² are each a C _1-4 alkyl group,
(5 ′) the agent according to the above (2 ′), wherein R ³ is a hydrogen atom,
(6 ′) the agent according to the above (2 ′), wherein R ⁴ is an optionally substituted C _6-14 aryl group or an optionally substituted 5-14 membered heterocyclic ring,
(7 ′) the agent according to the above (2 ′), wherein R ⁵ is a hydrogen atom,
(8 ′) The agent according to (2 ′) above, wherein R ⁶ is an optionally substituted alkyl group or an optionally substituted amino group, and Y is —CO—.
(9 ′) R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, The agent described in (2 ′) above, which may be a hydroxy group, an optionally substituted mercapto group, or an optionally substituted amino group,
(10 ′) The agent according to (1 ′), wherein X is an oxygen atom,
(11 ′) The agent according to the above (1 ′), wherein R ⁰ is substituted at the 5-position of the condensed heterocyclic ring shown in the formula (I ₀ ),
(12 ′) The description of (11 ′) above, wherein an _optionally substituted C _6-14 aryl-C _1-4 alkyl group is further substituted at the 7-position of the condensed heterocyclic ring shown in formula (I ₀ ) Agent,
(13 ′) The agent according to (1 ′), wherein ring A ⁰ is a benzene ring having 1 to 3 C _1-6 alkyl groups in addition to R ⁰ ,
(14 ′) The agent according to the above (1 ′), wherein the compound represented by the formula (I ₀ ) or a salt thereof is a cannabinoid receptor agonist,
(15 ′) The agent according to the above (14 ′), wherein the cannabinoid receptor is a cannabinoid type 1 receptor,
(16 ′) The agent according to the above (1 ′), wherein the compound represented by the formula (I ₀ ) or a salt thereof is a cannabinoid receptor antagonist,
(17 ′) The agent according to the above (16 ′), wherein the cannabinoid receptor is a cannabinoid type 1 receptor,
(18 ′) The agent according to the above (1 ′), which is a prophylactic / therapeutic agent for cerebrovascular disorder acute phase, spinal cord injury, head trauma, multiple sclerosis, glaucoma, or asthma,
(19 ′) The agent according to the above (1 ′), which is a preventive / therapeutic agent for memory impairment, mental illness, or obesity,
(20 ′) Formula (I ″)

[式中、Ｒ^3’は水素原子、置換されていてもよい炭化水素基、置換されていてもよいヒドロキシ基、置換されていてもよいメルカプト基、または置換されていてもよいアミノ基を示し、Ｒ^4’は置換されていてもよいアリール基、または置換されていてもよい複素環基を示し、環Ａ’は式

[Wherein R ^{3 ′} represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted mercapto group, or an optionally substituted amino group. , R ^{4 ′} represents an optionally substituted aryl group or an optionally substituted heterocyclic group, and ring A ′ is a compound represented by the formula

（式中、各記号は前記と同意義を示す）で示される基以外に更に置換基を有していてもよいベンゼン環を示し、他の記号は前記（２’）と同意義を示す。］
で表される化合物またはその塩、
（２１’）Ｒ^３’が水素原子である前記（２０’）記載の化合物、
（２２’）Ｒ^４’が置換されていてもよいＣ_６−１４アリール基、または置換されていてもよい５〜１４員複素環基である前記（２０’）記載の化合物、
（２３’）Ｒ^４’が置換されていてもよいフェニル基である前記（２０’）記載の化合物、
（２４’）Ｘが酸素原子である前記（２０’）記載の化合物、
（２５’）式

(Wherein each symbol is as defined above) represents a benzene ring which may further have a substituent other than the group shown above, and other symbols are as defined above (2 ′). ]
Or a salt thereof,
(21 ′) the compound according to the above (20 ′), wherein R ^{3 ′} is a hydrogen atom,
(22 ′) the compound according to the above (20 ′), wherein R ^{4 ′} is an optionally substituted C _6-14 aryl group, or an optionally substituted 5-14 membered heterocyclic group,
(23 ′) the compound according to (20 ′) above, wherein R ^{4 ′} is an optionally substituted phenyl group,
(24 ′) the compound according to the above (20 ′), wherein X is an oxygen atom,
(25 ') formula

（式中、各記号は前記と同意義を示す）で示される基が式（Ｉ”）中に示す縮合複素環の５位に置換している前記（２０’）記載の化合物、
（２６’）環Ａが、式

(Wherein each symbol is as defined above), the compound according to (20 ′) above, wherein the group represented by formula (I ″) is substituted at the 5-position of the condensed heterocyclic ring,
(26 ′) Ring A is a compound of the formula

（式中、各記号は前記と同意義を示す）で示される基以外に更に１〜３個のＣ_１−６アルキル基を有しているベンゼン環である前記（２０’）記載の化合物、
（２７’）前記（２０’）記載の化合物のプロドラッグ、
（２８’）前記（２０’）記載の化合物または前記（２７’）記載のプロドラッグからなる医薬、
（２９’）前記（２０’）記載の化合物または前記（２７’）記載のプロドラッグおよび医薬上許容される担体を含む医薬組成物、等を提供するものである。

(Wherein each symbol is as defined above), the compound according to (20 ′) above, which is a benzene ring further having 1 to 3 C _1-6 alkyl groups,
(27 ′) a prodrug of the compound described in (20 ′) above,
(28 ′) a medicament comprising the compound according to (20 ′) or the prodrug according to (27 ′),
(29 ′) A pharmaceutical composition comprising the compound described in (20 ′) above or the prodrug described in (27 ′) above and a pharmaceutically acceptable carrier, and the like.

  According to the present invention, an excellent cannabinoid receptor modulator is provided. Also provided are novel compounds represented by the above formulas (I ′) and (I ″) or salts thereof.

A compound represented by the formula (I ₀ ) or a salt thereof [hereinafter sometimes simply referred to as a compound (I ₀ ). ] Is preferably a compound represented by the above formula (I) [hereinafter simply abbreviated as compound (I). Or a salt thereof. As described above, the compounds represented by the formulas (I ′) and (I ″) or the salts thereof included in the compounds (I ₀ ) and (I) are novel compounds [hereinafter referred to as the formula (I ′) However, the same applies to the compound represented by the formula (I ″). In addition, the compound represented by the formula (I ′) or a salt thereof may hereinafter be simply abbreviated as the compound (I ′). ].

As the acylamino group represented by R ⁰ in the above formula, for example, the formula

［式中、Ｙは、−ＣＯ−、−ＳＯ−、または−ＳＯ_２−を示し、Ｒ^５は、水素原子または置換されていてもよい炭化水素基を示し、Ｒ^６は、水素原子、置換されていてもよい炭化水素基、置換されていてもよいヒドロキシ基、または置換されていてもよいアミノ基を示すか、あるいは、Ｒ^５とＲ^６は隣接する炭素原子または硫黄原子および窒素原子と一緒になって置換されていてもよい環を形成してもよい。］で表されるアシルアミノ基などが挙げられる。
ここで、Ｙとしては−ＣＯ−が好ましく、Ｒ^５としては水素原子等が好ましく、Ｒ^６としては置換されていてもよい炭化水素基および置換されていてもよいアミノ基等が好ましい。

[Wherein Y represents —CO—, —SO—, or —SO ₂ —, R ⁵ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ⁶ represents a hydrogen atom or a substituted group. Represents an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, or an optionally substituted amino group, or R ⁵ and R ⁶ represent an adjacent carbon atom or sulfur atom and a nitrogen atom. Together, they may form an optionally substituted ring. And the like.
Here, Y is preferably —CO—, R ⁵ is preferably a hydrogen atom or the like, and R ⁶ is preferably a hydrocarbon group which may be substituted, an amino group which may be substituted, or the like.

Examples of the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ⁵ , R ⁶ and R ^{6 ′} include a chain or cyclic hydrocarbon group (eg, alkyl, alkenyl, alkynyl, cycloalkyl). , Cycloalkenyl, cycloalkanedienyl, aryl, etc.) and a combination thereof (eg, C _7-14 aralkyl such as benzyl; C _2-6 alkyl-C _6-14 aryl such as ethylphenyl, propylphenyl, etc.); And C _2-6 alkenyl-C _6-14 aryl such as vinylphenyl and isopropenylphenyl). Among these, a linear or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable. Among them, alkyl is preferable for R ⁶ .

Examples of “alkyl” include C 1-10 alkyl (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methyl Propyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl, 1 -Ethylhexyl, n-octyl, 1-methylheptyl, nonyl, etc.) are preferred. Among them, more preferably C 1-6 alkyl for R 5, C 1-4 alkyl is especially preferred. On the other hand, R 6 is more preferably C 2-10 alkyl, and particularly preferably C 2-6 alkyl.

Examples of “alkenyl” include C _2-6 alkenyl (eg, vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1- Hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.) are preferred.

Examples of “alkynyl” include C _2-6 alkynyl (eg, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4 -Pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like) are preferred.

As the “cycloalkyl”, for example, C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like are preferable.

Examples of “cycloalkenyl” include C _3-6 cycloalkenyl (eg, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1 -Cyclobuten-1-yl, 1-cyclopenten-1-yl, etc.) are preferred.

Examples of “cycloalkanedienyl” include C _5-6 cycloalkanedienyl (eg, 2,4-cyclopentanedien-1-yl, 2,4-cyclohexanedien-1-yl, 2,5-cyclohexanediene). -1-yl etc.) are preferred.

As “aryl”, for example, C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl, etc.) and the like are preferable.

As “aralkyl”, for example, a C _6-14 aryl-C _1-6 alkyl group (eg, benzyl, α-methylbenzyl and the like) and the like are preferable.

Examples of the “substituent” of the “optionally substituted hydrocarbon group” include (1) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (2) C _1-3 alkylenedioxy (eg, , Methylenedioxy, ethylenedioxy, etc.), (3) nitro, (4) cyano, (5) optionally halogenated or hydroxylated C _1-6 alkyl, (6) optionally halogenated C _2-6 alkenyl, (7) optionally halogenated C _2-6 alkynyl, (8) optionally halogenated C _3-6 cycloalkyl, (9) C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl, etc.), (10) halogenated or acylated which may be _{C 1-6} alkoxy, (11) optionally _{C 1} may be halogenated ₆ alkylthio or mercapto, (12) hydroxy, (13) amino, (14) mono _{-C 1-6} alkylamino (e.g., methylamino, ethylamino, etc.), (15) _{mono--C 6-14} arylamino (e.g. , Phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), (16) di-C _1-6 alkylamino (eg, dimethylamino, diethylamino etc.), (17) di-C _6-14 arylamino (eg, , Diphenylamino, etc.), (18) acyl, (19) acylamino, (20) acyloxy, (21) optionally substituted 5-7 membered saturated cyclic amino, (22) 5-10 membered heterocyclic group (example 2-, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, -Or 10-membered aromatic heterocyclic groups such as 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl; 5-10 members such as 1,3-dioxolan-2-yl Non-aromatic heterocyclic group), (23) sulfo, (24) C _6-14 aryloxy (eg, phenyloxy, naphthyloxy, etc.), (25) oxo and the like.

  The “hydrocarbon group” may have, for example, 1 to 5, preferably 1 to 3 substituents at the substitutable positions. When the number of substituents is 2 or more, each substituent is They may be the same or different.

The “optionally halogenated or hydroxylated C _1-6 alkyl” is, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) or hydroxy C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) which may have a group, and the like can be mentioned. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoro Propyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6- And trifluorohexyl.

The “optionally halogenated C _2-6 alkenyl” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _2-6 alkenyl (eg, vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.) and the like may be mentioned. Specific examples include vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, 3,3,3-trifluoro-1-propenyl, 4,4,4-trifluoro-1-butenyl and the like.

The “optionally halogenated C _2-6 alkynyl” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _2-6 alkynyl (eg, ethynyl, propargyl, butynyl, 1-hexynyl, etc.) and the like may be mentioned. Specific examples include ethynyl, propargyl, butynyl, 1-hexynyl, 3,3,3-trifluoro-1-propynyl, 4,4,4-trifluoro-1-butynyl and the like.

The “optionally halogenated C _3-6 cycloalkyl” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like may be mentioned. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl and the like.

Examples of the “halogenated, hydroxylated, alkoxylated or acylated C _1-6 alkoxy” include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxy group, C _1-6 alkoxy. Selected from groups (eg, methoxy, ethoxy, etc.) and acyl groups (eg, C _1-6 alkyl-carbonyl such as acetyl and propionyl; C _1-6 alkoxy-carbonyl such as methoxycarbonyl and ethoxycarbonyl) For example, C _1-6 alkoxy optionally having 1 to 5, preferably 1 to 3 substituents (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, Hexyloxy, etc.). Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, Examples include pentyloxy and hexyloxy.

The “optionally halogenated C _1-6 alkylthio” has, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) and the like. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.

Examples of the “acyl” include formyl, carboxy, carbamoyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), C _3-6 cycloalkyl-carbonyl (eg, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl). Etc.), C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C _6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.) , _{C 7-16} aralkyl - carbonyl (e.g., phenylacetyl, phenylpropionyl, _{etc.), C 6-14} aryloxy - carbonyl (e.g., phenoxycarbonyl, _{etc.), C 7-16} aralkyloxy - carbonyl (e.g., benzyl Xyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-membered heterocyclic carbonyl (eg, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl 1-pyrrolidinylcarbonyl, etc.), mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethyl) carbamoyl, _{etc.), C 6-14} aryl - carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, _{etc.), C 1-6} alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, _{etc.), C 6-14} arylsulfonyl (e.g., phenylsulfonyl 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, etc.), C _6-14 arylsulfinyl (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthyl) Sulfinyl and the like).

Examples of the “acylamino” include formylamino, C _1-6 alkyl-carbonylamino (eg, acetylamino, etc.), C _6-14 aryl-carbonylamino (eg, phenylcarbonylamino, naphthylcarbonylamino, etc.), C _{1. -6} alkoxy-carboquinylamino (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _{6 -14} arylsulfonylamino (eg, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.) and the like.

Examples of the “acyloxy” include C _1-6 alkyl-carbonyloxy (eg, acetoxy, propionyloxy, etc.), C _6-14 aryl-carbonyloxy (eg, benzoyloxy, naphthylcarbonyloxy, etc.), C _1-6. Alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di- C _1-6 alkyl - carbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, _{etc.), C 6-14} aryl - carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyl oxy ), Nicotinoyloxy oxy and the like.

Examples of the “5- to 7-membered saturated cyclic amino” of the “optionally substituted 5- to 7-membered saturated cyclic amino” include morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl and the like. Can be mentioned. Examples of the “substituent” of the “optionally substituted 5- to 7-membered saturated cyclic amino” include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert -Butyl, pentyl, hexyl, etc.), C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.), 5- to 10-membered aromatic heterocyclic group (eg, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3 -Indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl and the like. The “5- to 7-membered saturated cyclic amino” may have 1 to 3 such substituents.

Examples of the substituent in the “optionally substituted hydroxy group” and the “optionally substituted amino group” represented by R ⁶ and R ^{6 ′} include the “optionally substituted hydroxy group” represented by R ⁵ and R ^6. The same thing as a "good hydrocarbon group" and its substituent is mentioned. The “amino group” may have 1 to 2 such substituents.

The “ring” that R ⁵ and R ⁶ may form together with adjacent carbon atoms and nitrogen atoms is selected from, for example, oxygen atoms, sulfur atoms, nitrogen atoms and the like as ring-constituting atoms in addition to nitrogen atoms 5- to 7-membered saturated or unsaturated nitrogen-containing heterocycles (e.g., pyrrolidin-2-one, thiazolidine-2-one, thiazolidine-4-one, oxazolidine) 2-one, oxazolidine-4-one, imidazolidin-2-one, imidazolidin-4-one, piperidin-2-one, thiazinan-4-one, thiomorpholin-3-one, azepan-2-one, Dihydropyrrol-2-one, dihydropyridin-2-one, pyridin-2-one, tetrahydroazepin-2-one, dihydroazepin-2-one, etc.) . The number of heteroatoms contained in the “nitrogen-containing heterocycle” is preferably one or two. This “ring” may further have a substituent in addition to the oxo group, and as the “substituent”, the “optionally substituted hydrocarbon group” represented by R ⁵ and R ⁶ can be used. The same thing as a substituent is mentioned. The number of the “substituents” is, for example, 1 to 5 (preferably 1 to 3, more preferably 1 to 2).

The ring A ⁰ in the above formula may further have a substituent other than R ⁰ , and the ring A in the above formula has the formula

（式中、各記号は前記と同意義を示す）で示される基以外に更に有していてもよい置換基、および前記式中の環Ａ’が式

(Wherein each symbol is as defined above), a substituent that may further be present, and ring A ′ in the formula is represented by the formula

（式中、各記号は前記と同意義を示す）で示される基以外に更に有していてもよい置換基（以下、これらをまとめて単に環Ａ等が更に有していてもよい置換基と称する場合がある。）としては、置換されていてもよい炭化水素基、置換されていてもよい複素環基、アシル基、置換されていてもよいヒドロキシ基、置換されていてもよいアミノ基、ハロゲン原子（例、フッ素、塩素、臭素、ヨウ素）、およびジヒドロキシボリル等が挙げられる。当該「置換されていてもよい炭化水素基」、「置換されていてもよいヒドロキシ基」および「置換されていてもよいアミノ基」としては、それぞれＲ^６で示される「置換されていてもよい炭化水素基」、「置換されていてもよいヒドロキシ基」および「置換されていてもよいアミノ基」と同様のものが挙げられる。当該「置換されていてもよい複素環基」としては、後記の「環Ｂで示される置換されていてもよい５員複素環の置換基」としての「置換されていてもよい複素環基」と同様のものが挙げられる。当該「アシル基」としては、Ｒ^０で示されるアシルアミノにおけるアシル基：Ｒ^６−Ｙ−と同様のものが挙げられる。

(Wherein each symbol has the same meaning as described above) may further have a substituent (hereinafter, these are collectively referred to as a substituent that ring A and the like may further have. As an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted hydroxy group, and an optionally substituted amino group. , Halogen atoms (eg, fluorine, chlorine, bromine, iodine), dihydroxyboryl and the like. As the “optionally substituted hydrocarbon group”, “optionally substituted hydroxy group” and “optionally substituted amino group”, each of “optionally substituted hydrocarbon group” represented by R ⁶ may be used. Examples thereof include the same as the “hydrocarbon group”, “optionally substituted hydroxy group” and “optionally substituted amino group”. The “optionally substituted heterocyclic group” is the “optionally substituted heterocyclic group” as the “substituent of the optionally substituted 5-membered heterocyclic ring represented by ring B” described later. The same thing is mentioned. Examples of the “acyl group” include those similar to the acyl group in the acylamino represented by R ⁰ : R ⁶ —Y—.

As the substituent that ring A and the like may further have, among them, a C _1-6 alkyl group that may be substituted, a C _6-12 aryl group that may be substituted, and a substituent that may be substituted Preferred 5- or 6-membered heterocyclic groups and acyl groups are preferred. In particular, the substituent that the ring A and the like may further have is a 7-position of the condensed heterocyclic ring shown in the formula (I ₀ ), the formula (I), and the formula (I ′) (in the following formula, the numeral 7 In the case of substituting, it is also preferable to use an optionally substituted C _6-14 aryl-C _1-6 alkyl group. The As _{"C 6-14} aryl _{-C 1-6} alkyl group" of the "optionally substituted _{C 6-14} aryl _{-C 1-6} alkyl group", for example, benzyl, alpha-methylbenzyl and the like Examples of the substituent include the same groups as the substituents of the “optionally substituted hydrocarbon group” represented by R ⁶ .

環Ａ等が更に有していてもよい「置換基」の数は、例えば１〜３個（好ましくは２〜３個）である。環Ａ等が更に有していてもよい「置換基」が２個以上である場合は、そのうちの２つの置換基が、それらが結合している炭素原子と一緒になって、置換基を有していてもよい５〜６員の環を形成してもよい。当該「５〜６員の環」として好ましくは飽和または不飽和のＣ_５−６炭素環である。当該「５〜６員の環」の置換基としては、例えば、Ｃ_１−６アルキル基、Ｃ_１−６アルコキシ基、ニトロ基、ヒドロキシ基、アミノ基およびハロゲン原子等が挙げられる。

The number of “substituents” that ring A and the like may further have is, for example, 1 to 3 (preferably 2 to 3). When there are two or more “substituents” that ring A or the like may further have, two of them together with the carbon atom to which they are bonded have a substituent. A 5- to 6-membered ring which may be formed may be formed. The “5- to 6-membered ring” is preferably a saturated or unsaturated C _5-6 carbocycle. Examples of the substituent of the “5- to 6-membered ring” include a C _1-6 alkyl group, a C _1-6 alkoxy group, a nitro group, a hydroxy group, an amino group, and a halogen atom.

（式中、各記号は式（Ｉ）と同意義を示す）
で表される環が好ましい。ここで、Ｒ^２とＲ^３が一緒になって結合を表す場合、この環は、次式

（式中、各記号は式（Ｉ）と同意義を示す）
で表される５員環である。
前記式中のＸで示される「置換されていてもよい硫黄原子」としては、無置換の硫黄原子、または酸化された硫黄原子（例、ＳＯ、ＳＯ_２）が好ましい。また、前記式中のＸで示される「置換されていてもよいイミノ基」の置換基としては、例えば、ハロゲン原子、シアノ基、ニトロ基またはヒドロキシ基でそれぞれ置換されていてもよい、Ｃ_１−６アルキル基またはＣ_２−６アルケニル基が挙げられる。 As the “optionally substituted 5-membered heterocycle” represented by ring B in the above formula,

(Wherein each symbol has the same meaning as in formula (I))
The ring represented by is preferable. Here, when R ² and R ³ together represent a bond, the ring has the formula

(Wherein each symbol has the same meaning as in formula (I))
It is a 5-membered ring represented by.
The “optionally substituted sulfur atom” represented by X in the above formula is preferably an unsubstituted sulfur atom or an oxidized sulfur atom (eg, SO, SO ₂ ). In addition, examples of the substituent of the “optionally substituted imino group” represented by X in the above formula include C ₁ which may be substituted with a halogen atom, a cyano group, a nitro group or a hydroxy group, respectively. _{A -6} alkyl group or a _C2-6 alkenyl group is mentioned.

  That is, examples of the 5-membered heterocycle of the “optionally substituted 5-membered heterocycle” represented by ring B include dihydropyrrole, ethene, pyrrole, dihydrothiophene, dihydrothiophene-1-oxide, dihydrothiophene-1 , 1-dioxide, thiophene, dihydrofuran, and furan.

Examples of the substituent of the “optionally substituted 5-membered heterocyclic ring” represented by ring B in the above formula include an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, and a substituted group. And an amino group which may be substituted, a heterocyclic group which may be substituted, a mercapto group which may be substituted, and the like. Ring B may have 1 to 5 (preferably 2 to 4) such substituents. When ring B is unsubstituted, ring A, ring A ₀ , and ring A ′ are in the 7-position of the fused heterocycle shown in formula (I ₀ ), formula (I), and formula (I ′), respectively. The above-described “optionally substituted C _6-14 aryl-C _1-6 alkyl group” is preferably substituted.

The “optionally substituted hydrocarbon group”, “optionally substituted hydroxy group”, and “optionally substituted amino group” are the same as those represented by R ^6. Examples thereof include the same groups as “good hydrocarbon group”, “optionally substituted hydroxy group”, and “optionally substituted amino group”.

  The “heterocyclic group” of the “optionally substituted heterocyclic group” is preferably a 5- to 14-membered heterocyclic group. The 5- to 14-membered heterocyclic group includes at least one (preferably 1 to 4) 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. A cyclic group (aromatic heterocyclic group, saturated or unsaturated non-aromatic heterocyclic group) and the like.

  The “aromatic heterocyclic group” is, for example, 5 to 14 members (preferably 5 or more) containing 1 or more (for example 1 to 4) heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms. 10-membered) aromatic heterocyclic group and the like. Specifically, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, furan, isoindolizine, xanthrene, phenoxathiin, pyrrole, imidazole , Pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, Aromatic heterocycles such as acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazane, phenoxazine, or the like Can be obtained by removing one hydrogen atom from a ring formed by condensing a ring (preferably a single ring) with one or more (preferably 1 or 2) aromatic rings (eg, benzene ring). Groups and the like. Examples thereof include 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or Examples include 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl, 2- or 3-thienyl.

  Examples of the “non-aromatic heterocyclic group” include 3 to 8 members (preferably 5) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl. Or a 6-membered) saturated or unsaturated non-aromatic heterocyclic group.

Examples of the substituent of the “optionally substituted heterocyclic group” include those similar to the substituents of the “optionally substituted hydrocarbon group” represented by R ⁵ and R ⁶ .

Examples of the substituent of the “optionally substituted mercapto group” include those similar to the substituents of the “optionally substituted hydrocarbon group” represented by R ⁵ and R ⁶ .

  Any one of these optional substituents may be substituted at a substitutable position (preferably 1 to 4, more preferably 1 to 2).

The “optionally substituted hydrocarbon group”, “optionally substituted heterocyclic group”, “substituted” represented by R ¹ , R ² , R ³ _, R ^{3 ′} , and R ⁴ in the above formula The “optionally substituted hydroxy group”, “optionally substituted mercapto group” and “optionally substituted amino group” are substituted with the “optionally substituted 5-membered heterocyclic ring” represented by ring B. These groups are the same as those described above.

R ¹ , R ² , R ³ _, and R ^{3 ′} are, among others, a hydrogen atom, a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) Etc.) are preferred. R ³ and R ^3a are more preferably a hydrogen atom or the like.

R ⁴ is preferably an alkyl group that may be substituted, an aryl group that may be substituted, a heterocyclic group that may be substituted, or the like.

Examples of the “alkyl group” of the “optionally substituted alkyl group” include the same groups as the “alkyl groups” exemplified for R ⁵ , R ⁶ and R ^{6 ′} . As the substituent of the “optionally substituted alkyl group”, the “optionally substituted hydrocarbon group” as the substituent of the “optionally substituted 5-membered heterocyclic ring” represented by ring B can be used. And the same groups as the “substituent” in the above.

As the “aryl group” of the “optionally substituted aryl group” (and the “optionally substituted aryl group” represented by R ^{4 ′} ), for example, C _6-14 aryl (eg, phenyl, 1 -Naphthyl, 2-naphthyl, biphenylyl, anthryl, etc.). As the substituent of the “optionally substituted aryl group”, the “optionally substituted hydrocarbon group” as the substituent of the “optionally substituted 5-membered heterocyclic ring” represented by ring B is shown. And the same groups as the “substituent” in the above.

The heterocyclic group of the “optionally substituted heterocyclic group” (and “optionally substituted heterocyclic group” represented by R ^{4 ′} ) is “optionally substituted” represented by ring B. Examples thereof include the same groups as the “optionally substituted heterocyclic group” as the substituent of the “5-membered heterocyclic ring”.

R ⁴ (and R ^{4 ′} ) is particularly preferably an optionally substituted phenyl group, and most preferably an optionally substituted C _1-4 alkyl group (eg, methyl, ethyl, n-propyl). , Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl) or an optionally substituted C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy) A phenyl group which may be substituted with The “C _1-4 alkyl group” and “C _1-4 alkoxy group” are preferably present at the 4-position of the phenyl group. The “substituent” of the “optionally substituted C _1-4 alkyl group” and the “optionally substituted C _1-4 alkyl group” as the substituent is preferably, for example, a nitro group, a hydroxy group An amino group, a halogen atom, and the like.

Examples of the “optionally substituted ring” that R ¹ and R ² may form together with adjacent carbon atoms include a 3- to 8-membered allocyclic or heterocyclic ring. Examples of the “3- to 8-membered homocyclic ring” include C _3-8 cycloalkane.

  The “3- to 8-membered heterocycle” includes, for example, a 3- to 8-membered heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (eg, aziridine, azetidine, morpholine). Thiomorpholine, piperazine, piperidine, pyrrolidine, hexamethyleneimine, heptamethyleneimine, hexahydropyrimidine and the like.

R ¹ and R ² may be formed together with adjacent carbon atoms. The “substituent” of the “optionally substituted ring” is the “substituted” represented by R ⁵ and R ⁶ above. The same number as the “substituent” of “optional hydrocarbon group” is used.

（式中、各記号は前記と同意義を示す）で示される基は、それぞれ式（I_０）、式（I）、および式（I’）中に示す縮合複素環の５位に置換していることが好ましい。すなわち、それぞれ式（I_０）、式（I）、および式（I’）で表される化合物としては、それぞれ、

(Wherein each symbol is as defined above) is substituted at the 5-position of the condensed heterocyclic ring shown in Formula (I ₀ ), Formula (I), and Formula (I ′), respectively. It is preferable. That is, as the compounds represented by formula (I ₀ ), formula (I), and formula (I ′), respectively,

（式中、環近傍の数字は、位置番号を示す）
が好ましい。

(In the formula, the number near the ring indicates the position number)
Is preferred.

Examples of the salt of the compound represented by formula (I ₀ ), formula (I), and formula (I ′) (hereinafter, these may be abbreviated as compound (I) etc.) include When having an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, a transition metal such as zinc, iron or copper) or an organic base (eg, Trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, organic amines such as N, N'-dibenzylethylenediamine, basic amino acids such as arginine, lysine and ornithine) Salt.

On the other hand, when the compound (I) has a basic group such as an amino group, an inorganic acid or an organic acid (eg, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid) , Fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), salts with acidic amino acids such as aspartic acid, glutamic acid, etc. Can be mentioned.
Prodrugs such as compound (I) may react with enzymes, gastric acid, etc. under physiological conditions in vivo, that is, enzymatically oxidize, reduce, hydrolyze, etc., or hydrolyze with gastric acid, etc. A compound that changes to the compound. Examples of such prodrugs include compounds in which an amino group such as compound (I) is acylated, alkylated, or phosphorylated (eg, amino group such as compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); compounds ( Compounds in which hydroxyl groups such as I) are acylated, alkylated, phosphorylated, or borated (eg, compound (I) hydroxyl groups are acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanyl , Dimethylaminomethylcarbonylated compound, etc.); the carboxyl group of the compound of the present invention is esterified, Amidated compounds (eg, the carboxyl group of the compound of the present invention is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, and the like). These compounds can be produced from compound (I) and the like by a method known per se.
In addition, such prodrugs are those that change to compound (I) or the like under physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals”, Vol. 7, pages 163 to 198 of molecular design. Also good.

Next, a method for producing the compound (I) of the present invention will be described.
The compound (I) and the like of the present invention can be produced by the method shown below or a method analogous thereto.

  Unless otherwise specified, each symbol of the compounds in the following reaction schemes has the same meaning as described above. The compound in the reaction formula includes a case where a salt is formed, and examples of the salt include those similar to the compound (I) and the like.

Compound (I) can be produced by the method described in Reaction Scheme 1 below.
Reaction formula 1

反応式１中、Ｌは脱離基を示し、Ｒ^７は環Ａが式

In Reaction Scheme 1, L represents a leaving group, R ⁷ represents ring A

（式中、各記号は前記と同意義を示す）で示される基またはそれに対応する基以外に更に有していてもよい置換基を示し、Ｒ^８はＲ^６で示される置換されていてもよいアミノ基からＮＨ基を除いた基を示し、他の記号は前記と同意義である。

(In the formula, each symbol is as defined above) or a substituent that may further be present in addition to the group corresponding thereto, and R ⁸ may be a substituent represented by R ⁶ The group which remove | excluded NH group from the good amino group is shown, and other symbols are as defined above.

  Compound (I) can be produced by reacting compound (II) with compound (IIIa), compound (IIIb) or compound (IV), optionally in the presence of a base or acid.

  Compound (IIIa), compound (IIIb) or compound (IV) is commercially available, and can also be produced according to a method known per se or a method analogous thereto.

Examples of the “leaving group” represented by L include hydroxy, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), optionally halogenated C _1-5 alkylsulfonyloxy (eg, methanesulfonyloxy). , Ethanesulfonyloxy, trichloromethanesulfonyloxy and the like), optionally substituted C _6-10 arylsulfonyloxy, optionally substituted phenyloxy group, optionally substituted 2-thiobenzothiazole and the like. It is done. Examples of the “ _optionally substituted C _6-10 arylsulfonyloxy” include C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl). Etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) and 1 to 3 substituents selected from nitro C _6-10 arylsulfonyloxy (eg, phenylsulfonyloxy, naphthylsulfonyloxy, etc.) and the like may be mentioned, and specific examples include benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy and the like. It is done.

  The amount of compound (IIIa), compound (IIIb) or compound (IV) to be used is about 1.0 to 10 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (II).

  Examples of the “base” include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4 -Tertiary amines such as dimethylaminopyridine, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide, lithium Examples thereof include metal amides such as hexamethyldisilazide, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide.

  Examples of the “acid” include methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like.

  The amount of the “base” to be used is about 0.1 to 10 equivalents, preferably 0.8 to 2 equivalents, relative to compound (II).

  The amount of the “acid” to be used is about 0.1 to 10 equivalents, preferably 0.8 to 3 equivalents, relative to compound (II).

  This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, water, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane, hexane, Amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl Solvents such as sulfoxides such as sulfoxide, nitrogen-containing aromatic hydrocarbons such as pyridine, lutidine, and quinoline, or a mixed solvent thereof are preferable. The reaction temperature is about -40 to 150 ° C, preferably 0 to 100 ° C. The reaction time is usually 5 minutes to 24 hours, preferably 10 minutes to 5 hours.

  The product (I) obtained as described above can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

  Alternatively, compound (II) and compound (IIIa) may be reacted in the presence of a suitable condensing agent.

  The amount of compound (IIIa) to be used is about 0.8 to about 10.0 mol, preferably about 0.8 to about 2.0 mol, per 1 mol of compound (II).

The "condensing agent", for example, N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), such as hydrochloride N, N '- mosquito Rubo di imides, N , Azolites such as N'-carbonylimidazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diethyl cyanophosphate, phosphorus oxychloride, acetic anhydride and the like, 2-chloromethylpyridinium iodide, A 2-halogenopyridinium salt such as 2-fluoro-1-chloromethylpyridinium iodide is used.

  The amount of the condensing agent to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (II).

  If desired, the reaction may be carried out in the presence of a base together with a condensing agent. Examples of the “base” include basic salts such as potassium acetate and sodium acetate, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N-methylpiperidine, N-methylpyrrolidine, N-methyl Tertiary amines such as morpholine, 1-hydroxy-1H-benzotriazole (HOBt) monohydrate, and the like. The amount of the base to be used is about 0.5 to about 5.0 mol, preferably about 2.0 to about 3.0 mol, per 1 mol of compound (II).

  This reaction is advantageously performed using a solvent inert to the reaction. Examples of such solvents include alcohols such as methanol, ethanol, and propanol, hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and the like. Ethers, amides such as N, N-dimethylformamide, N, N-dimethylacetamide hexamethylphosphoric triamide, sulfoxides such as dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. Solvents such as halogenated carbons, nitriles such as acetonitrile and propionitrile, acid anhydrides such as acetic anhydride, or a mixed solvent thereof are preferable.

  The reaction time is usually about 10 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is generally about −20 to about 150 ° C., preferably about 0 to about 100 ° C.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

When R ⁵ is an optionally substituted alkyl group, compound (I) can also be produced by the method described in Reaction Scheme 2 below.

  Reaction formula 2

反応式２中、Ｌ^１は脱離基であり、他の記号は前記と同意義である。

In Reaction Scheme 2, L ¹ is a leaving group, and other symbols are as defined above.

Examples of the “leaving group” represented by L ¹ include hydroxy, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), optionally halogenated C _1-5 alkylsulfonyloxy (eg, methane). Sulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy and the like), optionally substituted C _6-10 arylsulfonyloxy and the like.

  Compound (Ia) is reacted with an alkylating agent (V) corresponding to compound (I), optionally in the presence of a base.

  The amount of the alkylating agent (V) to be used is about 1.0 to about 10.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (Ia).

Examples of the “base” include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4 -Tertiary amines such as dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide, lithium diisopropylamide, metal amides such as lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, metal alkoxides such as potassium tert-butoxide.

  The amount of the base used is approximately 1.0 to approximately 10.0 mol, preferably approximately 1.0 to approximately 2.0 mol, with respect to 1 mol of the compound (Ia).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene, Hydrocarbons such as cyclohexane and hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, acetonitrile, A solvent such as a nitrile such as propionitrile, a sulfoxide such as dimethyl sulfoxide, or a mixed solvent thereof is preferable.

  The reaction time is usually about 30 minutes to about 48 hours, preferably about 1 hour to about 24 hours. The reaction temperature is usually about −20 to about 200 ° C., preferably about 0 to about 150 ° C.

  The compound (Ib) included in the compound (I) can also be produced by the method described in the following reaction scheme 3.

  Reaction formula 3

反応式３中、Ｍは金属を示し、他の記号は前記と同意義である。

In Reaction Scheme 3, M represents a metal, and other symbols are as defined above.

In the formula, the organometallic compound (VII) represented by R ⁴ -M is commercially available, and is a method known per se, for example, 4th edition Experimental Chemistry Course, 25 (Edited by Chemical Society of Japan), Maruzen Co., Ltd. It can also be manufactured by the method described in the company.

  As shown in Reaction Scheme 3, compound (Ib) can be obtained by reacting compound (VI) with organometallic compound (VII).

  As the organometallic compound (VII), a Grignard reagent or an organolithium reagent is preferable.

  The amount of compound (VII) to be used is about 0.8 to about 30 mol, preferably about 1.0 to about 10 mol, per 1 mol of compound (VI).

This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, hydrocarbons such as hexane, cyclohexane, benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc. ethers, di-chloromethane, chloroform, carbon tetrachloride, or a mixed solvent thereof and the like, such as halogenated hydrocarbons such 1,2-dichloroethane, or the like is used.

  The reaction time is usually about 10 minutes to about 24 hours, preferably about 30 minutes to about 5 hours. The reaction temperature is usually about −100 to about 120 ° C., preferably about −80 to about 60 ° C.

  The product can be used as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). be able to.

  The compound (Ic) and the compound (Id) included in the compound (I) are respectively produced from the compound (Ib) produced by the method described in the reaction scheme 3 by each method described in the following reaction scheme 4. it can.

  Reaction formula 4

反応式４中、各記号は前記と同意義である。

In Reaction Scheme 4, each symbol is as defined above.

  Compound (Ib) is subjected to a known reaction of acylation reaction, etherification reaction, amination reaction, halogenation reaction, alkylation reaction alone or in combination of two or more thereof to produce compound (Ic). it can.

For example, when R ³ is alkoxy (eg, methoxy, ethoxy, phenoxy, etc.), compound (Ic) is obtained by reacting compound (Ib) with an alcohol (eg, methanol, ethanol, phenol, etc.) in the presence of an acid catalyst. .

  Examples of the “acid catalyst” include organic acids such as formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid, mineral acids such as sulfuric acid, hydrochloric acid and hydrobromic acid, and Lewis acids such as zinc chloride.

  The amount of alcohol used is about 0.8 mol to an excess amount per 1 mol of compound (Ib). The amount of the acid catalyst to be used is about 0.1 to about 100 mol, preferably about 0.1 to about 50 mol, per 1 mol of compound (Ib).

This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, hydrocarbons such as hexane, cyclohexane, benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc. Ethers, N, N-dimethylformamide, N, N-dimethylacetamide , amides such as hexamethylphosphoric triamide , sulfoxides such as dimethyl sulfoxide, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. Of these, preferred are halocarbons, nitriles such as acetonitrile and propionitrile, and mixed solvents thereof.

  The reaction time is usually about 10 minutes to about 48 hours, preferably about 30 minutes to about 12 hours. The reaction temperature is usually about 0 to about 200 ° C, preferably about 25 to about 100 ° C.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

  Compound (Id) can be produced by subjecting compound (Ib) to a reductive dehydration reaction.

  Examples of the reductive dehydration include a catalytic reduction method known per se, a method using an organic silyl reagent (such as an alkylsilane reagent), and the like.

  In the catalytic reduction method, compound (Id) can be produced by reacting compound (Ib) with a metal catalyst in a hydrogen atmosphere. If desired, an appropriate acid catalyst may be added.

  As the “metal catalyst”, Raney nickel, platinum oxide, metal palladium, activated carbon with palladium, or the like is used. The amount of the “metal catalyst” to be used is generally about 0.1 to about 1000 wt%, preferably about 1 to about 20 wt%, relative to compound (Ib), respectively.

  As the “acid catalyst”, organic acids such as formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid, and mineral acids such as sulfuric acid, hydrochloric acid and hydrobromic acid are used. The amount of the “acid catalyst” to be used is about 0.1 to an excess amount per 1 mol of compound (Ib).

  This reaction is advantageously performed using a solvent inert to the reaction. Although it does not specifically limit as long as reaction advances as such a solvent, For example, ethers, such as methanol, ethanol, propanol, diethyl ether, tetrahydrofuran, a dioxane, 1, 2- dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, organic acids such as acetic acid, solvents such as water, or a mixed solvent thereof are preferable. The hydrogen pressure is usually about 1 to about 100 atmospheres, preferably about 1 to about 5 atmospheres. The reaction time is usually about 30 minutes to about 48 hours, preferably about 1 to 24 hours. The reaction temperature is usually about 0 to about 120 ° C, preferably about 20 to about 80 ° C.

  After removing the catalyst, the product can be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.).

  In the method using an organic silyl reagent (alkylsilane reagent), compound (Id) can be produced by reacting compound (Ib) with an alkylsilane reagent and an acid.

  As the alkylsilane reagent, for example, triethylsilane, phenyldimethylsilane or the like is used. The amount of the “alkylsilane reagent” to be used is about 0.8 to about 20 mol, preferably about 1 to about 5 mol, per 1 mol of compound (Ib).

  As the acid, for example, an organic acid such as trifluoroacetic acid is used. The amount of the acid used is about 0.1 to excess with respect to 1 mol of compound (Ib).

  This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Although it does not specifically limit as long as reaction advances as such a solvent, For example, ethers, such as diethyl ether, tetrahydrofuran, a dioxane, 1, 2- dimethoxyethane, Hydrocarbons, such as benzene, toluene, a cyclohexane, hexane, a dichloromethane, chloroform Solvents such as halogenated carbons such as carbon tetrachloride and 1,2-dichloroethane, organic acids such as acetic acid and trifluoroacetic acid, or a mixed solvent thereof are preferable.

  The product can be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.).

When the compound (X) represented by R ⁴ —H is an amine, alcohol, thiol, phenol or thiophenol, the compound (I) corresponding to such compound (X) is It can also be produced by the method described in Reaction Scheme 5.

  Reaction formula 5

反応式５中、各記号は前記と同意義である。

In the reaction formula 5, each symbol is as defined above.

Compound (X) represented by R ⁴ —H can be obtained as a commercial product, and can also be produced by a method known per se.

According to Reaction Scheme 5 , compound (I) can be obtained by reacting compound (IX) and compound (X) in the presence of an acid catalyst or in the presence of a base.

  The amount of compound (X) to be used is about 1 mol to about 50 mol per 1 mol of compound (IX). Preferably, it is about 1 to about 5 moles.

  Examples of the “acid catalyst” include organic acids such as formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid, mineral acids such as sulfuric acid, hydrochloric acid and hydrobromic acid, and Lewis acids such as zinc chloride.

  Examples of the “base” include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4- Tertiary amines such as dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide Metal amides such as lithium diisopropylamide and lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide.

  The amount of the acid catalyst to be used is about 0.1 mol to excess per 1 mol of compound (IX). Preferably, it is about 0.1 to about 50 moles.

  The amount of the base to be used is about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (IX).

  This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene and cyclohexane , Hydrocarbons such as hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, A solvent such as a nitrile such as pionitrile, a sulfoxide such as dimethyl sulfoxide, or a mixed solvent thereof is preferable.

  The reaction time is usually about 10 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is usually −20 to 200 ° C., preferably 0 to 150 ° C.

  Instead of the reaction, Mitsunobu reaction (Synthesis, 1981, pp. 1 to 27) can also be used.

In the reaction, compound (X) and compound (IX) in which L ¹ is OH are converted into azodicarboxylates (eg, diethylazodicarboxylate) and phosphines (eg, triphenylphosphine, tributyl). Reaction in the presence of phosphine).

  The amount of compound (X) to be used is about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (IX).

  The amount of the “azodicarboxylates” and “phosphines” to be used is about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (IX). .

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N, Amides such as N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, etc. Solvents such as sulfoxides or mixed solvents thereof are preferred.

  The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The reaction temperature is generally −20 to 200 ° C., preferably 0 to 100 ° C. The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

When R ⁴ is an optionally substituted amino group, the following compound (Id) included in the compound (I) can also be produced by a reductive amination reaction described in the following reaction scheme 6.

  Reaction formula 6

反応式６中、Ｒ^４は置換されていてもよいアミノ基であり、他の記号は前記と同意義である。

In Reaction Scheme 6, R ⁴ is an optionally substituted amino group, and other symbols are as defined above.

  The compound (Id) is produced by condensing the compound (VI) and the compound (X) which is an amine, and reducing with a reducing agent.

  The amount of compound (X) to be used is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (VI).

  As the “reducing agent”, metal hydrides such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, boranes such as borane tetrahydrofuran complex, hydrosilanes such as triethylsilane, formic acid, etc. are used. . If desired, an acid catalyst may be added together with the reducing agent. Examples of the acid catalyst include mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, organic acids such as acetic acid, propionic acid and trifluoroacetic acid, zinc chloride and aluminum chloride. Lewis acids such as are used.

  The amount of the “reducing agent” to be used is about 0.25 to about 5.0 mol, preferably about 0.5 to about 2.0 mol, per 1 mol of compound (VI).

  The amount of the acid catalyst used is, for example, in the case of mineral acids, usually about 1 to about 100 mol, preferably about 1 to about 20 mol, per 1 mol of compound (VI).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene and cyclohexane , Hydrocarbons such as hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, Solvents such as nitriles such as pionitrile or a mixed solvent thereof are preferable.

  The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is usually about −20 to about 200 ° C., preferably about 0 to about 100 ° C.

  The reaction is also produced by a catalytic hydrogenation reaction in which various catalysts coexist in a hydrogen atmosphere instead of condensing compound (VI) and compound (X) and then reducing with a reducing agent. As the catalyst used, platinum oxide, activated carbon with platinum, activated carbon with palladium, nickel, copper-chromium oxide, rhodium, cobalt, ruthenium and the like are used. The amount of the catalyst to be used is about 0.1 to about 1000% by weight, preferably about 1 to about 1000% by weight, relative to compound (VI).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene and cyclohexane Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, solvents such as water, or a mixed solvent thereof are preferable.

  The reaction time is usually about 30 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is usually about 0 to about 120 ° C, preferably about 20 to about 80 ° C.

  The product can be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.).

  The following compounds (Ie to Ik) contained in the compound (I) are produced from the compound (I) by the method described in the following reaction scheme 7.

  Reaction formula 7

反応式７中、P’はヒドロキシ基の保護基を、R^１５は置換されても良いアルキル基（メチル、エチル、フェニル基等）を、Arは置換されても良い芳香環（ベンゼン環、ナフタレン環、ピリジン環、フラン環、チオフェン環、イミダゾール環等）を、Ar-halは芳香族ハライドを示し、各記号は前記と同意義である。

In Reaction Scheme 7, P ′ is a hydroxy protecting group, R ¹⁵ is an optionally substituted alkyl group (methyl, ethyl, phenyl group, etc.), Ar is an optionally substituted aromatic ring (benzene ring, naphthalene) A ring, a pyridine ring, a furan ring, a thiophene ring, an imidazole ring, etc.), Ar-hal represents an aromatic halide, and each symbol is as defined above.

Compound (Ie) having an acyl group as one of substituents for R ⁷ can be produced by acylating compound (I) such as Friedel-Crafts reaction.

  The reaction is carried out by reacting compound (I) and compound (XXVIII) in the presence of an acid catalyst.

  The amount of compound (XXVIII) to be used is about 1 mol to about 20 mol per 1 mol of compound (I). Preferably, it is about 1 to about 5 moles.

  As the “acid catalyst”, Lewis acid such as aluminum chloride, iron chloride, stannic chloride, titanium tetrachloride, boron trifluoride diethyl ether, zinc chloride, and polyphosphoric acid are used. The amount of the acid catalyst to be used is about 0.5 mol to about 20 mol with respect to 1 mol of compound (I) in the case of Lewis acid. Preferably, it is about 0.8 to about 5 moles. In the case of polyphosphoric acid, it is about 5 mol to excess amount per 1 mol of compound (I).

  This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, hydrocarbons such as hexane, cyclohexane, benzene, toluene, xylene, and halogenated compounds such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like. Solvents such as carbons and carbon disulfide or a mixed solvent thereof are preferred.

  The reaction time is usually 10 minutes to 48 hours, preferably 30 minutes to 12 hours. The reaction temperature is generally -70 to 150 ° C, preferably -20 to 100 ° C.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

As one of the substituents for R ⁷ , a compound (Ig) having a bromine group can be produced by reacting compound (I) with a bromination reagent.

  As the “bromination reagent”, bromine adducts such as bromine, N-bromosuccinimide, copper bromide, and benzyltrimethylammonium tribromide are used. The amount of the brominating reagent to be used is about 0.5 mol to about 10 mol per 1 mol of compound (I). Preferably, it is about 1 to about 3 moles.

  This reaction is carried out in the presence of a base, a Lewis acid or iron, if desired.

  Examples of the “base” include basic salts such as sodium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and potassium acetate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, And tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, and the like.

  The amount of the base to be used is about 0.8 to about 10 mol per 1 mol of compound (I).

  Examples of the “Lewis acid” include aluminum chloride, iron chloride, stannic chloride, titanium tetrachloride, boron trifluoride diethyl ether and the like. The amount of the Lewis acid to be used is about 0.01 to about 2 mol per 1 mol of compound (I).

  As “iron”, the amount of iron used is about 0.01 to about 2 moles per mole of Compound (I).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, benzene , Hydrocarbons such as toluene, carbon disulfide, cyclohexane, hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogens such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Hydrocarbons, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, organic acids such as acetic acid and propionic acid, nitroalkanes such as nitromethane, and mixed solvents thereof are used.

  The reaction temperature is usually −20 to 200 ° C., preferably 0 to 100 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

As one of the substituents of R ^7, the compound having a formyl group (If) can be obtained by a method known per se, for example, Journal of Organic Chemistry (J. Org. Chem.), 49, 409 (1984), Journal of the It can be produced according to the method described in J. Indian Chem. Soc, 36, 76 (1959) or a method analogous thereto.

Compound (Ih) having boric acid as one of substituents for R ⁷ is produced by reacting boric acid ester (XXIX) after lithiation or Grignard reagent of compound (Ig).

  As the “lithiation reagent”, alkyllithiums such as n-butyllithium are used. The amount of the lithiation reagent to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (Ig).

  As the “Grignard reagent”, magnesium or the like is used. The amount of magnesium and the like to be used is about 0.8 to about 5.0 moles, preferably about 1.0 to about 2.0 moles compared to 1 mole of Compound (Ig).

  As the “borate ester”, trimethyl borate ester, triisopropyl borate ester and the like are used. The amount of the borate ester to be used is about 0.9 to about 30 mol, preferably about 0.9 to about 15 mol, per 1 mol of compound (Ig).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, benzene, toluene, carbon disulfide, cyclohexane, hexane And hydrocarbons such as these and mixed solvents thereof.

  The reaction temperature is usually −100 to 120 ° C., preferably −80 to 70 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

  This reaction can be further treated with an acid (eg, hydrogen chloride, hydrochloric acid, sulfuric acid, acetic acid, etc.) as necessary to give compound (Ih).

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

As one of the substituents for R ⁷ , compound (Ii) having an aromatic ring (benzene ring, naphthalene ring, pyridine ring, furan ring, thiophene ring, imidazole ring, etc.) is obtained by reacting compound (Ig) with aromatic boronic acid ( XXX) can be prepared by reacting in the presence of a transition metal catalyst under basic conditions in a solvent.

  The amount of the “aromatic boronic acid (XXX)” to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (Ig).

  Examples of the “base” include alkali metal or alkaline earth metal carbonate (eg, sodium carbonate, potassium carbonate, etc.), alkali metal or alkaline earth metal hydrogen carbonate (eg, sodium bicarbonate, potassium bicarbonate, etc.), Alkali metal or alkaline earth metal hydroxides (for example, sodium hydroxide, potassium hydroxide, etc.), triethylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine, triethylenediamine, 4-methylmorpholine, etc. are used. .

  Examples of the “transition metal catalyst” include palladium catalysts [eg, tetrakis (triphenylphosphine) palladium, 1,1-bis (diphenylphosphino) ferrocenedichloropalladium, dichlorobis (triphenylphosphine) palladium, etc.]. The amount of the transition metal catalyst to be used is about 0.001 to about 3 mol, preferably about 0.02 to about 0.2 mol, per 1 mol of compound (Ig).

  Examples of the solvent include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, carbonization such as benzene, toluene, carbon disulfide, cyclohexane and hexane. Hydrogens, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile , Sulfoxides such as dimethyl sulfoxide, water, or a mixed solvent thereof.

  The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.

  In this reaction, the reaction time can be shortened by using a microwave reaction apparatus or the like.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

  Compound (Ii) can also be produced by reacting compound (Ih) and an aromatic halide in a solvent in the presence of a transition metal catalyst under basic conditions.

  The amount of the “aromatic halide” to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (Ih).

  Examples of the “base” include alkali metal or alkaline earth metal carbonate (eg, sodium carbonate, potassium carbonate, etc.), alkali metal or alkaline earth metal hydrogen carbonate (eg, sodium bicarbonate, potassium bicarbonate, etc.), Alkali metal or alkaline earth metal hydroxides (for example, sodium hydroxide, potassium hydroxide, etc.), triethylamine, 4-dimethylaminopyridine, N, N-diisopropylethylamine, triethylenediamine, 4-methylmorpholine, etc. are used. .

  Examples of the “transition metal catalyst” include palladium catalysts [eg, tetrakis (triphenylphosphine) palladium, 1,1-bis (diphenylphosphino) ferrocenedichloropalladium, dichlorobis (triphenylphosphine) palladium, etc.]. The amount of the transition metal catalyst to be used is about 0.001 to about 3 mol, preferably about 0.02 to about 0.2 mol, per 1 mol of compound (Ih).

  Examples of the solvent include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, carbonization such as benzene, toluene, carbon disulfide, cyclohexane and hexane. Hydrogens, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile , Sulfoxides such as dimethyl sulfoxide, water, or a mixed solvent thereof.

  The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.

  In this reaction, the reaction time can be shortened by using a microwave reaction apparatus or the like.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

The compound (Ij) having a hydroxylated hydrocarbon group as one of the substituents of R ⁷ is obtained by reacting the compound (If) with the organometallic compound (LV) represented by R ¹⁵ -M. Manufactured.

The organometallic compound (LV) represented by R ¹⁵ -M can be easily obtained as a commercial product. Also, a method known per se, for example, 4th edition Experimental Chemistry Course, 25 (Edited by Chemical Society of Japan), Maruzen Co., Ltd. It is also produced by the method described.

  As the organometallic compound (LV), a Grignard reagent or an organic lithium reagent is preferable.

  The amount of the organometallic compound (LV) to be used is about 0.8 to about 30 mol, preferably about 1.0 to about 10 mol, per 1 mol of compound (If).

This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, hydrocarbons such as hexane, cyclohexane, benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc. ethers, di-chloromethane, chloroform, carbon tetrachloride, or a mixed solvent thereof and the like, such as halogenated hydrocarbons such 1,2-dichloroethane, or the like is used.

  The reaction time is usually about 10 minutes to about 24 hours, preferably about 30 minutes to about 5 hours. The reaction temperature is usually about −100 to about 120 ° C., preferably about −80 to about 60 ° C.

  The product can be used as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). be able to.

  Compound (Ij) can also be produced by reducing compound (Ie).

  As the “reducing agent”, metal hydrides such as aluminum hydride and isobutylaluminum hydride, metal hydrogen complex compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride and the like are used. The amount of the reducing agent to be used is about 0.3 to about 5.0 mol, preferably about 0.5 to about 2.0 mol, per 1 mol of compound (Ie).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, benzene , Hydrocarbons such as toluene, carbon disulfide, cyclohexane, hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogens such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Hydrocarbons, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, or mixed solvents thereof are used.

  The reaction temperature is usually -40 to 120 ° C, preferably -20 to 80 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 5 hours.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

Compound (Ie) can also be produced by oxidizing compound (Ij).
“Oxidizing agents” include chromates such as chromic anhydride, pyridinium chlorochromate, pyridinium dichromate, sodium dichromate and potassium dichromate, paraperiodic acid, metaperiodic acid, metaperiodic acid Periodate salts such as sodium, metal oxides such as manganese dioxide, silver oxide and lead oxide. A combination of a sulfoxide such as dimethyl sulfoxide and a dehydrating agent such as oxalyl chloride or N, N-dicyclohexylcarbodiimide is used. The amount of the oxidizing agent to be used is about 1 to about 30 mol, preferably about 1 to about 5 mol, per 1 mol of compound (Ij).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, benzene , Hydrocarbons such as toluene, carbon disulfide, cyclohexane, hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogens such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Hydrocarbons, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, water or a mixed solvent thereof are used.

  The reaction temperature is usually −90 to 200 ° C., preferably −80 to 120 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 10 minutes to about 16 hours.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

Compound (Ik) having a hydroxylated aralkyl group (R ¹⁵ CH ₂ ) as one of R ⁷ substituents can be produced by subjecting compound (Ij) to a reductive dehydration reaction.

  Examples of the reductive dehydration include a catalytic reduction method known per se, a method using an organic silyl reagent (such as an alkylsilane reagent), and the like.

  In the catalytic reduction method, compound (Ik) can be produced by reacting compound (Ij) with a metal catalyst in a hydrogen atmosphere. If desired, an appropriate acid catalyst may be added.

  As the “metal catalyst”, Raney nickel, platinum oxide, metal palladium, activated carbon with palladium, or the like is used. The amount of the “metal catalyst” to be used is generally about 0.1 to about 1000 wt%, preferably about 1 to about 20 wt%, relative to compound (Ij), respectively.

  As the “acid catalyst”, organic acids such as formic acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid, and mineral acids such as sulfuric acid, hydrochloric acid and hydrobromic acid are used. The amount of the “acid catalyst” to be used is about 0.1 to an excess amount per 1 mol of compound (Ij).

  This reaction is advantageously performed using a solvent inert to the reaction. Although it does not specifically limit as long as reaction advances as such a solvent, For example, ethers, such as methanol, ethanol, propanol, diethyl ether, tetrahydrofuran, a dioxane, 1, 2- dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, organic acids such as acetic acid, solvents such as water, or a mixed solvent thereof are preferable. The hydrogen pressure is usually about 1 to about 100 atmospheres, preferably about 1 to about 5 atmospheres. The reaction time is usually about 30 minutes to about 48 hours, preferably about 1 to 24 hours. The reaction temperature is usually about 0 to about 120 ° C, preferably about 20 to about 80 ° C.

  After removing the catalyst, the product can be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.).

  In the method using an organic silyl reagent (alkylsilane reagent), compound (Ik) can be produced by reacting compound (Ij) with an alkylsilane reagent and an acid.

  As the alkylsilane reagent, for example, triethylsilane, phenyldimethylsilane or the like is used. The amount of the “alkylsilane reagent” to be used is about 0.8 to about 20 mol, preferably about 1 to about 5 mol, per 1 mol of compound (Ij).

  As the acid, for example, an organic acid such as trifluoroacetic acid is used. The amount of the acid used is about 0.1 to an excess amount per 1 mol of compound (Ij).

  This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Although it does not specifically limit as long as reaction advances as such a solvent, For example, ethers, such as diethyl ether, tetrahydrofuran, a dioxane, 1, 2- dimethoxyethane, Hydrocarbons, such as benzene, toluene, a cyclohexane, hexane, a dichloromethane, chloroform Solvents such as halogenated carbons such as carbon tetrachloride and 1,2-dichloroethane, organic acids such as acetic acid and trifluoroacetic acid, or a mixed solvent thereof are preferable.

  The product can be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.).

  The compound (II) is produced by a method known per se, for example, the method described in JP-A No. 5-140142 or the like, or a method analogous thereto.

  In addition, compound (IIa) which is a dihydrobenzofuran derivative included in compound (II) is represented by the following reaction formula 8 or reaction formula 9, as in a method known per se, for example, the method described in WO2003-004485. It can be manufactured by a method. Furthermore, if necessary, other compounds included in the compound (II) can be produced from the compound (IIa) using a known method.

Reaction formula 8

反応式８中、Ｒ^９は水素原子またはＲ^１からメチレンを１つ除いた基を示す。Ｒ^１０はＲ^５からメチレンを１つ除いた基を示す。他の記号は前記と同意義である。

In Reaction Scheme 8, R ⁹ represents a hydrogen atom or a group obtained by removing one methylene from R ¹ . R ¹⁰ represents a group obtained by removing one methylene from R ⁵ . Other symbols are as defined above.

  The obtained compound (IIa) can be subjected to an alkylation reaction as necessary. The alkylation reaction can be carried out by reacting compound (IIa) with an alkylating agent corresponding to target compound (II), optionally in the presence of a base.

  The amount of the alkylating agent to be used is about 1.0 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (IIa).

  Examples of the “base” include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4 -Tertiary amines such as dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium Examples thereof include metal amides such as amide, lithium diisopropylamide and lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide.

  The amount of the base used is approximately 1.0 to approximately 5.0 mol, preferably approximately 1.0 to approximately 2.0 mol, with respect to 1 mol of the compound (IIa).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene, Hydrocarbons such as cyclohexane and hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, acetonitrile, A solvent such as a nitrile such as propionitrile, a sulfoxide such as dimethyl sulfoxide, or a mixed solvent thereof is preferable.

  The reaction time is usually about 30 minutes to about 48 hours, preferably about 1 hour to about 24 hours. The reaction temperature is usually about −20 to about 200 ° C., preferably about 0 to about 150 ° C.

  As another method, compound (IIa) and compound (XVI) can be reacted in the presence of a base or an acid, if desired, and the synthesized acylamide is reduced with a reducing agent.

  The amount of compound (XVI) to be used is about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (IIa).

  Examples of the “base” include organic bases such as triethylamine and pyridine.

  Examples of the “acid” include methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid and the like.

  The amount of the “base” to be used is about 0.1 to 10 equivalents, preferably 0.8 to 2 equivalents, relative to compound (IIa).

  The amount of the “acid” to be used is about 0.1 to 10 equivalents, preferably 0.8 to 3 equivalents, relative to compound (IIa).

  This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N, Amides such as N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, etc. Preferred are solvents such as sulfoxides, nitrogen-containing aromatic hydrocarbons such as pyridine, lutidine and quinoline, or mixed solvents thereof. The reaction temperature is about -20 to 150 ° C, preferably 0 to 100 ° C. The reaction time is usually 5 minutes to 24 hours, preferably 10 minutes to 5 hours.

  The acylamide obtained as described above can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, such as recrystallization, distillation, chromatography, etc. It can be easily purified by this separation means.

  Examples of the reducing agent include metal hydrides such as sodium borohydride and lithium aluminum hydride, and boranes such as borane tetrahydrofuran complex.

  Moreover, you may add an acid catalyst with a reducing agent if desired. As the acid catalyst, for example, Lewis acids such as trifluoroborane diethyl ether complex and aluminum chloride are used.

  The amount of the reducing agent to be used is about 0.25 to about 10 mol, preferably about 0.5 to about 5 mol, per 1 mol of acylamide.

  The amount of the Lewis acid used is about 0.25 to about 10 moles, preferably about 0.5 to about 5 moles per mole of acylamide.

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene, Preferred are hydrocarbons such as cyclohexane and hexane, solvents such as water, or mixed solvents thereof.

  The reaction time is usually about 30 minutes to about 24 hours, preferably about 1 hour to about 16 hours. The reaction temperature is usually about 0 to about 150 ° C, preferably about 20 to about 100 ° C.

  The product (II) obtained as described above can be used as the reaction solution or as a crude product in the method described in the reaction formula (I), but it can be isolated from the reaction mixture using a known isolation means. And can be easily purified by separation means such as recrystallization, distillation, chromatography and the like.

Reaction formula 9

反応式９中、Ｐ’はヒドロキシ基の保護基を示し、他の記号は前記と同意義である。

In Reaction Scheme 9, P ′ represents a protecting group for a hydroxy group, and other symbols are as defined above.

  Compound (XVII) is produced by subjecting compound (XII) to a protecting group addition reaction as generally used in peptide chemistry and the like.

  If necessary, compound (IIa) is subjected to the next reaction in the same manner as in the method described in Reaction Scheme 8.

Further, the compounds (IIb), (IIc), and (IId) included in the compound (II) are also produced by the method described in the following reaction scheme 10.
Reaction formula 10

反応式１０中、halはハロゲン原子（例、フッ素、塩素、臭素、ヨウ素等）を示し、各記号は前記と同意義である。

In Reaction Scheme 10, hal represents a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and each symbol is as defined above.

  Compound (XXIII) can be produced by reacting compound (XXI) with compound (XXII) under acid conditions.

  Compound (XXI) is commercially available, and is a method known per se, for example, the method described in 4th edition Experimental Chemistry Course 20 (Edited by The Chemical Society of Japan), pages 111 to 185, Maruzen Co., Ltd. Also, it can be produced according to a method equivalent thereto.

  Compound (XXII) is commercially available, and can also be produced according to a method known per se and a method analogous thereto.

  Examples of the “acid” include Lewis acids such as aluminum chloride, iron chloride, stannic chloride, titanium tetrachloride, and boron trifluoride diethyl ether, mineral acids such as polyphosphoric acid and sulfuric acid, trifluoroacetic acid, methanesulfonic acid, p -Organic acids such as toluenesulfonic acid and trifluoromethanesulfonic acid are used.

  For example, in the case of mineral acids, the amount of acid used is usually about 0.5 to about 100 moles, preferably about 10 to about 50 moles per mole of compound (XXI). XXI) about 0.1 to about 20 moles, preferably about 0.1 to about 5 moles per mole.

  This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, when mineral acids are used, examples of the solvent include saturated hydrocarbons such as cyclohexane and hexane, aromatic hydrocarbons such as benzene, toluene and xylene, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether and diisopropyl. Ethers such as ether, mixed solvents of water and organic solvents such as halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and water are preferable.

  The reaction time is usually about 30 minutes to about 24 hours, preferably about 30 minutes to about 6 hours. The reaction temperature is generally about −78 to about 200 ° C., preferably about −20 to about 150 ° C.

  The product can be used in the next reaction as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). You can also.

Compound (XXIV) is produced by reducing compound (XXIII).
Examples of the reducing agent include metal hydrides such as aluminum hydride and diisobutylaluminum hydride, sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and the like. Examples thereof include metal-hydrogen complex compounds, borane complexes such as borane tetrahydrofuran complex and borane dimethyl sulfide, alkylboranes such as texylborane and diciamylborane, and diborane.

  Moreover, you may add an acid catalyst with a reducing agent if desired. As the acid catalyst, for example, Lewis acids such as trifluoroborane diethyl ether complex and aluminum chloride are used.

  The amount of the reducing agent to be used is about 0.25 to about 10 mol, preferably about 0.5 to about 5 mol, per 1 mol of compound (XXIII).

  The amount of the Lewis acid to be used is about 0.25 to about 10 mol, preferably about 0.5 to about 5 mol, per 1 mol of compound (XXIII).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene, Preferred are hydrocarbons such as cyclohexane and hexane, solvents such as water, or mixed solvents thereof.

  The reaction time is usually about 30 minutes to about 24 hours, preferably about 1 hour to about 16 hours. The reaction temperature is usually about 0 to about 150 ° C, preferably about 20 to about 100 ° C.

  The product (XXIV) thus obtained can be isolated from the reaction mixture using a known isolation means, and can be easily purified by a separation means such as recrystallization, distillation, chromatography and the like. it can.

Compound (XXV) is produced by subjecting compound (XXIV) (eg, a compound in which L ¹ is hydroxy) to a sulfonate or a halide, followed by a ring closure reaction. The sulfonate compound is obtained by reacting compound (XXIV) with the corresponding sulfonyl chloride compound (for example, benzenesulfonyl chloride, toluenesulfonyl chloride, C 1-4 alkylsulfonyl chloride such as methanesulfonyl chloride, etc.) in the presence of a base. Is synthesized.

The amount of the sulfonyl chloride compound to be used is about 1.0 to about 10 mol, preferably about 1.0 to about 5 mol, per 1 mol of compound (XXIV).
Examples of the base include organic bases such as triethylamine and pyridine.

  The amount of the base to be used is about 1.0 to about 50 mol, preferably about 1.0 to about 20 mol, per 1 mol of compound (XXIV).

  This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene and cyclohexane , Hydrocarbons such as hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, Nitriles such as pionitrile, sulfoxides such as dimethyl sulfoxide, nitrogen-containing aromatic hydrocarbons such as pyridine, lutidine, and quinoline, or mixed solvents thereof are preferable. The reaction temperature is about -78 to 150 ° C, preferably -30 to 100 ° C. The reaction time is usually 5 minutes to 24 hours, preferably 10 minutes to 5 hours.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

  Halides are synthesized by reacting compound (XXIV) with a halogenating agent (for example, phosphorus halides such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, halogen, thionyl chloride, etc.). The

  The amount of the halogenating agent to be used is about 1.0 to about 100 mol, preferably about 1.0 to about 10 mol, per 1 mol of compound (XXIV). This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N, Amides such as N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, etc. A sulfoxide solvent or a mixed solvent thereof is preferred. The reaction temperature is about 0 to 200 ° C, preferably 10 to 100 ° C. The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 5 hours.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

  Compound (XXV) can also be synthesized by subjecting the sulfonate compound thus obtained or a halide to a ring-closing reaction in the presence of a base. Examples of the base include organic bases such as triethylamine and pyridine.

  The amount of the base to be used is about 1.0 to about 50 mol, preferably about 1.0 to about 20 mol, per 1 mol of the sulfonate compound or halide. This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene and cyclohexane , Hydrocarbons such as hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, Nitriles such as pionitrile, esters such as ethyl acetate, solvents such as water, or mixed solvents thereof are preferred. The reaction temperature is about -10 to 250 ° C, preferably 0 to 120 ° C. The reaction time is usually 10 minutes to 6 hours, preferably 10 minutes to 2 hours.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

  Alternatively, the Mitsunobu reaction (Synthesis, 1981, pp. 1-27) can also be used.

In this reaction, compound (XXIV) in which L ¹ is OH in the compound is present in the presence of azodicarboxylates (eg, diethyl azodicarboxylate) and phosphines (eg, triphenylphosphine, tributylphosphine, etc.) Lower intramolecular ring closure gives compound (XXV).

  The amount of the “azodicarboxylates” and “phosphines” to be used is about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (XXIV). .

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N, Amides such as N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide, etc. Solvents such as sulfoxides or mixed solvents thereof are preferred.

  The reaction time is usually 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The reaction temperature is generally −20 to 200 ° C., preferably 0 to 100 ° C.

  Compound (XXVI) can be synthesized by nitrating compound (XXV). Examples of the nitrating agent include mixed acid, acetyl nitrate, fuming nitric acid, potassium nitrate, ammonium nitrate, nitronium tetrafluoroborate, nitronium trifluoromethanesulfonate, and the like. The nitrating agent is used in an amount of about 1.0 to about 50 moles, preferably about 1.0 to about 10 moles per mole of Compound (XXV). This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, organic acids such as acetic acid and trifluoroacetic acid, acid anhydrides such as acetic anhydride and trifluoroacetic anhydride, mineral acids such as sulfuric acid and nitric acid, hexane , Solvents such as saturated hydrocarbons such as cyclohexane, halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or a mixed solvent thereof.

  The reaction time is usually about 10 minutes to about 24 hours, preferably about 10 minutes to about 16 hours. The reaction temperature is generally about −10 to about 200 ° C., preferably about −10 to about 120 ° C.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

Compound (IIb) is produced by reducing compound (XXVI).
Examples of the reducing agent used for the reduction include metal hydrides such as aluminum hydride and diisobutylaluminum hydride, metal hydrogen complex compounds such as sodium borohydride and lithium aluminum hydride, borane tetrahydrofuran complex, and borane dimethyl. Examples thereof include borane complexes such as sulfide, alkylboranes such as texylborane and diciamylborane, diborane, metals such as zinc, aluminum, tin and iron, alkali metal / liquid ammonia (birch reduction) such as sodium and lithium. As the hydrogenation catalyst, for example, a catalyst such as palladium carbon, platinum oxide, Raney nickel, Raney cobalt, or the like is used. As the hydrogen source, formic acid, ammonium formate, hydrazine and the like are used in addition to gaseous hydrogen.

  The amount of the “reducing agent” used is, for example, about 1.0 to about 10 moles, preferably about 1.0 to about 3 moles per mole of the compound (XXVI) in the case of metal hydrides and metal hydrogen complex compounds. In the case of 0.0 mol, borane complexes, alkylboranes and diborane, about 1.0 to about 10 mol, preferably about 1.0 to about 5.0 mol, metals, In the case of an alkali metal, about 1.0 to about 20 equivalents, preferably about 1.0 to about 5.0 equivalents. In the case of hydrogenation, a catalyst such as palladium carbon, platinum oxide, Raney nickel, Raney cobalt or the like is used as a compound (XXVI). About 5 to 1000% by weight, preferably about 10 to 300% by weight. When a hydrogen source other than gaseous hydrogen is used, the amount is about 1.0 to about 20 mol, preferably about 2.0 to about 10 mol, per 1 mol of compound (XXVI).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene, Hydrocarbons such as cyclohexane and hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, organic acids such as formic acid and acetic acid, solvents such as water or a mixed solvent thereof are preferable. When using Raney nickel or Raney cobalt catalysts, amines such as ammonia may be added to suppress side reactions.

  The reaction time varies depending on the kind and amount of the reducing agent used, or the activity and amount of the catalyst, but is usually about 1 hour to about 100 hours, preferably about 1 hour to about 50 hours. The reaction temperature is usually about 0 to about 150 ° C, preferably about 20 to about 100 ° C. When a hydrogenation catalyst is used, the hydrogen pressure is usually 1 to 100 atm.

  The product (IIb) obtained as described above can be isolated from the reaction mixture using a known isolation means, and can be easily purified by a separation means such as recrystallization, distillation, chromatography and the like. it can.

  Compound (XXVII) is produced by reacting compound (XXV) with a halogenating reagent.

  As the “halogenation reagent”, chlorine, bromine, iodine, imides such as N-chlorosuccinimide and N-bromosuccinimide, and halogen adducts such as benzyltrimethylammonium tribromide are used. The amount of the “halogenating reagent” to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (XXV).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, benzene , Hydrocarbons such as toluene, cyclohexane, hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, organic acids such as acetic acid and propionic acid, nitroalkanes such as nitromethane, aromatic amines such as pyridine, lutidine and quinoline, or these A mixed solvent or the like is used.

  This reaction is carried out in the presence of a base, a Lewis acid or iron, if desired.

  Examples of the “base” include basic salts such as sodium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and potassium acetate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, And tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, and the like. The amount of the base to be used is about 0.8 to about 10 mol per 1 mol of compound (XXV).

  Examples of the “Lewis acid” include iron chloride, aluminum chloride, boron trifluoride and the like. The amount of the Lewis acid to be used is about 0.01 to about 5 mol per 1 mol of compound (XXV).

  As "iron", the amount of iron used is about 0.01 to about 5 moles per mole of compound (XXV).

  The reaction temperature is usually about −50 to about 150 ° C., preferably about −20 to about 100 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 12 hours.

  In addition, when a halogen atom is substituted on the A ring of the compound (XXI), the compound (XXVII) can be produced without halogenation.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

  Compound (IIc) is produced by reacting compound (XXVII) with benzylamine, optionally in the presence of a base. If necessary, for example, catalysts such as copper and copper salts may be used, and catalysts and ligands such as palladium and nickel according to the method described in Chemistry Letters, 1983, pages 927-928. (For example, phosphine and pyridines) may be used.

  The amount of benzylamine to be used is about 0.8 to about 10.0 moles, preferably about 1.0 to about 5.0 moles compared to 1 mole of Compound (XXVII).

  Examples of the “base” include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4 -Tertiary amines such as dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium Examples thereof include metal amides such as amide, lithium diisopropylamide, and lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.

  The amount of the “base” to be used is about 0.8 to about 10.0 moles, preferably about 1.0 to about 5.0 moles compared to 1 mole of Compound (XXVII).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene, Hydrocarbons such as cyclohexane and hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, acetonitrile, A solvent such as a nitrile such as propionitrile, a sulfoxide such as dimethyl sulfoxide, or a mixed solvent thereof is preferable.

As the “copper catalyst”, copper, copper halide (CuI, CuBr, CuCl, etc.), copper oxide (CuO) and the like are used.
The amount of the copper catalyst to be used is about 0.1 to about 10.0 mol, preferably about 0.5 to about 2.0 mol, per 1 mol of compound (XXVII).

  As the “ligand”, phosphine is preferable, and trialkylphosphine, triarylphosphine, trialkoxyphosphine and the like are used. As the palladium catalyst, palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, bis (dibenzylidene) are used. Acetone) palladium or the like may be used.

  The amount of “phosphine” to be used is about 0.001 to about 10.0 mol, preferably about 0.01 to about 1.0 mol, per 1 mol of compound (XXVII). The amount of the palladium catalyst to be used is about 0.001 to about 5.0 mol, preferably about 0.01 to about 0.5 mol, per 1 mol of compound (XXVII).

  The reaction time is usually about 30 minutes to about 72 hours, preferably about 1 hour to about 48 hours. The reaction temperature is usually about −20 to about 200 ° C., preferably about 0 to about 150 ° C.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

  Compound (IIb) is produced by debenzylating compound (IIc). The debenzylation reaction is a reaction known per se, such as the method described in the chapters of Protective Groups in Organic Synthesis (3rd edition, 1999), (Protection for the Amino Group) by TW Green. Just follow.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

  Compound (IId) is produced from compound (IIb) by the same method as in the production of compound (II) from compound (IIa) shown in Reaction Scheme 9, as necessary.

When R ³ is a hydrogen atom, the compound (IIf) and the compound (IIg) contained in the compound (II) are also produced by the method described in the following reaction scheme 11.
Reaction formula 11

反応式１１中、各記号は前記と同意義である。

In the reaction formula 11, each symbol is as defined above.

  Compound (XXXII) is produced by reacting compound (XXI) with compound (XXXI), optionally in the presence of a base.

  Compound (XXXI) is commercially available or can be produced by a method known per se.

  Examples of the “base” include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4 -Tertiary amines such as dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium Examples thereof include metal amides such as amide, lithium diisopropylamide and lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide.

  The amount of compound (XXXI) to be used is about 0.7 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XXI).

  The amount of the base to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XXI). If desired, it can also be produced by reacting with a base in the presence of a quaternary ammonium salt. Examples of the “quaternary ammonium salt” include tetrabutylammonium iodide.

  The amount of the quaternary ammonium salt used is approximately 0.1 to approximately 2.0 mol, preferably approximately 0.5 to approximately 1.0 mol, with respect to 1 mol of the compound (XXI).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N Amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide A solvent such as sulfoxides such as these or a mixed solvent thereof is preferred.

  The reaction time is usually about 30 minutes to about 96 hours, preferably about 1 hour to about 72 hours. The reaction temperature is usually about 0 to about 120 ° C, preferably about 0 to about 60 ° C.

  Instead of the above reaction, Mitsunobu reaction (Synthesis, 1981, pp. 1 to 27) can also be used.

In the reaction, compound (XXI) and compound (XXXI) in which L ¹ is OH are converted into azodicarboxylates (eg, diethylazodicarboxylate, etc.) and phosphines (eg, triphenylphosphine, tributylphosphine, etc.). In the presence of. The amount of compound (XXXI) to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XXI).

  The amount of the “azodicarboxylates” and “phosphines” to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XXI), respectively. It is.

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N Amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide A solvent such as a sulfoxide such as a mixed solvent thereof or the like is preferable.

  The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is usually about −20 to about 200 ° C., preferably about 0 to about 100 ° C.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

  Compound (XXXIII) is produced by subjecting compound (XXXII) to a cyclization reaction known per se.

  An acid is used for this cyclization reaction.

Examples of the “acid” include Lewis acids such as aluminum chloride, iron chloride, stannic chloride, titanium tetrachloride, and boron trifluoride diethyl ether, mineral acids such as polyphosphoric acid and sulfuric acid, trifluoroacetic acid, methanesulfonic acid, p - toluenesulfonic acid, organic acids such as trifluoromethanesulfonic acid, zeolite, Amberlyst, such as acid resin, clays such as montmorillonite is employed.

  The amount of the “acid” to be used is a catalytic amount to an excess amount, preferably about 0.8 to about 5 mol per 1 mol of compound (XXXII), relative to compound (XXXII). The amount of the acidic resin / clay is about 0.1 to 50 grams, preferably 1 to 5 grams, relative to 1 gram of compound (XXXII).

  This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, Carbon disulfide, nitroalkanes such as nitromethane, nitroaryls such as nitrobenzene, halogenated carbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,2-dichlorobenzene, acetic acid, trifluoroacetic acid The solvent of organic acids, such as these, or these mixed solvents are preferable.

  The reaction time is usually about 10 minutes to about 96 hours, preferably about 30 minutes to about 16 hours. The reaction temperature is generally about −70 to about 200 ° C., preferably about −20 to about 150 ° C.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

Compound (XXXIV) is produced by reducing compound (XXXIII).
Examples of the reduction reaction include a catalytic reduction method and a method using an organic silyl reagent (such as an alkylsilane reagent).

  The catalytic reduction method is a reaction known per se, for example, using a catalyst such as palladium carbon in a hydrogen atmosphere, and after removing the catalyst, the product can be used in the next reaction as a reaction liquid or as a crude product. However, it can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.).

  In the method using an organic silyl reagent (alkylsilane reagent), compound (XXXIV) can be produced by reacting compound (XXXIII) with an alkylsilane reagent and an acid.

  As the alkylsilane reagent, for example, triethylsilane, phenyldimethylsilane or the like is used. The amount of the “alkylsilane reagent” to be used is about 0.8 to about 20 mol, preferably about 1 to about 5 mol, per 1 mol of compound (XXXIII).

  As the acid, for example, an organic acid such as trifluoroacetic acid is used. The amount of the acid used is about 0.1 to excess with respect to 1 mol of compound (XXXIII).

  This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Although it does not specifically limit as long as reaction advances as such a solvent, For example, ethers, such as diethyl ether, tetrahydrofuran, a dioxane, 1, 2- dimethoxyethane, Hydrocarbons, such as benzene, toluene, a cyclohexane, hexane, a dichloromethane, chloroform Solvents such as halogenated carbons such as carbon tetrachloride and 1,2-dichloroethane, organic acids such as acetic acid and trifluoroacetic acid, or a mixed solvent thereof are preferable.

  The product can be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.).

  Compound (XXXV) is produced by reacting compound (XXXIV) with a halogenating reagent.

  As the “halogenation reagent”, chlorine, bromine, iodine, imides such as N-chlorosuccinimide and N-bromosuccinimide, and halogen adducts such as benzyltrimethylammonium tribromide are used. The amount of the halogenating reagent to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (XXXIV).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, benzene , Hydrocarbons such as toluene, cyclohexane, hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, organic acids such as acetic acid and propionic acid, nitroalkanes such as nitromethane, aromatic amines such as pyridine, lutidine and quinoline, or these A mixed solvent or the like is used.

  This reaction is carried out in the presence of a base, a Lewis acid or iron, if desired.

  Examples of the “base” include basic salts such as sodium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and potassium acetate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, And tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, and the like. The amount of the base to be used is about 0.8 to about 10 mol per 1 mol of compound (XXXIV).

  Examples of the “Lewis acid” include iron chloride, aluminum chloride, boron trifluoride and the like. The amount of the Lewis acid to be used is about 0.01 to about 5 mol per 1 mol of compound (XXXIV).

  As "iron", the amount of iron used is about 0.01 to about 5 moles with respect to 1 mole of compound (XXXIV).

  The reaction temperature is usually about −50 to about 150 ° C., preferably about −20 to about 100 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 12 hours. The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography). Etc.) can be easily purified.

In addition, when a halogen atom is substituted on the benzene ring of compound (XXI), compound (XXXV) can be produced without halogenation.
Compound (XXXVI) is produced by reacting compound (XXXV) with benzylamine, optionally in the presence of a base. If necessary, for example, catalysts such as copper and copper salts may be used, and catalysts and ligands such as palladium and nickel according to the method described in Chemistry Letters, 1983, pages 927-928. (For example, phosphine and pyridines) may be used.

  The amount of benzylamine to be used is about 0.8 to about 10.0 mol, preferably about 1.0 to about 5.0 mol, per 1 mol of compound (XXXV).

  Examples of the “base” include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, Tertiary amines such as 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, Examples thereof include metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.

  The amount of the base to be used is about 0.8 to about 10.0 mol, preferably about 1.0 to about 5.0 mol, per 1 mol of compound (XXXV).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, benzene, toluene, Hydrocarbons such as cyclohexane and hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, acetonitrile, A solvent such as a nitrile such as propionitrile, a sulfoxide such as dimethyl sulfoxide, or a mixed solvent thereof is preferable.

As the copper catalyst, copper, copper halide (CuI, CuBr, CuCl, etc.), copper oxide (CuO), or the like is used.
The amount of the copper catalyst to be used is about 0.1 to about 10.0 mol, preferably about 0.5 to about 2.0 mol, per 1 mol of compound (XXXV).

  As the ligand, phosphine is preferable, and trialkylphosphine, triarylphosphine, trialkoxyphosphine and the like are used. As the palladium catalyst, palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) Palladium or the like may be used. The amount of phosphine to be used is about 0.001 to about 10.0 mol, preferably about 0.01 to about 1.0 mol, per 1 mol of compound (XXXV). The amount of the palladium catalyst to be used is about 0.001 to about 5.0 mol, preferably about 0.01 to about 0.5 mol, per 1 mol of compound (XXXV).

  The reaction time is usually about 30 minutes to about 72 hours, preferably about 1 hour to about 48 hours. The reaction temperature is usually about −20 to about 200 ° C., preferably about 0 to about 150 ° C. The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography). Etc.) can be easily purified.

  Compound (IIf) is produced by debenzylating compound (XXXVI). The debenzylation reaction may be performed according to a reaction known per se, for example, according to the method described in the chapter of Protection of the Amino Group in the 3rd edition of Protective Group in Organic Synthesis by T.W. The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography). Etc.) can be easily purified.

  Compound (IIg) is produced from compound (IIf) by a method similar to that for producing compound (II) from compound (IIa) shown in Reaction Scheme 9, as necessary.

Compound (VI) is also produced by the method described in Reaction Scheme 12 below.
Reaction formula 12

反応式１２中、−ＣＯ−Ｑで示される基はカルボン酸またはその反応性誘導体を示し、他の記号は前記と同意義である。

In Reaction Scheme 12, the group represented by —CO—Q represents a carboxylic acid or a reactive derivative thereof, and other symbols are as defined above.

  Compound (XXXVIII) is produced by reacting compound (XXI) with compound (XXXVII), optionally in the presence of a base.

  Examples of the “base” include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4 -Tertiary amines such as dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium Examples thereof include metal amides such as amide, lithium diisopropylamide and lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide.

  The amount of compound (XXXVII) to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XXI).

  The amount of the base to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XXI). If desired, it can also be produced by reacting with a base in the presence of a quaternary ammonium salt. Examples of the “quaternary ammonium salt” include tetrabutylammonium iodide.

  The amount of the quaternary ammonium salt used is approximately 0.1 to approximately 2.0 mol, preferably approximately 0.5 to approximately 1.0 mol, with respect to 1 mol of the compound (XXI).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N Amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide A solvent such as sulfoxides such as these or a mixed solvent thereof is preferred.

  The reaction time is usually about 30 minutes to about 96 hours, preferably about 1 hour to about 72 hours. The reaction temperature is usually about 0 to about 120 ° C, preferably about 0 to about 60 ° C.

  Instead of the above reaction, Mitsunobu reaction (Synthesis, 1981, pp. 1 to 27) can also be used.

In the reaction, compound (XXI) and compound (XXXVII) in which L ¹ is OH are converted into azodicarboxylates (eg, diethylazodicarboxylate) and phosphines (eg, triphenylphosphine, tributylphosphine, etc.). In the presence of.

  The amount of compound (XXXVII) to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XXI).

  The amount of the “azodicarboxylates” and “phosphines” to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XXI), respectively. It is.

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N Amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide A solvent such as a sulfoxide such as a mixed solvent thereof or the like is preferable.

  The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours. The reaction temperature is usually about −20 to about 200 ° C., preferably about 0 to about 100 ° C.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

  Compound (XXXIX) is produced by subjecting compound (XXXVIII) to a cyclization reaction known per se.

  Q in the formula is preferably a hydroxy group, a halogen atom or the like. In this reaction, compound (XXXVIII) is optionally reacted with an acid to give compound (XXXIX).

  Examples of the “acid” include Lewis acids such as aluminum chloride, iron chloride, stannic chloride, titanium tetrachloride, and boron trifluoride diethyl ether, mineral acids such as polyphosphoric acid and sulfuric acid, trifluoroacetic acid, methanesulfonic acid, p -Organic acids such as toluenesulfonic acid and trifluoromethanesulfonic acid are used.

  The amount of the “acid” to be used is a catalytic amount to an excess amount, preferably about 0.8 to about 5 mol per 1 mol of compound (XXXVIII), relative to compound (XXXVIII).

  This reaction is advantageously carried out without solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, nitroalkanes such as carbon disulfide and nitromethane, nitroaryls such as nitrobenzene, dichloromethane, 1,2-dichloroethane, and 1,2-diethyl. Solvents such as halogenated carbons such as chlorobenzene, organic acids such as acetic acid and trifluoroacetic acid, acid anhydrides such as acetic anhydride and trifluoroacetic anhydride, or a mixed solvent thereof are preferable.

  The reaction time is usually about 10 minutes to about 96 hours, preferably about 10 minutes to about 12 hours. The reaction temperature is generally about −70 to about 200 ° C., preferably about −40 to about 150 ° C.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

  Compound (XLIV) is produced from compound (XXXIX) by a method similar to the procedure for producing compound (IId) from compound (XXV).

Compound (VI) is produced from compound (XLIV) by a method similar to the procedure for producing compound (I) from compound (II).

When R ² of the compound (IIf) and the compound (IIg) contained in the compound (II) is H, the compound (IIf) can also be produced by the method described in the following reaction formula 13.
Reaction formula 13

反応式１３中、Arは置換されても良い芳香環（ベンゼン環、ナフタレン環、ピリジン環、フラン環、チオフェン環、イミダゾール環等）を示し、各記号は前記と同意義である。

In Reaction Formula 13, Ar represents an aromatic ring (benzene ring, naphthalene ring, pyridine ring, furan ring, thiophene ring, imidazole ring, etc.) that may be substituted, and each symbol is as defined above.

  Compound (XLVI) is produced by reacting compound (XLV) with a halogenating reagent.

  As the “halogenation reagent”, chlorine, bromine, iodine, imides such as N-chlorosuccinimide and N-bromosuccinimide, and halogen adducts such as benzyltrimethylammonium tribromide are used. The amount of the halogenating reagent to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 2.0 mol, per 1 mol of compound (XLV).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, benzene , Hydrocarbons such as toluene, cyclohexane, hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, organic acids such as acetic acid and propionic acid, nitroalkanes such as nitromethane, aromatic amines such as pyridine, lutidine and quinoline, or these A mixed solvent or the like is used.

  This reaction is carried out in the presence of a base, a Lewis acid or iron, if desired.

  Examples of the “base” include basic salts such as sodium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate and potassium acetate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, And tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, and the like. The amount of the base to be used is about 0.8 to about 10 mol per 1 mol of compound (XLV).

  Examples of the “Lewis acid” include iron chloride, aluminum chloride, boron trifluoride and the like. The amount of the Lewis acid to be used is about 0.01 to about 5 mol per 1 mol of compound (XLV).

  As "iron", the amount of iron used is about 0.01 to about 5 moles per mole of compound (XLV).

  The reaction temperature is usually about −50 to about 150 ° C., preferably about −20 to about 100 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 12 hours. The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography). Etc.) can be easily purified.

  In addition, when a halogen atom is substituted on the benzene ring of the compound (XLV), the compound (XLVI) can be produced without halogenation.

  Compound (XLVII) can be produced by reacting compound (XLVI) with a triflating agent in the presence of a base.

  Examples of the “triflating agent” include trifluoromethanesulfonic acid, trifluoromethanesulfonic anhydride, trifluoromethanesulfonic acid chloride, N-phenylbis (trifluoromethanesulfonimide) and the like.

  The amount of the triflating agent to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XLVI).

  Examples of the “base” include aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N -Tertiary amines such as methylpyrrolidine and N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide, Examples thereof include metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide.

  The amount of the base to be used is about 0.8 to about 5.0 mol, preferably about 1.0 to about 3.0 mol, per 1 mol of compound (XLVI).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N Amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide A solvent such as sulfoxides such as these or a mixed solvent thereof is preferred.

  The reaction time is usually about 30 minutes to about 96 hours, preferably about 1 hour to about 72 hours. The reaction temperature is usually about 0 to about 120 ° C, preferably about 0 to about 60 ° C.

  Compound (XLVIII) is produced by subjecting compound (XLVII) to Suzuki coupling.

  The reaction is carried out by using compound (XLVII) and a boronic acid such as a substituted boronic acid and a substituted boronic acid ester in a solvent under basic conditions in the presence of a transition metal catalyst.

  The amount of the “boronic acid” to be used is about 0.5 to about 10 mol, preferably about 0.9 to about 3 mol, per 1 mol of compound (XLVII).

  As the “base”, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethyl Tertiary amines such as aminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, etc. And metal alkoxides.

  As the “transition metal catalyst”, palladium catalysts such as palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, 1,1-bis (diphenylphosphino) ferrocenedichloropalladium, dichlorobis (triphenylphosphine) palladium and the like are used. It is done. The amount of the transition metal catalyst to be used is about 0.001 to about 3 mol, preferably about 0.02 to about 0.2 mol, per 1 mol of compound (XLVII).

  Examples of the solvent include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, carbonization such as benzene, toluene, carbon disulfide, cyclohexane and hexane. Hydrogens, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile , Sulfoxides such as dimethyl sulfoxide, water, or a mixed solvent thereof.

  The reaction temperature is usually 0 to 250 ° C., preferably 50 to 150 ° C. The reaction time is usually about 5 minutes to about 48 hours, preferably about 30 minutes to about 24 hours.

  In this reaction, the reaction time can be shortened by using a microwave reaction apparatus or the like.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

  Compound (XLIX) is produced from compound (XLVIII) by a method similar to the procedure for producing compound (XXXVI) from compound (XXXV) shown in Reaction Scheme 11.

  Compound (L) is produced from compound (XLIX) by a method similar to the procedure for producing compound (IIf) from compound (XXXVI) shown in Reaction Scheme 11.

  Compound (IIf) is produced from compound (L) by a method similar to the procedure for producing compound (XXXIV) from compound (XXXIII).

  Compound (IIg) is produced from compound (IIf) by a method similar to the procedure for producing compound (IId) from compound (XXV).

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). ) Can be easily purified.

Compound (LIV) can also be produced by the method described in Reaction Scheme 14 below.
Reaction formula 14

反応式１３中、各記号は前記と同意義である。

In the reaction formula 13, each symbol is as defined above.

  Compound (LI) is produced by reacting compound (XXI) with a brominating reagent.

  As the “bromination reagent”, bromine adducts such as bromine, N-bromosuccinimide, and benzyltrimethylammonium tribromide are used.

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, alcohols such as methanol, ethanol and propanol, benzene , Hydrocarbons such as toluene, carbon disulfide, cyclohexane, hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogens such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Hydrocarbons, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, organic acids such as acetic acid and propionic acid, nitroalkanes such as nitromethane, aromatic amines such as pyridine, lutidine and quinoline, Alternatively, a mixed solvent thereof or the like is used.

  The reaction temperature is usually about 0 to about 150 ° C, preferably about 20 to about 100 ° C. The reaction time is usually about 5 minutes to about 24 hours, preferably about 10 minutes to about 12 hours.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

  Compound (LIII) is produced by reacting compound (LI) and compound (LII) in the presence of a base.

  Examples of the “base” include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4 -Tertiary amines such as dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium Examples thereof include metal amides such as amide, lithium diisopropylamide and lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide.

  The amount of compound (LII) to be used is about 0.7 mol to excess amount per 1 mol of compound (LI).

  The amount of the base to be used is about 0.8 to about 10 mol, preferably about 1.0 to about 5 mol, per 1 mol of compound (LI). If desired, it can also be produced by reacting with a base in the presence of a quaternary ammonium salt.

  Examples of the “quaternary ammonium salt” include benzyltributylammonium iodide.

  The amount of the quaternary ammonium salt to be used is about 0.1 to about 2.0 mol, preferably about 0.5 to about 1.0 mol, per 1 mol of compound (LI).

  This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N Amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide A solvent such as sulfoxides such as these or a mixed solvent thereof is preferred.

  The reaction time is usually about 30 minutes to about 96 hours, preferably about 1 hour to about 72 hours. The reaction temperature is usually about 0 to about 120 ° C, preferably about 0 to about 60 ° C.

  The product can be used as it is in the reaction solution or as a crude product for the next reaction, but can be isolated from the reaction mixture according to a conventional method, and can be isolated by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.) Can also be easily purified.

Compound (LIV) is produced by subjecting compound (LIII) to a ring-closing reaction in the presence of a metal compound (eg, Grignard reagent, organolithium reagent, magnesium, etc.).
The amount of the metal compound to be used is about 0.8 to about 30 mol, preferably about 1.0 to about 10 mol, per 1 mol of compound (VIII).

This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, hydrocarbons such as hexane, cyclohexane, benzene, toluene, xylene, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc. ethers, di-chloromethane, chloroform, carbon tetrachloride, or a mixed solvent thereof and the like, such as halogenated hydrocarbons such 1,2-dichloroethane, or the like is used.

  The reaction time is usually about 10 minutes to about 24 hours, preferably about 30 minutes to about 5 hours. The reaction temperature is usually about −100 to about 120 ° C., preferably about −80 to about 60 ° C.

  The product can be used as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by ordinary separation means (eg, recrystallization, distillation, chromatography, etc.). be able to.

  The starting compound such as the compound (I) may form a salt and is not particularly limited as long as the reaction is achieved. For example, the same as the salt that the compound (I) or the like may form Salt or the like is used.

  Isomerization occurred for compound (I) and the like, and the configuration isomers (E, Z form) of compound (Ia), (Ib), (Ic), (Id) and compound (I ′) included therein. At this point, it can be isolated and purified by conventional separation means such as extraction, recrystallization, distillation, chromatography and the like, and a pure compound can be produced. In addition, according to the method described in New Experimental Chemistry Course 14 (Japan Chemical Society), pages 251 to 253, 4th edition Experimental Chemistry Course 19 (Japan Chemical Society), pages 273 to 274 and a method analogous thereto, heating, The corresponding pure isomer can also be obtained by proceeding with isomerization of the double bond by an acid catalyst, a transition metal complex, a metal catalyst, a radical species catalyst, light irradiation or a strong base catalyst.

  Compound (I) and the like may form stereoisomers depending on the type of substituent, and the present invention includes both the isomer and a mixture thereof.

  Compound (I) and the like may be hydrated or non-hydrated.

  In any case, further, as desired, each of deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction and substituent exchange reaction may be carried out alone or in combination of two or more thereof. Compound (I) and the like can be synthesized by carrying out in combination.

  When the desired product is obtained in the free state by the above reaction, it may be converted into a salt according to a conventional method, and when it is obtained as a salt, it is converted into a free form or other salt according to a conventional method. You can also. The compound (I) and the like thus obtained can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography and the like.

  In addition, when compound (I) etc. exists as a configurational isomer (configuration isomer), a diastereomer, a conformer, etc., each can be isolated by the said isolation | separation and a refinement | purification means if desired. Further, when the compound (I) or the like is a racemate, it can be separated into a d-form and an l-form by an ordinary optical resolution means.

  In each of the above reactions, when a functional group such as an amino group, a hydroxy group, or a carboxy group is present, it may be subjected to the reaction after a protective group generally used in peptide chemistry is introduced. The target compound can be obtained by removing the protecting group as necessary after the reaction.

Examples of the protecting group include formyl or each optionally substituted C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, etc.), phenylcarbonyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl). Etc.), phenyloxycarbonyl, C _7-10 aralkyloxy-carbonyl (eg, benzyloxycarbonyl etc.), trityl, phthaloyl and the like. As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, valeryl, etc.), nitro and the like are used. The number of substituents is, for example, 1 to 3.

  In addition, as a method for removing the protecting group, a method known per se or a method equivalent thereto is used. For example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate Or a reduction reaction is used.

Compound (I ₀ ) and a prodrug thereof have a cannabinoid receptor modulating action such as CB1 agonist, CB1 antagonist, or CB2 agonist.

Among the compounds represented by formula (I _0), primarily the formula (I ₀₎ compound 2-position of the fused heterocyclic ring is not substituted shown in (eg, wherein R ¹ and R ² are both hydrogen atoms (I ) Has a CB1 agonistic action and is useful for the treatment and prevention of various diseases as described in Clin. Pharmacokinet., 2003 42 (4) 327-360. Specifically, cerebrovascular disorders such as cerebral infarction and cerebral hemorrhage; head injury; spinal cord injury; oxygen deficiency and ischemia due to nerve gas damage; nausea, nausea and vomiting caused by anticancer drugs; Anorexia; emetic nausea; convulsions from multiple sclerosis; neuropathic pain; chronic pain; Tourette syndrome, ataxia; motor dysfunction such as levodopa-induced movement disorders; Refractory hiccups; depression; manic depression; anxiety; narcotics and alcoholism; withdrawal symptoms; renal disease such as renal failure; symptoms of Alzheimer's disease; autoimmunity such as multiple sclerosis, arthritis, rheumatism, Crohn's disease It is considered useful for, but not limited to, disease; hypertension; cancer; diarrhea; airway obstruction; sleep apnea.

Of the compounds represented by the formula (I ₀ ), compounds in which the 2-position of the condensed heterocyclic ring mainly represented by the formula (I ₀ ) is substituted (for example, a compound of the formula (I ¹ in which R ¹ and R ² are not hydrogen atoms at the same time) ) Has a CB1 antagonistic action and has anxiety, mood disorder, delirium, psychosis in general, schizophrenia, depression, alcoholism, nicotine dependence and other diseases related to drug abuse, neuropathy, migraine Dyskinetic disorder, memory stress, cognitive impairment, panic disorder, Parkinson's disease, Huntington's chorea, Raynaud's disease, tremor, obsessive / compulsive neurosis, senile / Alzheimer Type dementia, hyperactivity, arousal disorder, neuroprotection in neurodegenerative diseases, eating disorders, anorexia, bulimia, appetite suppression in obesity, type 2 diabetes, gastrointestinal disorders Diarrhea, ulcer, vomiting, urinary tract / bladder dysfunction, circulatory disorder, infertility, inflammatory pneumonia, infection, anticancer, smoking cessation, endotoxin shock, hemorrhagic shock, hypotension, treatment or prevention of insomnia, analgesia, It is useful for enhancing narcotic and non-narcotic analgesics and improving gastrointestinal motility, but is not limited to these uses. For detection and labeling of the CB1 receptor, it can be used as it is or as a radioisotope-labeled form as a pharmacological tool in humans or animals.

Furthermore, the compound represented by the formula (I ₀ ) has a CB2 agonistic action widely, multiple sclerosis, neurodegenerative disease, irritable enteritis, Crohn's disease, reflux esophagitis, COPD, psoriasis, autoimmune disease, transplantation It is considered useful for, but not limited to, single rejection, allergic diseases, neuropathic pain, hepatitis virus, prevention or treatment of hypertension, or adjustment of immunity.

  The compounds of the present invention have low toxicity (for example, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.) and are pharmacologically acceptable as they are or according to means known per se. A pharmaceutical composition mixed with a carrier, such as tablets (including sugar-coated tablets, film-coated tablets, orally disintegrating tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, Sustained-release preparations, patch preparations and the like can be produced and safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.).

  The content of the compound of the present invention in the preparation of the present invention is about 0.001 to about 100% by weight of the whole preparation.

  The dose varies depending on the administration subject, administration route, disease and the like, but when administered as an injection to an adult, for example, as a head injury treatment agent, the compound of the present invention is used as an active ingredient in an amount of about 0.001 to About 20 mg / kg body weight, preferably about 0.005 to about 5 mg / kg body weight, more preferably about 0.05 to about 1 mg / kg body weight, and can be administered in one to several times a day. .

In addition, other active ingredients [thrombolytic agents (eg, tissue plasminogen activator, urokinase, etc.), anticoagulants (eg, argatroban, warfarin, etc.), factor 10 inhibitors, thromboxane synthase inhibitors (eg, , Ozagrel, etc.), antioxidants (eg, edaravone, etc.), anti-edema agents (eg, glycerol, mannitol, etc.), neurogenesis / regeneration promoters (eg, Akt / PKB activator, GSK-3β inhibitor, etc.) Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine, galantamine, zanapezil, etc.), β amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitors [β secretase inhibitors (eg, compounds described in WO 98/38156, WO 02/2505, WO 02/2506, WO 02/2512 Description, OM99-2 (WO 01/00663)), γ-secretase inhibitor, β-amyloid protein aggregation inhibitor Examples: PTI-00703, ALZHEMED (NC-531), PPI-368 (Special Tables Hei 11-514333), PPI-558 (Special Tables Hei 2001-500852), SKF-74652 (Biochem. J. (1999), 340 (1), 283-289)), β-amyloid vaccine, β-amyloid-degrading enzyme, etc.], brain function stimulants (eg, aniracetam, nicergoline, etc.), other Parkinson's disease drugs [(eg, dopamine receptor agonist ( L-dopa, bromocriptene, pergolide, talipexol, pramipexole , cabergoline, adamantazine, etc.), monoamine oxidase (MAO) inhibitors (deprenyl, sergiline (selegiline), remacemide, riluzole, etc.), anti Choline drugs (eg, trihexyphenidyl, biperiden, etc.), COMT inhibitors (eg, entacapone, etc.)], amyotrophic lateral sclerosis Antihyperlipidemic drugs (eg, pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrate (eg, clofibrate, etc.) Etc.), Squalene Synthetic Fermentation Inhibitor], Abnormal Behavior with Dementia Progression, Acupuncture, etc. (eg, Sedative, Anxiolytics, etc.), Apoptosis Inhibitor (eg, CPI-1189, IDN-6556, CEP) -1347, etc.), neuronal differentiation / regeneration promoters (Leteprinim, Xaliproden; SR-57746-A, SB-216763, etc.)], antihypertensives, antidiabetics, antidepressants, anxiolytics, non-steroidal anti-inflammatory drugs (eg, meloxicam, Teokishikamu, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin down, etc.), disease-modifying antirheumatic drugs (DM RDs), anti-cytokine drugs (TNF inhibitors, MAP kinase inhibitors, etc.), steroid drugs (eg, dexamethasone, hexestrol, cortisone acetate, etc.), sex hormones or derivatives thereof (eg, progesterone, estradiol, estradiol benzoate, Etc.), parathyroid hormone (PTH), calcium receptor antagonist, interferon (eg, interferon α, interferon β) and the like]. The other active ingredient and the compound of the present invention or a salt thereof are mixed according to a method known per se, and a single pharmaceutical composition (eg, tablet, powder, granule, capsule (including soft capsule), liquid, injection) , Suppositories, sustained-release agents, etc.) may be formulated and used together, or each may be formulated separately and administered to the same subject simultaneously or with a time difference.

  Examples of the pharmacologically acceptable carrier that may be used for the production of the preparation of the present invention include various organic or inorganic carrier substances that are commonly used as preparation materials. For example, excipients, lubricants in solid preparations, Examples include binders, disintegrants, solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers, and soothing agents. Further, if necessary, additives such as ordinary preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can be used.

  Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.

  Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

  Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.

  Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

  Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, hydrophilic surfactants such as Tween 80, cholesterol, cyclodextrin (for example, α-, β- or γ-cyclodextrin or 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin), triethanolamine, sodium carbonate, sodium citrate and the like.

  Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, Examples thereof include hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.

  Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.

  Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.

  Examples of soothing agents include benzyl alcohol.

  Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.

  Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

  The present invention is further explained in detail by the following reference examples, examples, formulation examples and experimental examples, but these examples are merely examples and do not limit the present invention, and the scope of the present invention. You may change in the range which does not deviate from.

  “Room temperature” in the following Reference Examples and Examples usually indicates about 10 to about 35 ° C. % Indicates weight percent unless otherwise specified.

  Other abbreviations used in the text have the following meanings.

s: singlet
d: Doublet
dd: doublet of doublets
dt: doublet of triplets
t: triplet
q: quartet
septet: Septet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
CDCl ₃ : Deuterated chloroform
DMSO-d ₆ : Heavy dimethyl sulfoxide
¹ H-NMR: Proton nuclear magnetic resonance
THF: tetrahydrofuran
DMF: Dimethylformamide
BINAP: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl Further, ¹ H-NMR does not describe a very gentle peak in the proton on the hydroxyl group or amino group. Moreover, about the compound which forms the salt, it described as the free base about the data in a free body.

For silica gel chromatography, Merck's Kiesselgel 60 was used, and for basic silica gel chromatography, Fuji Silysia Chemical's Chromatorex NH was used.
[Reference Example 1]

Hydroxy (4-isopropylphenyl) acetic acid To a mixture of lithium chloride (17.0 g, 418 mmol), potassium hydroxide (44.9 g, 800 mmol) and ice (150 g), bromoform (17.5 mL, 200 mmol) and 4-isopropyl A solution of benzaldehyde (30.3 mL, 200 mmol) in 1,4-dioxane (150 mL) was added at 0 ° C., stirred at 5-10 ° C. for 24 hours, and then stirred at 35 ° C. for 24 hours. The mixture was diluted with water and extracted with diethyl ether. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was crystallized from hexane-ethyl acetate to obtain 28.5 g (yield 73%) of the title compound. Melting point 156-157 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7.0 Hz), 2.91 (1H, septet, J = 7.0 Hz), 5.21 (1H, s), 7.24 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 2H not confirmed.
[Reference Example 2]

3- (4-Isopropylphenyl) -4,6,7-trimethyl-1-benzofuran-2 (3H) -one Hydroxy (4-isopropylphenyl) acetic acid synthesized in Reference Example 1 (11.8 g, 60.8 mmol), 2 , 3,5-trimethylphenol (12.4 g, 91.2 mmol), 70% sulfuric acid (10 mL) was added at room temperature, and the mixture was stirred at 115 ° C. for 12 hours. The mixture was added to water and extracted with diisopropyl ether. The extract was washed with water and saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 8: 1) to obtain 10.9 g (yield 65%) of the title compound. Melting point 107-108 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.6 Hz), 1.93 (3H, s), 2.24 (3H, s), 2.29 (3H, s), 2.88 (1H, septet, J = 6.6 Hz), 4.76 (1H, s), 6.76 (1H, s), 7.07 (2H, d, J = 8.1 Hz), 7.17 (2H, d, J = 8.1 Hz).
[Reference Example 3]

3- (4-Isopropylphenyl) -6,7-dimethyl-1-benzofuran-2 (3H) -one In the same manner as in Reference Example 2, hydroxy (4-isopropylphenyl) acetic acid synthesized in Reference Example 1 and 2, The title compound was synthesized using 3-dimethylphenol. Yield 44%. Melting point 58-60 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.27 (3H, s), 2.32 (3H, s), 2.88 (1H, septet, J = 6.6 Hz), 4.85 ( 1H, s), 6.91 (1H, d, J = 7.8 Hz), 6.95 (1H, d, J = 7.8 Hz), 7.13 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz).
[Reference Example 4]

3- (4-Isopropylphenyl) -4,6-dimethyl-1-benzofuran-2 (3H) -one
In the same manner as in Reference Example 2, the title compound was synthesized using hydroxy (4-isopropylphenyl) acetic acid and 3,5-dimethylphenol synthesized in Reference Example 1. Yield 45%. Melting point 76-77 ° C. (Ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 7.0 Hz), 1.97 (3H, s), 2.38 (3H, s), 2.88 (1H, septet, J = 7.0 Hz), 4.73 ( 1H, s), 6.78 (1H, s), 6.84 (1H, s), 7.07 (2H, d, J = 8.2 Hz), 7.18 (2H, d, J = 8.2 Hz).
[Reference Example 5]

5-Bromo-3- (4-isopropylphenyl) -1-benzofuran-2 (3H) -one Hydroxy (4-isopropylphenyl) acetic acid and 4-bromophenol synthesized in Reference Example 1 in the same manner as Reference Example 2. Was used to synthesize the title compound. Yield 30%. Melting point 157-158 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.9 Hz), 2.90 (1H, septet, J = 6.9 Hz), 4.86 (1H, s), 7.06 (1H, d, J = 8.7 Hz), 7.11 (2H, d, J = 8.4 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.33 (1H, s), 7.47 (1H, d, J = 8.7 Hz).
[Reference Example 6]

3- (4-Isopropylphenyl) -3,4,6,7-tetramethyl-1-benzofuran-2 (3H) -one 3- (4-Isopropylphenyl) -4,6,7 synthesized in Reference Example 2 -Trimethyl-1-benzofuran-2 (3H) -one (2.10 g, 7.13 mmol) in DMF (30 mL) was added sodium hydride (60% liquid paraffin dispersion, 314 mg, 7.84 mmol) at 0 ° C. And stirred at room temperature for 30 minutes. Methyl iodide (1.11 g, 7.84 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to give 2.07 g of the title compound as an oil. (Yield 94%) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 1.94 (3H, s), 1.98 (3H, s), 2.25 (3H, s), 2.29 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 6.77 (1H, s), 7.09-7.22 (4H, m).
[Reference Example 7]

3- (4-Isopropylphenyl) -3,6,7-trimethyl-1-benzofuran-2 (3H) -one
In the same manner as in Reference Example 6, the title compound was synthesized using 3- (4-isopropylphenyl) -6,7-dimethyl-1-benzofuran-2 (3H) -one synthesized in Reference Example 3. Yield 59%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.8 Hz), 1.87 (3H, s), 2.28 (3H, s), 2.33 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 6.94 (1H, d, J = 7.8 Hz), 6.94 (1H, d, J = 7.8 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4 Hz).
[Reference Example 8]

2- (2-Hydroxy-1- (4-isopropylphenyl) ethyl) -3,5,6-trimethylphenol
Hydrogenation of a solution of 3- (4-isopropylphenyl) -4,6,7-trimethyl-1-benzofuran-2 (3H) -one (8.42 g, 28.6 mmol) synthesized in Reference Example 2 in THF (80 mL) Aluminum lithium (1.63 g, 42.9 mmol) was added at 0 ° C., and the mixture was heated to reflux for 1 hour. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 8.00 g (yield 94%) of the title compound. Melting point 101-102 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.13-2.35 (10H, m), 2.86 (1H, septet, J = 6.9 Hz), 4.24 (1H, dd, J = 10.8 Hz), 4.42 (1H, dd, J = 10.8, 5.1 Hz), 4.50 (1H, dd, J = 5.1, 2.7 Hz), 6.58 (1H, s), 7.15 (4H, s), 8.01 (1H , br s).
[Reference Example 9]

6- (2-Hydroxy-1- (4-isopropylphenyl) ethyl) -2,3-dimethylphenol 3- (4-isopropylphenyl) -6,7 synthesized in Reference Example 3 in the same manner as Reference Example 8. The title compound was synthesized using -dimethyl-1-benzofuran-2 (3H) -one. Yield 36%. Melting point 83-84 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7.2 Hz), 2.03 (1H, br s), 2.18 (3H, s), 2.25 (3H, s), 2.87 (1H, septet, J = 7.2 Hz), 4.18-4.39 (3H, m), 6.68 (1H, d, J = 7.8 Hz), 6.77 (1H, d, J = 7.8 Hz), 6.84 (1H, s), 7.14 (2H, d, J = 9.0 Hz), 7.18 (2H, d, J = 9.0 Hz).
[Reference Example 10]

2- (2-Hydroxy-1- (4-isopropylphenyl) ethyl) -3,5-dimethylphenol
In the same manner as in Reference Example 8, the title compound was synthesized using 3- (4-isopropylphenyl) -4,6-dimethyl-1-benzofuran-2 (3H) -one synthesized in Reference Example 4. Yield 93%. Melting point 101-102 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 2.19 (3H, s), 2.25 (3H, s), 2.27 (1H, br s), 2.86 (1H, septet, J = 6.9 Hz), 4.21 (1H, dd, J = 11.1, 2.7 Hz), 4.39 (1H, dd, J = 11.1, 5.1 Hz), 4.48 (1H, dd, J = 5.1, 2.7 Hz), 6.57 ( 1H, s), 6.62 (1H, s), 7.15 (4H, s), 8.14 (1H, br s).
[Reference Example 11]

4-Bromo-2- (2-hydroxy-1- (4-isopropylphenyl) ethyl) phenol 5-Bromo-3- (4-isopropylphenyl) -1 synthesized in Reference Example 5 in the same manner as Reference Example 8. The title compound was synthesized using -benzofuran-2 (3H) -one. Yield 44%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.9 Hz), 1.38 (1H, br s), 2.88 (1H, septet, J = 7.2 Hz), 4.18-4.37 (3H, m) , 6.76 (1H, d, J = 8.1 Hz), 7.08-7.25 (6H, m), 7.47 (1H, br s).
[Reference Example 12]

2- (2-Hydroxy-1- (4-isopropylphenyl) -1-methylethyl) -3,5,6-trimethylphenol 3- (4-Isopropyl) synthesized in Reference Example 6 in the same manner as Reference Example 8. The title compound was synthesized using (phenyl) -3,4,6,7-tetramethyl-1-benzofuran-2 (3H) -one. Yield 83%. Melting point 116-117 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.73 (6H, s), 2.20 (3H, s), 2.21 (3H, s), 2.56-2.64 (1H, m ), 2.88 (1H, septet, J = 6.9 Hz), 3.77 (1H, dd, J = 11.1, 3.6 Hz), 4.13-4.22 (1H, m), 6.49 (1H, s), 7.11 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz), 8.70 (1H, s).
[Reference Example 13]

3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran 2- (2-hydroxy-1- (4-isopropylphenyl) ethyl)-obtained in Reference Example 8 To a solution of 3,5,6-trimethylphenol (7.85 g, 26.3 mmol) and triphenylphosphine (7.58 g, 28.9 mmol) in THF (60 mL), diethyl azodicarboxylate (40% toluene solution, 12.6 g, 28.9 mmol) ) Was added under ice cooling and stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 10: 1) to give 5.70 g (yield 84%) of the title compound. Melting point 48-49 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.37-4.56 (2H, m), 4.79-4.88 (1H, m), 6.48 (1H, s), 7.06 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).
[Reference Example 14]

3- (4-Isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran
In the same manner as in Reference Example 13, the title compound was synthesized using 6- (2-hydroxy-1- (4-isopropylphenyl) ethyl) -2,3-dimethylphenol synthesized in Reference Example 9. Yield 80%. Melting point 50-51 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 2.18 (3H, s), 2.25 (3H, s), 2.88 (1H, septet, J = 6.9 Hz), 4.35- 4.42 (1H, m), 4.62 (1H, t, J = 8.7 Hz), 4.82-4.90 (1H, m), 6.67 (1H, d, J = 7.8 Hz), 6.75 (1H, d, J = 7.8 Hz) ), 7.13 (2H, d, J = 9.0 Hz), 7.17 (2H, d, J = 9.0 Hz).
[Reference Example 15]

3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran
In the same manner as in Reference Example 13, the title compound was synthesized using 2- (2-hydroxy-1- (4-isopropylphenyl) ethyl) -3,5-dimethylphenol synthesized in Reference Example 10. Yield 85%. Melting point 46-47 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 7.0 Hz), 1.92 (3H, s), 2.29 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 4.35- 4.53 (2H, m), 4.75-4.90 (1H, m), 6.47 (1H, s), 6.55 (1H, s), 7.05 (2H, d, J = 8.0 Hz), 7.13 (2H, d, J = 8.0 Hz).
[Reference Example 16]

5-bromo-3- (4-isopropylphenyl) -2,3-dihydro-1-benzofuran 4-bromo-2- (2-hydroxy-1- (s) synthesized in Reference Example 11 in the same manner as Reference Example 13. The title compound was synthesized using 4-isopropylphenyl) ethyl) phenol. Yield 62%. Melting point 90-91 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.8 Hz), 2.90 (1H, septet, J = 6.8 Hz), 4.37-4.47 (1H, m), 4.56-4.67 (1H, m ), 4.89 (1H, dd, J = 9.6, 8.8 Hz), 6.74 (1H, d, J = 8.4 Hz), 7.07-7.29 (6H, m).
[Reference Example 17]

3- (4-Isopropylphenyl) -3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran
In the same manner as in Reference Example 13, 2- (2-hydroxy-1- (4-isopropylphenyl) -1-methylethyl) -3,5,6-trimethylphenol synthesized in Reference Example 12 was used to give the title compound. Synthesized. Yield 95%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.74 (3H, s), 1.80 (3H, s), 2.15 (3H, s), 2.22 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.38 (1H, d, J = 8.4 Hz), 4.46 (1H, d, J = 8.4 Hz), 6.45 (1H, s), 7.13 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz).
[Reference Example 18]

5-Bromo-3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran 3- (4-isopropylphenyl) -4,6,7 synthesized in Reference Example 13 -Bromine (1.17 mL, 22.9 mmol) was added to a mixture of trimethyl-2,3-dihydro-1-benzofuran (6.10 g, 21.8 mmol) and sodium acetate (1.97 g, 24.0 mmol) in acetonitrile (30 mL) at room temperature. The mixture was stirred at the same temperature for 1 hour. Water was poured into the reaction mixture and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was crystallized from methanol to obtain 7.90 g (yield 99%) of the title compound. Melting point 86-87 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.04 (3H, s), 2.23 (3H, s), 2.38 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.41 (1H, dd, J = 8.4, 4.8 Hz), 4.54 (1H, dd, J = 9.0, 4.8 Hz), 4.81 (1H, t, J = 9.0 Hz), 7.01 (2H, d , J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).
[Reference Example 19]

5-Bromo-3- (4-isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran
In the same manner as in Reference Example 18, the title compound was synthesized using 3- (4-isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran synthesized in Reference Example 14. Yield 68%. Melting point 114-115 ° C. (methanol). ¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7.0 Hz), 2.23 (3H, s), 2.33 (3H, s), 2.89 (1H, septet, J = 7.0 Hz), 4.39 ( 1H, dd, J = 8.4, 7.8 Hz), 4.54-4.66 (1H, m), 4.86 (1H, dd, J = 9.2, 8.4 Hz), 7.03 (1H, s), 7.11 (2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz).
[Reference Example 20]

5-Bromo-3- (4-isopropylphenyl) -3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran 3- (synthesized in Reference Example 17 in the same manner as Reference Example 18. The title compound was synthesized using 4-isopropylphenyl) -3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran. Yield 98%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.74 (3H, s), 1.90 (3H, s), 2.23 (3H, s), 2.38 (3H, s), 2.88 (1H, septet, J = 6.9 Hz), 4.37 (1H, d, J = 8.7 Hz), 4.42 (1H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.4 Hz), 7.19 ( 2H, d, J = 8.4 Hz).
[Reference Example 21]

5-Bromo-3- (4-isopropylphenyl) -3,6,7-trimethyl-1-benzofuran-2 (3H) -one In the same manner as in Reference Example 18, 3- (4- The title compound was synthesized using (isopropylphenyl) -3,6,7-trimethyl-1-benzofuran-2 (3H) -one. Yield 73%. Melting point 116-117 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.86 (3H, s), 2.34 (3H, s), 2.41 (3H, s), 2.88 (1H, septet, J = 6.9 Hz), 7.15-7.25 (5H, m).
[Reference Example 22]

4-bromo-6- (2-hydroxy-1- (4-isopropylphenyl) -1-methylethyl) -2,3-dimethylphenol 5-bromo- synthesized in Reference Example 21 in the same manner as Reference Example 8. The title compound was synthesized using 3- (4-isopropylphenyl) -3,6,7-trimethyl-1-benzofuran-2 (3H) -one. Yield 83%. Melting point 110-111 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.9 Hz), 1.58 (3H, s), 2.15 (3H, s), 2.37 (3H, s), 2.89 (1H, septet, J = 6.9 Hz), 3.99 (1H, d, J = 11.7 Hz), 4.23 (1H, d, J = 11.7 Hz), 6.27 (1H, br s), 7.19 (4H, s), 7.40 (1H, s) , 1H Unconfirmed.
[Reference Example 23]

5-Bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran 3- (4-isopropylphenyl) -4,6-dimethyl-2 synthesized in Reference Example 15 , 3-Dihydro-1-benzofuran (5.62 g, 21.1 mmol) in acetonitrile (60 mL) was added N-bromosuccinimide (3.76 g, 21.1 mmol) at 0 ° C. and stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 10: 1) to obtain 5.95 g (yield 82%) of the title compound. Melting point 90-91 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.05 (3H, s), 2.39 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.41 ( 1H, dd, J = 8.4, 4.5 Hz), 4.52 (1H, dd, J = 9.0, 4.5 Hz), 4.78-4.86 (1H, m), 6.66 (1H, s), 7.01 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).
[Reference Example 24]

N-benzyl-3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine 5-bromo-3- (4-isopropyl) obtained in Reference Example 18 To a solution of phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran (920 mg, 2.56 mmol) and benzylamine (0.34 mL, 3.07 mmol) in toluene (10 mL), palladium acetate (6 mg, 0.03 mmol) and BINAP (48 mg, 0.09 mmol) were added at room temperature, and the mixture was stirred for 15 minutes under an argon stream. Sodium tert-butoxide (344 mg, 3.58 mmol) was added to the reaction solution at room temperature, and the mixture was heated to reflux for 18 hours under an argon stream. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 50: 1) to obtain 900 mg (yield 91%) of the title compound as an oil. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.87 (3H, s), 2.20 (3H, s), 2.27 (3H, s), 2.67-3.02 (2H, m ), 3.91 (2H, s), 4.38 (1H, dd, J = 8.4, 4.8 Hz), 4.52 (1H, dd, J = 9.0, 4.8 Hz), 4.80 (1H, t, J = 9.0 Hz), 7.03 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.20-7.42 (5H, m).
[Reference Example 25]

N-benzyl-3- (4-isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine
In the same manner as in Reference Example 24, the title compound was synthesized using 5-bromo-3- (4-isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran synthesized in Reference Example 19. . Yield 85%. Melting point 108-109 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.9 Hz), 2.08 (3H, s), 2.22 (3H, s), 2.88 (1H, septet, J = 7.0 Hz), 3.42 ( 1H, br s), 4.18 (2H, s), 4.28 (1H, t, J = 7.5 Hz), 4.55-4.64 (1H, m), 4.79 (1H, t, J = 9.0 Hz), 6.30 (1H, s), 7.11 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz), 7.21-7.37 (5H, m).
[Reference Example 26]

N-benzyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
In the same manner as in Reference Example 24, the title compound was synthesized using 5-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran synthesized in Reference Example 23. . Yield 99%. Melting point 82-83 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.27 (3H, s), 2.67-3.02 (2H, m), 3.93 (2H, s ), 4.38 (1H, dd, J = 8.4, 4.5 Hz), 4.49 (1H, dd, J = 9.0, 4.5 Hz), 4.75-4.83 (1H, m), 6.59 (1H, s), 7.02 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.19-7.39 (5H, m).
[Reference Example 27]

N-benzyl-3- (4-isopropylphenyl) -2,3-dihydro-1-benzofuran-5-amine 5-bromo-3- (4-isopropyl) synthesized in Reference Example 16 in the same manner as Reference Example 24 The title compound was synthesized using (phenyl) -2,3-dihydro-1-benzofuran. Yield 89%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 6.9 Hz), 2.88 (1H, septet, J = 6.9 Hz), 3.42 (1H, br s), 4.20 (2H, s), 4.31 (1H, dd, J = 8.7, 7.8 Hz), 4.51-4.59 (1H, m), 4.80 (1H, dd, J = 9.0, 8.7 Hz), 6.38 (1H, d, J = 2.4 Hz), 6.46 ( 1H, dd, J = 8.1, 2.4 Hz), 6.71 (1H, d, J = 8.1 Hz), 7.08-7.37 (9H, m).
[Reference Example 28]

N-benzyl-3- (4-isopropylphenyl) -3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine Synthesized in Reference Example 20 in the same manner as Reference Example 24 The title compound was synthesized using 5-bromo-3- (4-isopropylphenyl) -3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran. Yield 25%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.73 (3H, s), 1.74 (3H, s), 2.20 (3H, s), 2.27 (3H, s), 2.78-3.10 (2H, m), 3.88 (1H, d, J = 13.2 Hz), 3.93 (1H, d, J = 13.2 Hz), 4.35 (1H, d, J = 8.4 Hz), 4.39 (1H, d , J = 8.4 Hz), 7.10-7.38 (9H, m).
[Reference Example 29]

N-benzyl-3- (4-isopropylphenyl) -3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine 4-bromo-6- (2-hydroxy) obtained in Reference Example 22 In a solution of -1- (4-isopropylphenyl) -1-methylethyl) -2,3-dimethylphenol (830 mg, 2.21 mmol) and triphenylphosphine (638 mg, 2.43 mmol) in THF (60 mL), azo Diethyl dicarboxylate (40% toluene solution, 1.06 g, 2.43 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 10: 1), and then oily 5-bromo-3- (4-isopropylphenyl) -3,6,7- 660 mg of trimethyl-2,3-dihydro-1-benzofuran was obtained. To a solution of this compound (660 mg, 1.84 mmol) and benzylamine (0.24 mL, 2.21 mmol) in toluene (10 mL) was added palladium acetate (4 mg, 0.02 mmol) and BINAP (34 mg, 0.6 mmol) at room temperature. The mixture was added and stirred for 15 minutes under an argon stream. Sodium tert-butoxide (248 mg, 2.58 mmol) was added to the reaction mixture at room temperature, and the mixture was heated to reflux for 18 hours under an argon stream. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 50: 1) to obtain 660 mg (yield 77%) of the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 7.0 Hz), 1.69 (3H, s), 2.09 (3H, s), 2.22 (3H, s), 2.87 (1H, septet, J = 7.0 Hz), 3.47 (1H, br s), 4.23 (2H, s), 4.35 (1H, d, J = 8.4 Hz), 4.48 (1H, d, J = 8.4 Hz), 6.32 (1H, s) , 7.07-7.42 (9H, m).
[Reference Example 30]

3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-3- (4-isopropylphenyl) -4 obtained in Reference Example 24 , 6,7-Trimethyl-2,3-dihydro-1-benzofuran-5-amine (900 mg, 2.33 mmol), 10% -palladium carbon (50% water content, 90 mg) Ammonium formate (294 mg, 4.66 mmol) Of ethanol (10 mL) was heated to reflux for 2 hours. The solid was removed and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was crystallized from ethyl acetate-hexane to obtain 510 mg (yield 74%) of the title compound. Melting point 171-173 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.84 (3H, s), 2.11 (3H, s), 2.20 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.26 (2H, br s), 4.30-4.41 (1H, m), 4.47-4.60 (1H, m), 4.70-4.82 (1H, m), 7.05 (2H, d, J = 8.1 Hz ), 7.12 (2H, d, J = 8.1 Hz).
[Reference Example 31]

3- (4-Isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine
In the same manner as in Reference Example 30, using N-benzyl-3- (4-isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine synthesized in Reference Example 25, the title The compound was synthesized. Yield 88%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 2.00 (2H, br s), 2.08 (3H, s), 2.20 (3H, s), 2.88 (1H, septet, J = 6.9 Hz), 4.31 (1H, t, J = 7.8 Hz), 4.56 (1H, t, J = 7.8 Hz), 4.75-4.83 (1H, m), 6.29 (1H, s), 7.14 (2H, d, J = 9.0 Hz), 7.17 (2H, d, J = 9.0 Hz).
[Reference Example 32]

3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
In the same manner as in Reference Example 30, using N-benzyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine synthesized in Reference Example 26, the title The compound was synthesized. Yield 72%. Melting point 81-82 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.18 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.07 ( 2H, br s), 4.35 (1H, dd, J = 8.4, 4.5 Hz), 4.49 (1H, dd, J = 9.0, 4.5 Hz), 4.71-4.80 (1H, m), 6.54 (1H, s), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).
[Reference Example 33]

3- (4-Isopropylphenyl) -2,3-dihydro-1-benzofuran-5-amine N-benzyl-3- (4-isopropylphenyl) -2 synthesized in Reference Example 27 in the same manner as Reference Example 30 , 3-Dihydro-1-benzofuran-5-amine was used to synthesize the title compound. Yield 77%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 2.88 (1H, septet, J = 6.9 Hz), 3.32 (2H, br s), 4.32 (1H, dd, J = 8.7, 7.5 Hz), 4.49-4.57 (1H, m), 4.80 (1H, dd, J = 9.0, 8.7 Hz), 6.38 (1H, d, J = 2.4 Hz), 6.49 (1H, dd, J = 8.1 , 2.4 Hz), 6.67 (1H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.4 Hz).
[Reference Example 34]

3- (4-Isopropylphenyl) -3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl synthesized in Reference Example 28 in the same manner as Reference Example 30 The title compound was synthesized using -3- (4-isopropylphenyl) -3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 79%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.69 (3H, s), 1.77 (3H, s), 2.15 (3H, s), 2.20 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.10 (2H, br s), 4.30 (1H, d, J = 8.4 Hz), 4.34 (1H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz).
[Reference Example 35]

3- (4-Isopropylphenyl) -3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-3-synthesized in Reference Example 29 in the same manner as Reference Example 30 The title compound was synthesized using (4-isopropylphenyl) -3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 71%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.69 (3H, s), 2.09 (3H, s), 2.20 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.30 (2H, br s), 4.35 (1H, d, J = 8.7 Hz), 4.50 (1H, d, J = 8.7 Hz), 6.29 (1H, s), 7.14 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz).
[Reference Example 36]

To a solution of 2- (2,3-dimethylphenoxy) -2-methylpropionic acid 2,3-dimethylphenol (25.0 g, 205 mmol) in dimethyl sulfoxide (200 mL) was added ethyl 2-bromoisobutyrate (60 mL, 409 mmol). ) And potassium carbonate (56.5 g, 409 mmol) were added at room temperature and stirred for 36 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude oily ethyl 2- (2,3-dimethylphenoxy) -2-methylpropionate. It was. To a mixed solution of this compound in THF (160 mL) and methanol (40 mL), 12N aqueous sodium hydroxide solution (20 mL, 240 mmol) was added at room temperature, stirred for 12 hours, and concentrated under reduced pressure. Water and hydrochloric acid were added to the reaction solution to make the aqueous layer acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized from ethyl acetate-hexane to obtain 21.3 g (yield 50%) of the title compound. Melting point 71-73 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.60 (6H, s), 2.16 (3H, s), 2.27 (3H, s), 6.72 (1H, d, J = 7.8 Hz), 6.88 (1H, d, J = 7.5 Hz), 7.00 (1H, 7, J = 7.8 Hz), 1H not confirmed.
[Reference Example 37]

2- (3,5-Dimethylphenoxy) -2-methylpropionic acid The title compound was synthesized in the same manner as in Reference Example 36 using 3,5-dimethylphenol. Yield 96%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.59 (6H, s), 2.27 (6H, s), 6.56 (1H, s), 6.72 (1H, s).
[Reference Example 38]

2- (2,5-dimethylphenoxy) -2-methylpropionic acid The title compound was synthesized in the same manner as in Reference Example 36 using 2,5-dimethylphenol. Yield 57%. Melting point 107-109 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.62 (6H, s), 2.20 (3H, s), 2.27 (3H, s), 6.64 (1H, s), 6.77 (1H, d, J = 7.5 Hz), 7.05 (1H, d, J = 7.5 Hz), 9.50 (1H, br s).
[Reference Example 39]

2- (2,3,5-Trimethylphenoxy) -2-methylpropionic acid In the same manner as in Reference Example 36, 2,3,5-trimethylphenol was used to synthesize the title compound. Yield 65%. Melting point 91-94 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.59 (6H, s), 2.12 (3H, s), 2.22 (3H, s), 2.23 (3H, s), 6.53 (1H, s), 6.71 (1H, s ), 1H unconfirmed.
[Reference Example 40]

2- (3,4,5-Trimethylphenoxy) -2-methylpropionic acid In the same manner as in Reference Example 36, the title compound was synthesized using 3,4,5-trimethylphenol. Yield 57%. Melting point 77-78 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.56 (6H, s), 2.11 (3H, s), 2.24 (6H, s), 6.61 (2H, s), 1H Not confirmed.
[Reference Example 41]

2,2,6,7-tetramethyl-1-benzofuran-3 (2H) -one 2- (2,3-dimethylphenoxy) -2-methylpropionic acid (21.0 g, 101 mmol) obtained in Reference Example 36 ) In THF (200 mL) was added DMF (0.1 mL), and oxalyl chloride (10.6 mL, 121 mmol) was added dropwise under ice cooling. The reaction mixture was warmed to room temperature, stirred for 1 hour, and concentrated under reduced pressure. The residue was dissolved in methylene chloride (200 mL), aluminum chloride (32.3 g, 242 mmol) was added at −70 ° C. or lower, and the temperature was raised to room temperature over 12 hours. The reaction solution was added to water under ice cooling, and then methylene chloride was distilled off under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized from hexane to obtain 17.5 g (yield 71%) of the title compound. Melting point 79-81 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.46 (6H, s), 2.21 (3H, s), 2.35 (3H, s), 6.88 (1H, d, J = 8.0 Hz), 7.40 (1H, d, J = 8.0 Hz).
[Reference Example 42]

2,2,4,6-tetramethyl-1-benzofuran-3 (2H) -one 2- (3,5-dimethylphenoxy) -2-methylpropion obtained in Reference Example 37 in the same manner as Reference Example 41 The title compound was synthesized using acid. Yield 92%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, s), 2.37 (3H, s), 2.54 (3H, s), 6.62 (1H, s), 6.66 (1H, s).
[Reference Example 43]

2,2,4,7-Tetramethyl-1-benzofuran-3 (2H) -one 2- (2,5-dimethylphenoxy) -2-methylpropion obtained in Reference Example 38 in the same manner as Reference Example 41 The title compound was synthesized using acid. Yield 97%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (6H, s), 2.25 (3H, s), 2.55 (3H, s), 6.70 (1H, d, J = 7.5 Hz), 7.26 (1H, d, J = 7.5 Hz).
[Reference Example 44]

2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 41, 2- (2,3,5) obtained in Reference Example 39 was used. The title compound was synthesized using -trimethylphenoxy) -2-methylpropionic acid. Yield 33%. Melting point 99-101 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (6H, s), 2.16 (3H, s), 2.30 (3H, s), 2.52 (3H, s), 6.63 (1H, s).
[Reference Example 45]

2,2,4,5,6-pentamethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 41, 2- (3,4,5-trimethylphenoxy) -2 obtained in Reference Example 40 -The title compound was synthesized using methylpropionic acid. Yield 90%. Melting point 77-78 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (6H, s), 2.14 (3H, s), 2.34 (3H, s), 2.57 (3H, s), 6.73 (1H, s).
[Reference Example 46]

2,2,6,7-Tetramethyl-5-nitro-1-benzofuran-3 (2H) -one 2,2,6,7-tetramethyl-1-benzofuran-3 (2H obtained in Reference Example 41) Ammonium nitrate (2.10 g, 32.8 mmol) was added to a solution of) -one (5.20 g, 27.3 mmol) in trifluoroacetic anhydride (50 mL) and chloroform (5 mL) at 0 ° C. and stirred at the same temperature for 2 hours. Concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 50: 1) to obtain 5.40 g (yield 84%) of the title compound. Melting point 131-132 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.50 (6H, s), 2.32 (3H, s), 2.52 (3H, s), 8.08 (1H, s).
[Reference Example 47]

2,2,4,7-Tetramethyl-5-nitro-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 46, 2,2,4,7-tetramethyl- obtained in Reference Example 43 was obtained. The title compound was synthesized using 1-benzofuran-3 (2H) -one. Yield 46%. Melting point 124-126 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.50 (6H, s), 2.32 (3H, s), 2.87 (3H, s), 8.11 (1H, s).
[Reference Example 48]

5-Bromo-2,2,4,6-tetramethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 18, 2,2,4,6-tetramethyl- obtained in Reference Example 42 was used. The title compound was synthesized using 1-benzofuran-3 (2H) -one. Yield 73%. Melting point 63-64 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (6H, s), 2.48 (3H, s), 2.68 (3H, s), 6.83 (1H, s).
[Reference Example 49]

5-Bromo-2,2,4,6,7-pentamethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 18, 2,2,4,6,7- The title compound was synthesized using pentamethyl-2,3-dihydro-1-benzofuran-3 (2H) -one. Yield 73%. Melting point 92-93 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (6H, s), 2.26 (3H, s), 2.47 (3H, s), 2.66 (3H, s).
[Reference Example 50]

7-Bromo-2,2,4,5,6-pentamethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 18, 2,2,4,5,6- The title compound was synthesized using pentamethyl-1-benzofuran-3 (2H) -one. Yield 79%. Melting point 145-146 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.49 (6H, s), 2.23 (3H, s), 2.49 (3H, s), 2.55 (3H, s).
[Reference Example 51]

5- (benzylamino) -2,2,4,6-tetramethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 24, 5-bromo-2,2,2 obtained in Reference Example 48 was used. The title compound was synthesized using 4,6-tetramethyl-2,3-dihydro-1-benzofuran-3 (2H) -one. Yield 75%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, s), 2.35 (3H, s), 2.54 (3H, s), 3.02 (1H, br s), 3.99 (2H, s), 6.73 (1H, s), 7.24-7.42 (5H, m).
[Reference Example 52]

5- (benzylamino) -2,2,4,6,7-pentamethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 24, 5-bromo-2,2 obtained in Reference Example 49 , 4,6,7-pentamethyl-1-benzofuran-3 (2H) -one was used to synthesize the title compound. Yield 88%. Melting point 98-99 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, s), 2.21 (3H, s), 2.35 (3H, s), 2.50 (3H, s), 3.04 (1H, br s), 3.94 (2H, s), 7.26-7.41 (5H, m).
[Reference Example 53]

7- (Benzylamino) -2,2,4,5,6-pentamethyl-1-benzofuran-3 (2H) -one 7-bromo-2,2 obtained in Reference Example 50 in the same manner as Reference Example 24. , 4,5,6-pentamethyl-1-benzofuran-3 (2H) -one was used to synthesize the title compound. Yield 72%. Melting point 108-109 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.38 (6H, s), 2.14 (3H, s), 2.28 (3H, s), 2.51 (3H, s), 3.61 (1H, br s), 4.27 (2H, s), 7.19-7.37 (5H, m).
[Reference Example 54]

5-Amino-2,2,6,7-tetramethyl-1-benzofuran-3 (2H) -one 2,2,6,7-tetramethyl-5-nitro-1-benzofuran obtained in Reference Example 46 -3 (2H) -one (5.0 g, 21.3 mmol), 10% -palladium carbon (containing 50% water, 500 mg), ammonium formate (7.06 g, 85.0 mmol) in methanol (100 mL) and heating the mixture to reflux for 2 hours did. The solid was removed and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized from ethyl acetate-hexane to obtain 4.0 g (yield 92%) of the title compound. Melting point 149-150 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, s), 2.19 (3H, s), 2.24 (3H, s), 3.50 (2H, br s), 6.78 (1H, s).
[Reference Example 55]

5-Amino-2,2,4,6-tetramethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 30, 5- (benzylamino) -2,2, obtained in Reference Example 51 The title compound was synthesized using 4,6-tetramethyl-1-benzofuran-3 (2H) -one. Yield 95%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, s), 2.19 (3H, s), 2.24 (3H, s), 3.50 (2H, br s), 6.78 (1H, s).
[Reference Example 56]

5-Amino-2,2,4,7-tetramethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 54, 2,2,4,7-tetramethyl-obtained in Reference Example 47 was obtained. The title compound was synthesized using 5-nitro-1-benzofuran-3 (2H) -one. Yield 97%. Melting point 124-126 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.42 (6H, s), 2.21 (3H, s), 2.40 (3H, s), 3.40 (2H, br s), 6.82 (1H, s).
[Reference Example 57]

5-Amino-2,2,4,6,7-pentamethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 30, 5- (benzylamino) -2,2 obtained in Reference Example 52 , 4,6,7-pentamethyl-1-benzofuran-3 (2H) -one was used to synthesize the title compound. Yield 88%. Melting point 92-93 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.41 (6H, s), 2.19 (3H, s), 2.21 (3H, s), 2.45 (3H, s), 3.44 (2H, br s).
[Reference Example 58]

7-amino-2,2,4,5,6-pentamethyl-1-benzofuran-3 (2H) -one 7- (benzylamino) -2,2 obtained in Reference Example 53 in the same manner as Reference Example 30. , 4,5,6-pentamethyl-1-benzofuran-3 (2H) -one was used to synthesize the title compound. Yield quantitative. Melting point 141-142 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (6H, s), 2.16 (3H, s), 2.19 (3H, s), 2.50 (3H, s), 3.59 (2H, br s).
[Reference Example 59]

(2,2,6,7-Tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl 5-amino-2,2,6 obtained in Reference Example 54 , 7-tetramethyl-1-benzofuran-3 (2H) -one (3.89 g, 19.5 mmol) and ditert-butyl dicarbonate (6.73 mL, 29.3 mmol) in THF (50 mL) were heated to reflux for 16 hours. . Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 4.80 g (yield 81%) of the title compound. Melting point 154-155 [deg.] C.
¹ H-NMR (CDCl ₃ ) δ: 1.44 (6H, s), 1.50 (9H, s), 2.24 (3H, s), 2.25 (3H, s), 6.12 (1H, br s), 7.58 (1H, s).
[Reference Example 60]

Tert-Butyl (2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamate 5 The title compound was synthesized using -amino-2,2,4,6-tetramethyl-1-benzofuran-3 (2H) -one. Yield 71%. Melting point 156-157 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.44 (6H, s), 1.50 (9H, s), 2.24 (3H, s), 2.25 (3H, s), 6.12 (1H, br s), 7.58 (1H, s).
[Reference Example 61]

Tert-butyl (2,2,4,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamate 5 The title compound was synthesized using -amino-2,2,4,7-tetramethyl-1-benzofuran-3 (2H) -one. Yield 96%. Melting point 144-145 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, s), 1.51 (9H, s), 2.25 (3H, s), 2.47 (3H, s), 6.11 (1H, br s), 7.66 (1H, s).
[Reference Example 62]

Tert-butyl (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamate obtained in the same manner as in Reference Example 59 The title compound was synthesized using 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3 (2H) -one. Yield 90%. Melting point 105-106 ° C. (ethyl acetate-hexane). ¹ H-NMR (CDCl ₃ ) δ: 1.42 (6H, s), 1.51 (9H, s), 2.19 (3H, s), 2.25 (3H, s), 2.49 (3H, s), 5.81 (1H, br s).
[Reference Example 63]

3,3-Dimethyl-N- (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide 5-amino- obtained in Reference Example 57 A solution of 2,2,4,6,7-pentamethyl-1-benzofuran-3 (2H) -one (3.00 g, 13.7 mmol) and tert-butylacetyl chloride (2.03 g, 15.1 mmol) in methylene chloride (30 mL) To the mixture was added triethylamine (2.3 mL, 16.4 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 2.34 g of the desired product (yield 54%). Melting point 155-156 [deg.] C.
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.43 (6H, s), 2.19 (3H, s), 2.22 (3H, s), 2.32 (2H, s), 2.47 (3H, s ), 6.62 (1H, br s).
[Reference Example 64]

3,3-Dimethyl-N- (2,2,4,5,6-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-7-yl) butanamide In the same manner as in Reference Example 63, Reference Example The title compound was synthesized using 7-amino-2,2,4,5,6-pentamethyl-1-benzofuran-3 (2H) -one obtained in 58. Yield 76%. Melting point 158-159 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.40 (6H, s), 2.16 (3H, s), 2.24 (3H, s), 2.32 (2H, s), 2.54 (3H, s ), 6.78 (1H, br s).
[Reference Example 65]

3,3-Dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide Similar to Reference Example 63, Reference Example 54 The title compound was synthesized using the obtained 5-amino-2,2,6,7-tetramethyl-1-benzofuran-3 (2H) -one. Yield 88%. Melting point 175-176 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.44 (6H, s), 2.24-2.26 (8H, m), 6.84 (1H, br s), 7.50 (1H, s).
[Reference Example 66]

(7-Bromo-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl
(2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl (4.86 g, 15.9 mmol) acetonitrile obtained in Reference Example 60 (70 mL) To the solution was added N-bromosuccinimide (5.67 g, 31.8 mmol), and the mixture was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, added to water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 3: 7) and recrystallized from ethyl acetate-hexane to give 4.40 g (yield 72%) of the title compound. Melting point 131-132 ° C.
¹ H-NMR (CDCl3) δ: 1.33-1.55 (15H, m), 2.46 (3H, s), 2.49 (3H, s), 5.87 (1H, br s).
[Reference Example 67]

3-Bromo-2,4,5-trimethylbenzaldehyde To a solution of 2,4,5-trimethylbenzaldehyde (21.3 g, 144 mmol) in methylene chloride (200 mL), aluminum chloride (48.0 g, 360 mmol) was cooled with ice. In addition, the temperature was raised to room temperature. Bromine (7.80 mL, 151 mmol) was added dropwise to the reaction solution at room temperature, and after stirring for 4 hours, the reaction solution was added to water, and methylene chloride was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, 5% aqueous sodium sulfite solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 32.5 g (yield 100%) of the title compound. Melting point 108-110 ° C.
¹ H-NMR (CDCl ₃ ) δ: 2.38 (3H, s), 2.46 (3H, s), 2.73 (3H, s), 7.54 (1H, s), 10.21 (1H, s).
[Reference Example 68]

3-Bromo-2,4,5-trimethylphenol To a solution of 3-bromo-2,4,5-trimethylbenzaldehyde (32.0 g, 141 mmol) obtained in Reference Example 67 in THF (100 mL), methanol (200 mL) ) Was added, and p-toluenesulfonic acid monohydrate (5.40 g, 28.4 mmol) was added under ice cooling. To the reaction solution, hydrogen peroxide (30%, 24.0 g, 212 mmol) was added dropwise at 10 ° C. or lower, and the mixture was warmed to room temperature and stirred for 12 hours. The reaction solution was further stirred at 50 ° C. for 36 hours, an aqueous sodium sulfite solution was added, and methanol and THF were distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 10: 1). The obtained crystals were washed with hexane to give the title compound 9.1 g (yield 30). %). Melting point 86-88 ° C.
¹ H-NMR (CDCl ₃ ) δ: 2.25 (3H, s), 2.30 (3H, s), 2.32 (3H, s), 4.63 (1H, s), 6.56 (1H, s).
[Reference Example 69]

2- (3-Bromo-2,4,5-trimethylphenoxy) -2-methylpropionic acid In the same manner as in Reference Example 36, 3-bromo-2,4,5-trimethylphenol obtained in Reference Example 68 was used. The title compound was synthesized. Yield 40%. Mp 151-153 ° C. (Hexane)
¹ H-NMR (CDCl ₃ ) δ: 1.59 (6H, s), 2.26 (3H, s), 2.33 (6H, s), 6.67 (1H, s), 9.60 (1H, br s).
[Reference Example 70]

6-Bromo-2,2,4,5,7-pentamethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 41, 2- (3-bromo-2,4 obtained in Reference Example 69 was obtained. , 5-trimethylphenoxy) -2-methylpropionic acid was used to synthesize the title compound. Yield 97%. Melting point 125-127 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.44 (6H, s), 2.34 (3H, s), 2.37 (3H, s), 2.60 (3H, s).
[Reference Example 71]

6- (Benzylamino) -2,2,4,5,7-pentamethyl-1-benzofuran-3 (2H) -one 6-bromo-2,2 obtained in Reference Example 70 in the same manner as Reference Example 24. , 4,5,7-pentamethyl-1-benzofuran-3 (2H) -one was used to synthesize the title compound. Yield 95%. Melting point 79-83 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (6H, s), 2.11 (3H, s), 2.16 (3H, s), 2.55 (3H, s), 3.86 (1H, br s), 4.34 (2H, s), 7.26-7.42 (5H, m).
[Reference Example 72]

6-Amino-2,2,4,5,7-pentamethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 30, 6- (benzylamino) -2,2 obtained in Reference Example 71 , 4,5,7-pentamethyl-1-benzofuran-3 (2H) -one was used to synthesize the title compound. Yield 87%. Melting point 150-151 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.41 (6H, s), 2.04 (3H, s), 2.06 (3H, s), 2.55 (3H, s), 4.27 (2H, br s).
[Reference Example 73]

(2,2,4,5,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl) formamide 6-amino-2,2,4,5 obtained in Reference Example 72 , 7-pentamethyl-1-benzofuran-3 (2H) -one (700 mg, 3.19 mmol) in formic acid (5 mL) was heated to reflux for 5 hours. The solvent was evaporated under reduced pressure, water and ethyl acetate were added to the residue, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 640 mg (yield 81%) of the title compound. Melting point: 191-192 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.40-1.52 (6H, m), 2.00-2.28 (3H, m), 2.56, 2.57 (1.5H x2, s), 2.60 (3H, s), 7.07 (0.5H , br s), 7.20-7.35 (0.5H, m), 8.18 (0.5H, d, J = 11.6 Hz), 8.46 (0.5H, d, J = 1.4 Hz).
[Reference Example 74]

3- (4-Isopropylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride 4-bromocumene (6.25 g, 31.4 mmol) in THF (50 mL A solution of n-butyllithium in hexane (1.60 M, 19.6 mL, 31.4 mmol) was added dropwise to the solution at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. Further, tert-butyl (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamate obtained in Reference Example 59 was added to the reaction solution at the same temperature. A solution of (500 mg, 2.02 mmol) in THF (5 mL) was added dropwise, the reaction mixture was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 10: 1) (3-hydroxy-3- (4-isopropylphenyl) -2,2,6,7-tetramethyl-2,3- Dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl was obtained. Triethylsilane (1.0 mL, 6.4 mmol) was added to a mixture of trifluoroacetic acid (10 mL) of this compound under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, the aqueous layer was made alkaline, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 10: 1) to obtain a free salt of the title compound. Then, the hydrochloride was converted to 4N hydrochloric acid / methanol solution to obtain 2.03 g (yield 37%) of the title compound. MP 166-168 ° C (decomposition) (methanol).
¹ H-NMR (DMSO-d ₆ ) δ: 0.90 (3H, s), 1.19 (6H, d, J = 6.8 Hz), 1.51 (3H, s), 2.14 (3H, s), 2.21 (3H, s ), 2.87 (1H, septet, J = 6.8 Hz), 4.39 (1H, s), 6.96 (1H, s), 6.97 (2H, d, J = 8.0 Hz), 7.20 (2H, d, J = 8.0 Hz) ), 10.1 (2H, br s), 1H unconfirmed.
[Reference Example 75]

3- (4-Isopropylphenyl) -2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride Like Reference Example 74, obtained in Reference Example 61 ( 2,2,4,7-Tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamic acid The title compound was synthesized using tert-butyl and 4-bromocumene. Yield 78%. MP 239-240 ° C (decomposition) (methanol).
¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (3H, s), 1.17 (6H, d, J = 6.9 Hz), 1.44 (3H, s), 1.85 (3H, s), 2.15 (3H, s ), 2.84 (1H, septet, J = 6.9 Hz), 4.29 (1H, s), 6.58-7.27 (5H, m), 9.98 (2H, br s), 1H Not confirmed.
[Reference Example 76]

3- (4-tert-Butylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride In the same manner as in Reference Example 74, Using the obtained (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl and 4-bromo-tert-butylbenzene, The title compound was synthesized. Yield 23%. Melting point 265-267 ° C. (decomposition) (methanol).
¹ H-NMR (DMSO-d ₆ ) δ: 0.96 (3H, s), 1.25 (9H, s), 1.43 (3H, s), 1.90 (3H, s), 2.12 (3H, s), 2.24 (3H , s), 4.26 (1H, s), 6.60-7.40 (4H, m), 9.46 (2H, br s), 1H Not confirmed.
[Reference Example 77]

3- (4-Isopropylphenyl) -2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-amine 4-bromocumene (2.01 g, 10.1 mmol) in THF (20 mL) To the solution, a solution of n-butyllithium in hexane (1.60 M, 6.25 mL, 10.0 mmol) was added dropwise at −78 ° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. Furthermore, (2,2,4,5,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl) formamide (500 mg) obtained in Reference Example 73 in the reaction solution at the same temperature. , 2.02 mmol) in THF (5 mL) was added dropwise, the reaction mixture was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) (3-hydroxy-3- (4-isopropylphenyl) -2,2,4,5,7-pentamethyl-2,3 -Dihydro-1-benzofuran-6-yl) formamide was obtained. Triethylsilane (0.5 mL, 3.2 mmol) was added to a mixture of trifluoroacetic acid (5 mL) of this compound under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, the aqueous layer was made alkaline, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Concentrated hydrochloric acid was added to a solution of the obtained residue in methanol (20 mL), and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and the residue was neutralized with 12N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 440 mg (yield 67%) of the title compound. Melting point 120-121 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.21 (6H, d, J = 7.0 Hz), 1.48 (3H, s), 1.84 (3H, s), 2.01 (3H, s), 2.10 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.58 (2H, br s), 4.07 (1H, s), 6.60-7.12 (4H, m).
[Reference Example 78]

3- (4-Isopropylphenyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amine
In the same manner as in Reference Example 74, tert-butyl (2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamate obtained in Reference Example 60 was obtained. The title compound was synthesized using 4-bromocumene. Yield 89%. Melting point 98-100 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.21 (6H, d, J = 7.2 Hz), 1.48 (3H, s), 1.79 (3H, s), 2.18 (3H, s), 2.85 (1H, septet, J = 7.2 Hz), 4.06 (1H, s), 4.60 (2H, br s), 6.49 (1H, s), 6.60-7.10 (4H, m).
[Reference Example 79]

3-Benzyl-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-amine Obtained in Reference Example 73 under an argon atmosphere (2,2,4,5,7- A solution of pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-6-yl) formamide (600 mg, 2.43 mmol) in THF (5 mL) was added to benzylmagnesium chloride (2.0 M THF solution, 10.0 mL, 20.0 mmol). ) In THF (20 mL) at 0 ° C. and stirred at room temperature for 2 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with water and 1N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to give (3-benzyl-3-hydroxy-2,2,4,5,7-pentamethyl-2,3-dihydro-1 -Benzofuran-6-yl) formamide was obtained. Triethylsilane (0.5 mL, 3.2 mmol) was added to a mixture of trifluoroacetic acid (5 mL) of this compound under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, the aqueous layer was made alkaline, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Concentrated hydrochloric acid (10 mL) was added to a methanol (20 mL) solution of the obtained residue, and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and the residue was neutralized with 12N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 440 mg (yield 62%) of the title compound. Melting point 75-76 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, s), 1.40 (3H, s), 1.79 (3H, s), 1.98 (3H, s), 2.05 (3H, s), 2.74 (1H, dd , J = 14.4, 5.7 Hz), 2.88 (1H, dd, J = 14.4, 8.4 Hz), 3.25 (1H, dd, J = 14.4, 8.4 Hz), 3.53 (2H, br s), 7.10-7.28 (5H , m).
[Reference Example 80]

Of 5-amino-2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-3-ol 4-bromotoluene (2.73 g, 16.0 mmol) To a THF (30 mL) solution, a solution of n-butyllithium in hexane (1.60 M, 10.0 mL, 16.0 mmol) was added dropwise at −78 ° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. Furthermore, 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3 (2H) -one (1.0 g, 4.56 mmol) of THF (1.0 g) obtained in Reference Example 57 was added to the reaction solution at the same temperature. 10 mL) The solution was added dropwise, the reaction mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 10: 1) to obtain 921 mg (yield 65%) of the title compound. Melting point 165-166 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, s), 1.50 (3H, s), 1.83 (3H, s), 2.11 (1H, s), 2.14 (3H, s), 2.18 (3H, s ), 2.34 (3H, s), 3.31 (2H, br s), 6.80-7.70 (4H, m).
[Reference Example 81]

5-Amino-2,2,4,6,7-pentamethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-3-ol In a similar manner to Reference Example 80, obtained in Reference Example 57. The title compound was synthesized using 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3 (2H) -one and 2-bromonaphthalene. Yield 66%. Melting point 121-122 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, s), 1.56 (3H, s), 1.79 (3H, s), 2.16 (3H, s), 2.22 (3H, s), 2.42 (1H, s ), 3.32 (2H, br s), 7.07-7.21 (1H, m), 7.37-8.00 (5H, m), 8.16-8.31 (1H, m).
[Reference Example 82]

1- (4-Isopropylphenyl) -1- (2-methoxyphenyl) -2-methylpropan-1-ol 2-bromoanisole (5.0 g, 26.7 mmol) in THF (50 mL) at −78 ° C. n-Butyllithium (1.6M, 18 mL, 29 mmol) was added and stirred at the same temperature for 30 minutes. 1- (4-Isopropylphenyl) -2-methylpropan-1-one (5.70 g, 30.0 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 20: 1) to obtain 3.4 g (yield 43%) of the title compound. Melting point 85-86 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 0.76 (3H, d, J = 6.9 Hz), 0.94 (3H, d, J = 6.9 Hz), 1.20 (6H, d, J = 6.9 Hz), 2.68 (1H, septet, J = 6.9 Hz), 2.83 (1H, septet, J = 6.9 Hz), 3.59 (3H, s), 4.91 (1H, s), 6.82 (1H, d, J = 8.1 Hz), 6.99 (1H, dt, J = 7.5, 1.5 Hz), 7.06 (2H, d, J = 7.5 Hz), 7.13-7.25 (3H, m), 7.52 (1H, dd, J = 7.5, 1.5 Hz).
[Reference Example 83]

3- (4-Isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran 1- (4-isopropylphenyl) -1- (2-methoxyphenyl) -2 obtained in Reference Example 82 A mixture of -methylpropan-1-ol (3.4 g, 11.4 mmol), 48% hydrobromic acid (50 mL) and acetic acid (10 mL) was heated to reflux for 16 hours under an argon atmosphere. After cooling, water was added to the reaction solution, extracted with ethyl acetate, the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 20: 1) to obtain 2.71 g (yield 89%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, s), 1.24 (6H, d, J = 7.2 Hz), 1.59 (3H, s), 2.89 (1H, septet, J = 7.2 Hz), 4.33 ( 1H, s), 6.77-6.89 (2H, m), 6.98-7.06 (3H, m), 7.12-7.19 (3H, m).
[Reference Example 84]

5-Bromo-3- (4-isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran 3- (4-isopropylphenyl) obtained in Reference Example 83 in the same manner as Reference Example 23. The title compound was synthesized using -2,2-dimethyl-2,3-dihydro-1-benzofuran. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, s), 1.25 (6H, d, J = 6.9 Hz), 1.57 (3H, s), 2.89 (1H, septet, J = 6.9 Hz), 4.30 ( 1H, s), 6.69 (1H, d, J = 8.2 Hz), 6.99 (2H, d, J = 8.1 Hz), 7.12-7.28 (4H, m).
[Reference Example 85]

N-benzyl-3- (4-isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine 5-bromo-obtained in Reference Example 84 in the same manner as in Reference Example 24. The title compound was synthesized using 3- (4-isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran. Yield 46%. Melting point 85-86 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, s), 1.25 (6H, d, J = 7.0 Hz), 1.57 (3H, s), 2.89 (1H, septet, J = 7.0 Hz), 3.62 ( 1H, br s), 4.22 (2H, s), 4.26 (1H, s), 6.40-6.55 (2H, m), 6.68 (1H, d, J = 8.2 Hz), 7.02 (2H, d, J = 8.0 Hz), 7.15 (2H, d, J = 8.0 Hz), 7.20-7.40 (5H, m).
[Reference Example 86]

3- (4-Isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-3- (4) obtained in Reference Example 85 in the same manner as Reference Example 30. The title compound was synthesized using -isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 98%. Melting point 109-110 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, s), 1.24 (6H, d, J = 6.9 Hz), 1.55 (3H, s), 2.89 (1H, septet, J = 6.9 Hz), 3.33 ( 2H, br s), 4.23 (1H, s), 6.44 (1H, d, J = 2.1 Hz), 6.52 (1H, d, J = 8.1, 2.1 Hz), 6.63 (1H, d, J = 8.2 Hz) , 7.02 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz).
[Reference Example 87]

1-Isopropyl-4- (2-methyl-3- (4-methylphenoxy) propen-1-yl) benzene p-cresol (3.50 g, 32.3 mmol) in DMF (70 mL) at 0 ° C. under nitrogen atmosphere Sodium hydride (60% liquid paraffin dispersion, 1.42 g, 35,5 mmol) was added and stirred at the same temperature for 30 minutes. 1- (3-Bromo-2-methyl-1-propenyl) -4-isopropylbenzene (9.0 g, 35.5 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the product was extracted with diisopropyl ether. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 20: 1) to obtain 8.20 g (yield 91%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 6.6 Hz), 1.98 (3H, s), 2.21 (3H, s), 2.90 (1H, septet, J = 7.0 Hz), 4.53 ( 2H, s), 6.58 (1H, s), 6.86 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 7.14-7.25 (4H, m).
[Reference Example 88]

4-((3- (4-Isopropylphenyl) -2-methyl-2-propenyl) oxy) -2,6-dimethylphenyl acetate In the same manner as in Reference Example 87, 4-hydroxy-2,6-dimethylphenyl acetate Was used to synthesize the title compound. Yield 83%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7.2 Hz), 1.97 (3H, s), 2.12 (6H, s), 2.32 (3H, s), 2.90 (1H, septet, J = 7.2 Hz), 4.49 (2H, s), 6.57 (1H, s), 6.66 (2H, s), 7.18-7.25 (4H, m).
[Reference Example 89]

2- (1- (4-Isopropylphenyl) -2-methyl-2-propenyl) -4-methylphenol 1-isopropyl-4- (2-methyl-3- (4-methylphenoxy) obtained in Reference Example 87 A solution of propen-1-yl) benzene (8.2 g, 29.2 mmol) in N, N-dimethylaniline (50 mL) was stirred at 215 ° C. for 16 hours under an argon atmosphere. The reaction mixture was cooled, diluted with diisopropyl ether, washed with 5N hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 7.80 g (yield 95%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 7.2 Hz), 1.83 (3H, s), 2.22 (3H, s), 2.89 (1H, septet, J = 7.2 Hz), 4.61 ( 1H, s), 4.75 (1H, s), 5.04 (1H, s), 5.12 (1H, s), 6.70-6.78 (2H, m), 6.94 (1H, d, J = 8.0 Hz), 7.09 (2H , d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz).
[Reference Example 90]

3- (4-Isopropylphenyl) -2,2,5-trimethyl-2,3-dihydro-1-benzofuran 2- (1- (4-isopropylphenyl) obtained in Reference Example 89 in the same manner as Reference Example 83. The title compound was synthesized using) -2-methyl-2-propenyl) -4-methylphenol. Yield 37%. Melting point 65-66 ° C.
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.25 (6H, d, J = 6.9 Hz), 1.57 (3H, s), 2.25 (3H, s), 2.89 (1H, septet, J = 6.9 Hz), 4.28 (1H, s), 6.71 (1H, d, J = 8.1 Hz), 6.86 (1H, s), 6.93-7.03 (3H, m), 7.15 (2H, d, J = 7.8 Hz ).
[Reference Example 91]

3- (4-Isopropylphenyl) -5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran 4-((3- (4-isopropylphenyl) obtained in Reference Example 88 ) -2-Methylpropen-2-yl) oxy) -2,6-dimethylphenyl acetate (6.3 g, 17.9 mmol) in N, N-dimethylaniline (30 mL) was stirred at 215 ° C. for 16 hours under an argon atmosphere. . The reaction mixture was cooled, diluted with diisopropyl ether, washed with 5N hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. A mixture of the obtained residue and 48% hydrobromic acid (30 mL) -acetic acid (5 mL) was heated to reflux for 16 hours under an argon atmosphere. After cooling, water was added to the reaction solution, extracted with ethyl acetate, the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Sodium hydride (60% liquid paraffin dispersion, 556 mg, 13.9 mmol) was added to a solution of the obtained residue in DMF (30 mL) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (1.97 g, 13.9 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to give 2.10 g of the title compound as an oil. (Yield 36%) was obtained. Melting point 121-123 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.22 (6H, d, J = 7.2 Hz), 1.49 (3H, s), 1.85 (3H, s), 2.27 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.63 (3H, s), 4.06 (1H, s), 6.49 (1H, s), 6.51-7.11 (4H, m).
[Reference Example 92]

7-Bromo-3- (4-isopropylphenyl) -2,2,5-trimethyl-2,3-dihydro-1-benzofuran 3- (4-isopropyl) obtained in Reference Example 90 in the same manner as in Reference Example 18. The title compound was synthesized using (phenyl) -2,2,5-trimethyl-2,3-dihydro-1-benzofuran. Yield 86%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.25 (6H, d, J = 6.9 Hz), 1.61 (3H, s), 2.23 (3H, s), 2.89 (1H, septet, J = 6.9 Hz), 4.35 (1H, s), 6.77 (1H, s), 6.99 (2H, d, J = 8.1 Hz), 7.10-7.21 (3H, m).
[Reference Example 93]

7-Bromo-3- (4-isopropylphenyl) -5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran Obtained in Reference Example 91 in the same manner as in Reference Example 18. The title compound was synthesized using 3- (4-isopropylphenyl) -5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.05 (3H, s), 1.23 (6H, d, J = 7.0 Hz), 1.53 (3H, s), 1.82 (3H, s), 2.36 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 3.62 (3H, s), 4.08 (1H, s), 6.60-7.20 (4H, m).
[Reference Example 94]

N-benzyl-3- (4-isopropylphenyl) -2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-amine 7- obtained in Reference Example 92 in the same manner as Reference Example 24 The title compound was synthesized using bromo-3- (4-isopropylphenyl) -2,2,5-trimethyl-2,3-dihydro-1-benzofuran. Yield 79%. Melting point 80-81 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, s), 1.24 (6H, d, J = 6.9 Hz), 1.56 (3H, s), 2.20 (3H, s), 2.89 (1H, septet, J = 6.9 Hz), 4.01 (1H, br s), 4.28 (2H, s), 4.37 (1H, s), 6.27 (1H, s), 6.37 (1H, s), 7.02 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz), 7.21-7.44 (5H, m).
[Reference Example 95]

N-benzyl-3- (4-isopropylphenyl) -5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-amine In the same manner as in Reference Example 24, The title compound was synthesized using 7-bromo-3- (4-isopropylphenyl) -5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran obtained in Example 93. . Yield 79%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 1.22 (6H, d, J = 6.9 Hz), 1.44 (3H, s), 1.78 (3H, s), 2.14 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.42-3.67 (4H, m), 4.01 (1H, s), 4.35 (1H, d, J = 14.4 Hz), 4.42 (1H, d, J = 14.4 Hz ), 6.50-7.18 (4H, m), 7.20-7.38 (5H, m).
[Reference Example 96]

3- (4-Isopropylphenyl) -2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-amine In the same manner as in Reference Example 30, N-benzyl-3-ethyl obtained in Reference Example 94 was obtained. The title compound was synthesized using (4-isopropylphenyl) -2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-amine. Yield 65%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.24 (6H, d, J = 7.2 Hz), 1.56 (3H, s), 2.18 (3H, s), 2.88 (1H, septet, J = 7.2 Hz), 3.50 (2H, br s), 4.26 (1H, s), 6.31 (1H, s), 6.43 (1H, s), 7.02 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz).
[Reference Example 97]

3- (4-Isopropylphenyl) -5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-amine Obtained in Reference Example 95 in the same manner as in Reference Example 30. The title compound was synthesized using N-benzyl-3- (4-isopropylphenyl) -5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-amine. . Yield 83%. Melting point 111-112 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.22 (6H, d, J = 6.9 Hz), 1.50 (3H, s), 1.78 (3H, s), 2.14 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.44 (2H, br s), 3.60 (3H, s), 4.08 (1H, s), 6.62-7.11 (4H, m).
[Reference Example 98]

N-benzyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amine 5- (benzylamino) -2,2,4,6-tetra obtained in Reference Example 51 To a methanol (20 mL) solution of methyl-1-benzofuran-3 (2H) -one (8.5 g, 28.8 mmol) was added sodium borohydride (2.18 g, 57.6 mmol) at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 5- (benzylamino) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-3- A crude product of oar was obtained. Triethylsilane (10 mL, 64 mmol) was added to a mixture of trifluoroacetic acid (30 mL) of this compound under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, the aqueous layer was made alkaline, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain 4.1 g (yield 51%) of the title compound. Melting point 80-81 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.47 (6H, s), 2.18 (3H, s), 2.23 (3H, s), 2.83 (1H, br s), 2.91 (2H, s), 3.96 (2H, s), 6.43 (1H, s), 7.25-7.42 (5H, m).
[Reference Example 99]

Ethyl 3- (4-isopropylphenyl) -2-methyl-2-acrylate A suspension of sodium hydride (60% liquid paraffin dispersion, 5.92 g, 148 mmol) in DMF (150 mL) at 0 ° C. with 2 -Triethyl phosphonopropionate (35.0 g, 148 mmol) was added and stirred at the same temperature for 10 minutes. 4-Isopropylbenzaldehyde (20.0 g, 135 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 30.1 g (yield 96%) of the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7.0 Hz), 1.35 (3H, t, J = 7.0 Hz), 2.13 (3H, s), 2.92 (1H, septet, J = 7.0 Hz), 4.27 (2H, q, J = 7.0 Hz), 7.21-7.38 (4H, m), 7.67 (1H, s).
[Reference Example 100]

Ethyl 2-methyl-3- (4-methylphenyl) -2-acrylate In the same manner as in Reference Example 99, 4-methylbenzaldehyde was used to synthesize the title compound. Yield 91%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.0 Hz), 2.12 (3H, d, J = 1.4 Hz), 2.37 (3H, s), 4.26 (2H, q, J = 7.0 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.66 (1H, s).
[Reference Example 101]

Ethyl 3- (4-fluorophenyl) -2-methyl-2-acrylate In the same manner as in Reference Example 99, the title compound was synthesized using 4-fluorobenzaldehyde. Yield 97%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, t, J = 7.0 Hz), 2.10 (3H, d, J = 1.2 Hz), 4.28 (2H, q, J = 7.0 Hz), 7.08 (2H, t, J = 8.8 Hz), 7.32-7.43 (2H, m), 7.65 (1H, s).
[Reference Example 102]

(E) -3- (4-Isopropylphenyl) -2-ethyl acrylate To a suspension of sodium hydride (60% liquid paraffin dispersion, 10.4 g, 260 mmol) in DMF (200 mL) at 0 ° C. Triethyl acetate (58.2 g, 236 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes. 4-Isopropylbenzaldehyde (35.0 g, 260 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 47.5 g (yield 92%) of the oily title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7.0 Hz), 1.33 (3H, t, J = 7.0 Hz), 2.92 (1H, septet, J = 7.0 Hz), 4.26 (2H, q, J = 7.0 Hz), 6.40 (1H, d, J = 15.8 Hz), 7.24 (2H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.2 Hz), 7.67 (1H, d, J = 15.8 Hz).
[Reference Example 103]

3- (4-Isopropylphenyl) -2-methyl-2-propen-1-ol ethyl 3- (4-isopropylphenyl) -2-methyl-2-acrylate synthesized in Reference Example 99 (9.00 g, 38.7 mmol) ) And cerium chloride (1.00 g, 4.06 mmol) in THF (50 mL) at −40 ° C., lithium aluminum hydride (1.47 g, 38.7 mmol) was added in four portions over 30 minutes at the same temperature. Stir for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 8: 1) to obtain 6.30 g (yield 86%) of the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7.0 Hz), 1.91 (3H, d, J = 1.4 Hz), 2.90 (1H, septet, J = 7.0 Hz), 4.17 (2H, d, J = 0.8 Hz), 6.49 (1H, dd, J = 2.6, 1.4 Hz), 7.15-7.25 (4H, m), 1H Not confirmed.
[Reference Example 104]

2-methyl-3- (4-methylphenyl) -2-propen-1-ol 2-methyl-3- (4-methylphenyl) -2-acryl synthesized in Reference Example 100 in the same manner as Reference Example 103 The title compound was synthesized using ethyl acid. Yield 42%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.87 (3H, s), 2.32 (3H, s), 4.13 (2H, s), 6.46 (1H, s), 7.08-7.22 (4H, m), 1H Not confirmed.
[Reference Example 105]

3- (4-Fluorophenyl) -2-methyl-2-propen-1-ol 3- (4-fluorophenyl) -2-methyl-2-acryl synthesized in Reference Example 101 in the same manner as Reference Example 103 The title compound was synthesized using ethyl acid. Yield 95%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, d, J = 1.6 Hz), 4.11 (2H, s), 6.58 (1H, s), 7.01 (2H, t, J = 8.8 Hz), 7.18- 7.28 (2H, m), 1H not confirmed.
[Reference Example 106]

3- (4-Bromophenyl) -2-methyl-2-propen-1-ol Under argon atmosphere, a solution of sodium tert-butoxide (10.6 g, 110 mmol) in DMF (60 mL) was added triethyl phosphonoacetate (26.2 g, 110 mmol) was added at −10 ° C., and the mixture was stirred at the same temperature for 1 hour. 4-Bromobenzaldehyde (18.5 g, 100 mmol) was added to the solution at 10 ° C. or lower, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was ice-cooled, water (60 mL) was added, and the mixture was extracted with toluene. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained oil was dissolved in toluene (200 mL), and dihydrobis (2-methoxyethoxy) sodium aluminate (70% toluene solution, 41.5 g, 144 mmol) was added dropwise at -10 ° C. Stir for 1 hour. 10% aqueous potassium sodium tartrate solution was added and the organic layer was separated. The organic layer was washed with 10% aqueous potassium sodium tartrate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 2: 1) to obtain 20.1 g (yield 88%) of the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.54 (1H, t, J = 6.0 Hz), 1.87 (3H, d, J = 1.2 Hz), 4.19 (2H, d, J = 6.0 Hz), 6.46 (1H, s), 7.14 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.4 Hz).
[Reference Example 107]

(E) -3- (4-Isopropylphenyl) -2-propen-1-ol (E) -3- (4-Isopropylphenyl) -2-acryl synthesized in Reference Example 102 in the same manner as Reference Example 103 The title compound was synthesized using ethyl acid. Yield 65%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7.0 Hz), 2.79-3.00 (2H, m), 4.30 (2H, d, J = 5.6 Hz), 6.35 (1H, dt, J = 15.8, 5.6 Hz), 6.59 (1H, d, J = 15.8 Hz), 7.10-7.39 (4H, m).
[Reference Example 108]

1- (3-Bromo-2-methyl-1-propenyl) -4-isopropylbenzene 3- (4-Isopropylphenyl) -2-methyl-2-propen-1-ol synthesized in Reference Example 103 (6.30 g, 33.1 mmol) in isopropyl ether (50 mL) was added phosphorus tribromide (5.98 g, 22.1 mmol) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with isopropyl ether. The organic layer was washed with water and saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 7.63 g (yield 91%) of the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7.0 Hz), 2.03 (3H, d, J = 1.4 Hz), 2.90 (1H, septet, J = 7.0 Hz), 4.15 (2H, d, J = 0.8 Hz), 6.62 (1H, s), 7.14-7.26 (4H, m).
[Reference Example 109]

1- (3-Bromo-2-methyl-1-propenyl) benzene In the same manner as in Reference Example 108, the title compound was synthesized using 2-methyl-3-phenyl-2-propen-1-ol. Yield 89%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, d, J = 1.4 Hz), 4.13 (2H, d, J = 0.8 Hz), 6.64 (1H, s), 7.19-7.44 (5H, m).
[Reference Example 110]

1- (3-Bromo-2-methyl-1-propenyl) -4-methylbenzene 2-methyl-3- (4-methylphenyl) -2-propene synthesized in Reference Example 104 in the same manner as Reference Example 108 The title compound was synthesized using -1-ol. Yield 80%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, s), 2.34 (3H, s), 4.13 (2H, s), 6.60 (1H, s), 7.09-7.22 (4H, m).
[Reference Example 111]

1- (3-Bromo-2-methyl-1-propenyl) -4-fluorobenzene 3- (4-fluorophenyl) -2-methyl-2-propene synthesized in Reference Example 105 in the same manner as Reference Example 108 The title compound was synthesized using -1-ol. Yield 79%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.87 (3H, s), 4.17 (2H, s), 6.48 (1H, s), 7.01 (2H, t, J = 8.8 Hz), 7.18-7.27 (2H, m ).
[Reference Example 112]

1-Bromo-4- (3-bromo-2-methyl-1-propenyl) benzene Triphenylphosphine (24.3 g, 92.7 mmol) in acetonitrile (180 mL) and bromine (4.78 mL, 185 mmol) at 0 ° C. The mixture was added dropwise and stirred at the same temperature for 30 minutes. To the solution was added an acetonitrile solution (60 mL) of 3- (4-bromophenyl) -2-methyl-2-propen-1-ol (20.1 g, 88.3 mmol) obtained in Reference Example 106, and the mixture was heated to 0 ° C. And stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, diethyl ether (200 mL) was added to the residue, and the insoluble material was removed by filtration. The filtrate was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give 25.0 g (yield 98%) of the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.99 (3H, d, J = 1.4 Hz), 4.12 (2H, s), 6.57 (1H, s), 7.15 (2H, d, J = 8.4 Hz), 7.45 ( 2H, d, J = 8.4 Hz).
[Reference Example 113]

1-((E) -3-bromo-1-propenyl) -4-isopropylbenzene (E) -3- (4-isopropylphenyl) -2-propene synthesized in Reference Example 107 in the same manner as Reference Example 108 The title compound was synthesized using -1-ol. Yield 72%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7.0 Hz), 2.89 (1H, septet, J = 7.0 Hz), 4.16 (2H, dd, J = 7.8, 0.8 Hz), 6.35 ( 1H, dt, J = 15.4, 7.8 Hz), 6.63 (1H, d, J = 15.4 Hz), 7.14-7.35 (4H, m).
[Reference Example 114]

N- (4-((3- (4-Isopropylphenyl) -2-methyl-2-propenyl) oxy) -2,3,6-trimethylphenyl) formamide N- (4-hydroxy-2,3,6- Sodium hydride (60% liquid paraffin dispersion, 0.74 g, 18.4 mmol) was added to a solution of trimethylphenyl) formamide (3.00 g, 16.7 mmol) in DMF (30 mL) at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 10 minutes. did. 1- (3-Bromo-2-methyl-1-propenyl) -4-isopropylbenzene (4.66 g, 18.4 mmol) synthesized in Reference Example 108 was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain 3.70 g (yield 63%) of the title compound. Melting point 153-155 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7.0 Hz), 2.00 (3H, s), 2.07-2.34 (9H, m), 2.91 (1H, septet, J = 7.0 Hz), 4.54 (2H, d, J = 5.4 Hz), 6.59-6.84 (3H, m), 7.17-7.36 (4H, m), 7.98 (0.5H, d, J = 12.0 Hz), 8.41 (0.5H, s) .
[Reference Example 115]

N- (2,3,6-trimethyl-4-((2-methyl-3-phenyl-2-propenyl) oxy) phenyl) formamide 1- (3 synthesized in Reference Example 109 in the same manner as Reference Example 114 The title compound was synthesized using -bromo-2-methyl-1-propenyl) benzene. Yield 41%. Melting point 152-154 ° C. (Ethyl acetate-hexane)
¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, d, J = 1.6 Hz), 2.10-2.32 (9H, m), 4.54 (2H, d, J = 5.2 Hz), 6.65 (1H, s), 6.67 (1H, s), 6.69-6.90 (1H, m), 7.11-7.41 (5H, m), 7.98 (0.5H, d, J = 12.0 Hz), 8.41 (0.5H, d, J = 1.4 Hz) .
[Reference Example 116]

N- (2,3,6-trimethyl-4-((2-methyl-3- (4-methylphenyl) -2-propenyl) oxy) phenyl) formamide Synthesized in Reference Example 110 in the same manner as Reference Example 114 The title compound was synthesized using 1- (3-bromo-2-methyl-1-propenyl) -4-methylbenzene. Yield 44%. Melting point 167-169 [deg.] C.
¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, s), 2.07-2.38 (9H, m), 2.35 (3H, s), 4.53 (2H, d, J = 6.6 Hz), 6.61 (1H, s ), 6.66 (1H, d, J = 2.4 Hz), 6.82-7.09 (1H, m), 7.11-7.31 (4H, m), 7.98 (0.5H, d, J = 12.2 Hz), 8.38 (0.5H, s).
[Reference Example 117]

N- (4-((3- (4-fluorophenyl) -2-methyl-2-propenyl) oxy) -2,3,6-trimethylphenyl) formamide Synthesized in Reference Example 111 in the same manner as Reference Example 114 The title compound was synthesized using 1- (3-bromo-2-methyl-1-propenyl) -4-fluorobenzene. Yield 52%. Melting point 164-165 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.96 (3H, s), 2.12-2.32 (9H, m), 4.53 (2H, d, J = 5.2 Hz), 6.60 (1H, s), 6.66 (1H, s ), 6.71-6.95 (1H, m), 7.04 (2H, t, J = 8.8 Hz), 7.22-7.33 (2H, m), 8.04 (0.5H, d, J = 12.0 Hz), 8.40 (0.5H, d, J = 1.4 Hz).
[Reference Example 118]

N- (4-((3- (4-Bromophenyl) -2-methyl-2-propenyl) oxy) -2,3,6-trimethylphenyl) formamide Synthesized in Reference Example 112 in the same manner as Reference Example 114 The title compound was synthesized using 1-bromo-4- (3-bromo-2-methyl-1-propenyl) benzene. Yield 79%.
¹ H-NMR (CDCl ₃ ) δ: 1.95-1.97 (3H, m), 2.18-2.27 (9H, m), 4.52 (2H, br d, J = 4.4 Hz), 6.58 (1H, br s), 6.65 (1H, br s), 6.78 (1H, br d, J = 15.0Hz), 7.17 (2H, d, J = 8.2 Hz), 7.47 (2H, d J = 8.2 Hz), 7.99 (0.5H, d, J = 8.1 Hz), 8.42 (0.5H, d, J = 1.5 Hz).
[Reference Example 119]

N- (4-((((E) -3- (4-isopropylphenyl) -2-propenyl) oxy) -2,3,6-trimethylphenyl) formamide 1-((E)-synthesized in Reference Example 113 The title compound was synthesized using 3-bromo-1-propenyl) -4-isopropylbenzene. Yield 59%. Melting point 165-167 [deg.] C. (Ethyl acetate-hexane)
¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 6.8 Hz), 2.13-2.27 (9H, m), 2.90 (1H, septet, J = 6.8 Hz), 4.66 (2H, t, J = 5.8 Hz), 6.37 (1H, dt, J = 15.8, 5.8 Hz), 6.65-6.88 (3H, m), 7.16-7.26 (2H, m), 7.35 (2H, d, J = 8.0 Hz), 7.98 (0.5H, d, J = 12.0 Hz), 8.40 (0.5H, d, J = 1.4 Hz).
[Reference Example 120]

3- (4-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine N- (4-((3- ( A solution of 4-isopropylphenyl) -2-methyl-2-propenyl) oxy) -2,3,6-trimethylphenyl) formamide (3.70 g, 10.5 mmol) in N, N-dimethylaniline (20 mL) under an argon atmosphere. Stir at 215 ° C. for 6 hours. The reaction mixture is cooled, diluted with ethyl acetate, washed with 2N hydrochloric acid and water, dried over magnesium sulfate, concentrated under reduced pressure, and N- (4-hydroxy-3- (1- (4-isopropylphenyl)- A crude product of 2-methyl-2-propenyl) -2,5,6-trimethylphenyl) formamide was obtained. A mixture of this compound (2.98 g, 8.47 mmol) and concentrated hydrochloric acid (20 mL) -methanol (60 mL) was heated to reflux for 2 hours under a nitrogen atmosphere. The solvent was concentrated under reduced pressure, and the resulting residue was neutralized with 8N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from isopropyl ether-hexane to obtain 2.23 g (yield 66%) of the title compound. Melting point 130-132 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.21 (6H, d, J = 6.6 Hz), 1.47 (3H, s), 1.78 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 2.40-2.60 (3H, m), 4.08 (1H, s), 6.72-7.00 (2H, m), 7.07 (2H, d, J = 8.0 Hz).
[Reference Example 121]

2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine N- (2,3,3) synthesized in Reference Example 115 in the same manner as Reference Example 120 The title compound was synthesized using 6-trimethyl-4-((2-methyl-3-phenyl-2-propenyl) oxy) phenyl) formamide. Yield 67%. Melting point 129-131 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.48 (3H, s), 1.77 (3H, s), 2.13 (3H, s), 2.19 (3H, s), 3.20 (2H, br s), 4.12 (1H, s), 6.70-7.30 (5H, m).
[Reference Example 122]

2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine N-- synthesized in Reference Example 116 in the same manner as Reference Example 120 The title compound was synthesized using (2,3,6-trimethyl-4-((2-methyl-3- (4-methylphenyl) -2-propenyl) oxy) phenyl) formamide. Yield 57%. Melting point 114-115 ° C. (petroleum ether).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.47 (3H, s), 1.77 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 2.30 (3H, s ), 3.23 (2H, br s), 4.08 (1H, s), 6.60-7.23 (4H, m).
[Reference Example 123]

3- (4-Fluorophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine N--synthesized in Reference Example 117 in the same manner as Reference Example 120 The title compound was synthesized using (4-((3- (4-fluorophenyl) -2-methyl-2-propenyl) oxy) -2,3,6-trimethylphenyl) formamide. Yield 78%. Melting point 125-127 ° C. (petroleum ether).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.47 (3H, s), 1.77 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 3.10 (2H, br s), 4.09 (1H, s), 6.62-7.20 (4H, m).
[Reference Example 124]

3- (4-Bromophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine In the same manner as in Reference Example 120, N- The title compound was synthesized using (4-((3- (4-bromophenyl) -2-methyl-2-propenyl) oxy) -2,3,6-trimethylphenyl) formamide. Yield 56%.
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.47 (3H, s), 1.77 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 3.23 (2H, br ), 4.07 (1H, s), 6.83 (2H, br), 7.36 (2H, brd, J = 8.0 Hz).
[Reference Example 125]

N- (4-hydroxy-3- (1- (4-isopropylphenyl) -2-propenyl) -2,5,6-trimethylphenyl) formamide N- (4-(((E)) synthesized in Reference Example 119 -3- (4-Isopropylphenyl) -2-propenyl) oxy) -2,3,6-trimethylphenyl) formamide (5.80 g, 17.2 mmol) in N, N-dimethylaniline (50 mL) under an argon atmosphere. Stir at 215 ° C. for 6 hours. The reaction mixture was cooled, diluted with ethyl acetate, washed with 2N hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 3.50 g (yield 60%) of the title compound. Melting point 170-171 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.40 (6H, m), 2.11-2.27 (9H, m), 2.77-3.00 (1H, m), 5.00-5.22 (2H, m), 5.30-5.42 ( 1H, m), 6.30-6.85 (2H, m), 7.10-7.37 (5H, m), 7.97 (0.5H, d, J = 12.2 Hz), 8.43 (0.5H, d, J = 1.4 Hz).
[Reference Example 126]

3- (4-Isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine hydrochloride N- (4-hydroxy-3- (1- (4- Isopropylphenyl) -2-propenyl) -2,5,6-trimethylphenyl) formamide (3.50 g, 10.4 mmol) and calcium carbonate (1.35 g, 13.5 mmol) in THF (15 mL) -methanol (15 mL) Benzyltrimethylammonium iododichloride (3.90 g, 11.4 mmol) was slowly added to the suspension. The reaction was stirred at room temperature for 30 minutes. The insoluble material was filtered off, the solvent was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers with 10% Hydro sulfite aqueous solution, water, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure, the 4.08 g N-(2-iodomethyl - 3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide was obtained. A toluene (30 mL) solution of this compound (4.08 g, 8.81 mmol) and 1,8-diazabicyclo (5,4,0) -7-undecene (6.58 mL, 44.0 mmol) in an argon atmosphere at 100 ° C. for 3 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with 2N hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 20: 1), and 2.40 g of N- (3- (4-Isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-yl) formamide was obtained. A mixture of this compound (2.40 g, 7.18 mmol) in concentrated hydrochloric acid (20 mL) -methanol (60 mL) was heated to reflux for 2 hours under a nitrogen atmosphere. The solvent was concentrated under reduced pressure, and the resulting residue was neutralized with 8N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 1.80 g of an oily free base. This free base (0.50 g, 1.63 mmol) was dissolved in a hydrochloric acid-methanol solution, the solvent was concentrated under reduced pressure, and the resulting residue was crystallized from methanol to obtain 0.41 g (yield 41%) of the desired product. Melting point 194-197 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J = 7.0 Hz), 2.30 (6H, s), 2.41 (3H, s), 2.60 (3H, s), 2.94 (1H, septet, J = 7.0 Hz), 7.13-7.26 (4H, m), 10.1 (2H, br s), 1H Not confirmed.
[Reference Example 127]

4-methoxy-2,3,6-trimethylaniline N- (4-hydroxy-2,3,6-trimethylphenyl) formamide (30.0 g, 167 mmol) was added to 4N aqueous potassium hydroxide (100 mL) and methanol (300 mL) was dissolved in a mixed solvent, dimethyl sulfate (42.0 g, 334 mmol) was added to the solution at room temperature, and the mixture was heated to reflux for 14 hours. The crystal precipitated after cooling was collected by filtration to obtain a crude product of N- (4-methoxy-2,3,6-trimethylphenyl) formamide. Concentrated hydrochloric acid (50 mL) was added to a suspension of this compound in methanol (200 mL), and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and neutralized with 8N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate, and the combined extracts were washed with 10% aqueous sodium hydrosulfite solution and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether to obtain 21.0 g of the desired product (yield 76%). Melting point 70-72 ° C.
¹ H-NMR (CDCl ₃ ) δ: 2.11 (3H, s), 2.16 (3H, s), 2.18 (3H, s), 3.16 (1H, br s), 3.74 (3H, s), 6.54 (1H, s).
[Reference Example 128]

4-methoxy-2,3,6-trimethylphenylcarbamic acid tert-butyl 4-methoxy-2,3,6-trimethylaniline (21.0 g, 127 mmol) and triethylamine (21.0 mL, 152 mmol) synthesized in Reference Example 127 ) In THF (150 mL) was added ditert-butyl dicarbonate (32 mL, 140 mmol) at room temperature, and the mixture was heated to reflux for 14 hours. The solvent was concentrated under reduced pressure, water was poured into the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 25.2 g (yield 75%) of the title compound. Melting point 104-106 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.12 (3H, s), 2.17 (3H, s), 2.24 (3H, s), 3.78 (3H, s), 5.81 (1H, br s), 6.58 (1H, s).
[Reference Example 129]

Tert-Butyl 3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate tert-butyl 4-methoxy-2,3,6-trimethylphenylcarbamate synthesized in Reference Example 128 (12.7 g, 47.9 mmol) ), Sodium acetate (4.72 g, 57.5 mmol) in acetic acid (50 mL) was added bromine (8.42 g, 52.7 mmol) at room temperature and stirred at the same temperature for 1 hour. Water (80 mL) was poured into the reaction mixture, and the precipitated crystals were collected by filtration and dissolved in ethyl acetate. The solution was washed with a saturated aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from methanol to obtain 15.0 g (yield 91%) of the title compound. Melting point 159-161 [deg.] C.
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.15 (3H, s), 2.24 (3H, s), 2.35 (3H, s), 3.74 (3H, s), 5.92 (1H, br s).
[Reference Example 130]

2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine 3-bromo-4-methoxy-2 synthesized in Reference Example 129, To a solution of tert-butyl 5,6-trimethylphenylcarbamate (27.8 g, 80.8 mmol) in THF (150 mL) at −78 ° C. was added n-butyllithium (1.6M, 110 mL, 176 mmol) in hexane, The mixture was stirred at the same temperature for 20 minutes. 2-Methyl-1- (4-methylphenyl) propan-1-one (13.1 g, 80.7 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water (150 mL) was poured into the reaction mixture, extracted three times with ethyl acetate, and the combined organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3- (1-hydroxy-2-methyl). 1- (4-Methylphenyl) propyl) -4-methoxy-2,5,6-trimethylphenylcarbamic acid 26.0 g of a crude product of tert-butyl was obtained. A mixture of this compound and 47% hydrobromic acid (100 mL) was heated to reflux for 4 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and then neutralized with 8N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate, and the combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to obtain 14.8 g (yield 62%) of the title compound. Melting point 114-115 ° C.
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.47 (3H, s), 1.78 (3H, s), 2.12 (3H, s), 2.17 (3H, s), 2.30 (3H, s ), 2.80 (2H, br s), 4.08 (1H, s), 6.60-7.10 (4H, m).
[Reference Example 131]

(+)-2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine 2,2,4 synthesized in Reference Example 130 6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine was subjected to high performance liquid chromatography (instrument: Waters semi-preparative system, column: CHIRALCEL OD (20 (i D) x 250 mm) manufactured by Daicel Chemical Industries, Ltd.), moving bed: hexane: isopropyl alcohol = 95: 5, flow rate: 5 mL / min, column temperature: 30 ° C., injection amount: 40 mg) I sorted the direction. Melting point 87-89 ° C. [Α] _D ²⁰ = + 4.7 ° (c = 0.495, methanol).
[Reference Example 132]

(−)-2,2,4,6,7-Pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine 2,2,4 synthesized in Reference Example 130 6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine was subjected to high performance liquid chromatography (instrument: Waters semi-preparative system, column: CHIRALCEL OD (20 (i , D) x 250 mm) manufactured by Daicel Chemical Industries, Ltd.), moving bed: hexane: isopropyl alcohol = 95: 5, flow rate: 5 mL / min, column temperature: 30 ° C., injection amount: 40 mg) I sorted the direction. Melting point 88-90 ° C. [Α] _D ²⁰ = −4.3 ° (c = 0.499, methanol).
[Reference Example 133]

(+)-3- (4-Bromophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine di-p-toluoyl-D-tartaric acid (3.86 g , 10 mmol) was dissolved in isopropyl alcohol (14.2 mL) at 70 ° C. and synthesized in 3- (4-bromophenyl) -2,2,4,6,7-pentamethyl-2,3- A solution of dihydro-1-benzofuran-5-amine (3.60 g, 10 mmol) in acetonitrile (47.5 mL) was added dropwise while maintaining an internal temperature of 60 ° C. The mixture was cooled to 30 ° C. over about 3 hours, and further stirred at the same temperature for 2 hours. Crystallized crystals were collected by filtration and washed with a small amount of cold acetonitrile. The obtained crude diastereomeric salt was suspended in acetonitrile (29.6 mL) and stirred overnight. The crystals were collected by filtration, washed with a small amount of cold acetonitrile, and dried under reduced pressure. The crystals were suspended in ethyl acetate (100 mL), saturated aqueous sodium hydrogen carbonate solution (100 mL) was added and stirred well, and the organic layer was separated. The organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was dried under reduced pressure and crystallized from cold hexane to obtain 1.13 g (yield 31%) of the title compound. Mp 143-144 ° C (hexane). [Α] _D ²⁰ = + 11.6 ° (c = 0.5, methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.47 (3H, s), 1.77 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 3.25 (2H, br s), 4.07 (1H, s), 6.85 (2H, br), 7.36 (2H, br d, J = 6.9 Hz).
[Reference Example 134]

(3R)-(+)-2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine In the same manner as in Reference Example 133, The title compound was obtained using 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine synthesized in Example 122. Yield 39%. Melting point 87-89 ° C. (hexane). [Α] _D ²⁰ = + 4.7 ° (c = 0.5, methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.47 (3H, s), 1.78 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 2.30 (3H, s ), 2.78 (2H, br), 4.09 (1H, s), 6.83 (2H, br), 7.04 (2H, br d, J = 7.4 Hz).
[Reference Example 135]

2- (2,3-Dimethylphenoxy) -2-methyl-1- (4-methylphenyl) propan-1-ol 2,3-dimethylphenol (12.2 g, 100 mmol) and potassium carbonate (27.4 g, 200 mmol) 2-bromo-1- (4-bromophenyl) -2-methylpropan-1-one (42.2 g, 175 mmol) was added to a mixture of dimethyl sulfoxide (138 mL) at room temperature and the temperature was raised to 35 ° C. did. The mixture was stirred at the same temperature for 24 hours, poured into cold water (300 mL), and extracted with diethyl ether. The organic layer was washed with 4N aqueous sodium hydroxide solution and saturated brine, and dried over sodium sulfate. The solvent was concentrated under reduced pressure, purified by silica gel column chromatography (ethyl acetate-hexane 1: 9), and 2- (2,3-dimethylphenoxy) -2-methyl-1- (4-methylphenyl) propane-1- The ON was obtained as an oil. The obtained oil was dissolved in methanol (200 mL), sodium borohydride (3.8 g, 100 mmol) was added at 0 ° C., and the mixture was warmed to room temperature. After stirring at the same temperature for 1 hour, the mixture was cooled to 0 ° C., neutralized with 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 17.1 g (yield 60%) of the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, s), 1.23 (3H, s), 2.19 (3H, s), 2.27 (3H, s), 2.35 (3H, s), 3.38 (1H, d , J = 2.0 Hz), 4.88 (1H, d, J = 2.0 Hz), 6.83-7.07 (3H, m), 7.14 (2H, d, J = 8.0 Hz), 7.37 (2H, d, J = 8.0 Hz) ).
[Reference Example 136]

2,2,6,7-Tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran 2- (2,3-dimethylphenoxy) -2-methyl synthesized in Reference Example 135 To a toluene solution (200 mL) of -1- (4-methylphenyl) propan-1-ol (17.0 g, 60 mmol) was added trifluoromethanesulfonic acid (0.53 mL, 6 mmol) at 0 ° C., and 50 ° C. The temperature was raised to. After stirring at the same temperature for 30 minutes, the reaction was carried out for 2 hours under reflux conditions. The reaction was cooled to 0 ° C. and poured into saturated aqueous sodium bicarbonate. The organic layer was separated, washed with saturated brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 9) to give 9.3 g (yield 58%) of the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.57 (3H, s), 2.16 (3H, s), 2.26 (3H, s), 2.33 (3H, s), 4.29 (1H, s ), 6.66 (1H, d, J = 7.6 Hz), 6.74 (1H, d, J = 7.6, Hz), 6.98 (2H, d, J = 8.0 Hz), 7.19 (2H, d, J = 8.0 Hz) .
[Reference Example 137]

5-bromo-2,2,6,7-tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran 2 obtained in Reference Example 136 in the same manner as Reference Example 18 , 2,6,7-Tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran was used to synthesize the title compound. Yield 92%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.55 (3H, s), 2.22 (3H, s), 2.33 (3H, s), 2.34 (3H, s), 4.27 (1H, s ), 6.96 (2H, d, J = 8.0 Hz), 7.04 (1H, s), 7.11 (2H, d, J = 8.0 Hz).
[Reference Example 138]

N-Benzyl-2,2,6,7-tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine Obtained in Reference Example 137 in the same manner as Reference Example 24. The title compound was synthesized using 5-bromo-2,2,6,7-tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran. Yield 99%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, s), 1.55 (3H, s), 2.09 (3H, s), 2.21 (3H, s), 2.33 (3H, s), 3.47 (2H, s ), 4.17 (1H, s), 4.27 (1H, s), 6.31 (1H, s), 6.97 (2H, d, J = 7.8 Hz), 7.09 (2H, d, J = 7.8 Hz), 7.20-7.36 (5H, m).
[Reference Example 139]

2,2,6,7-Tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine N-benzyl-2,2,6 obtained in Reference Example 138 , 7-Tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine (6.60 g, 17.8 mmol) in ethanol solution (70 mL) was added 12N hydrochloric acid (0.1 mL). ) And 10% -palladium carbon (50% water content, 0.33 g) were added, and the mixture was stirred at room temperature for 2 hours under 5 atmospheres of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to give 4.42 g (yield 88%) of the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, s), 1.54 (3H, s), 2.09 (3H, s), 2.18 (3H, s), 2.33 (3H, s), 3.25 (2H, br ), 4.23 (1H, s), 6.30 (1H, s), 7.00 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).
[Reference Example 140]

N- (3- (4-Isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 63, Reference Example 126 The title compound was synthesized using 3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine hydrochloride obtained in 1 above. Yield 24%. Melting point 253-254 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.30 (6H, d, J = 6.9 Hz), 1.97 (3H, s), 2.25 (3H, s), 2.30 (5H, s), 2.43 (3H, s), 2.96 (1H, septet, J = 6.9 Hz), 6.62 (1H, br s), 7.23 (4H, s).
[Reference Example 141]

(+)-(3R) -3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine
3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine (22.5 g, 80 mmol) and (2S, 3S)-(4) obtained in Reference Example 32 A suspension of '-methyl) -terthranilic acid (19.14 g, 80 mmol) in ethanol (480 mL) was heated to 85 ° C and dissolved. The solution was cooled to 0 ° C. over 2 hours, and the precipitated crystals were collected by filtration. It was washed with cold ethanol and dried under reduced pressure. The obtained crystals were suspended in 2N aqueous sodium hydroxide solution (400 mL) and extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 9.44 g (yield 34%) of the title compound as an oil. The obtained oil was crystallized from cold hexane as needed. Melting point 53-55 ° C. [Α] _D ²⁰ = + 64.0 ° (c = 0.44, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.18 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.52 ( 2H, br), 4.34 (1H, dd, J = 4.7, 8.8 Hz), 4.50 (1H, dd, J = 4.7, 8.8 Hz), 4.76 (1H, t, J = 8.8 Hz), 6.56 (1H, s ), 7.04 (2H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.0 Hz).
[Reference Example 142]

1- (4-Isopropylphenyl) -2- (3,5-dimethylphenoxy) ethanone cumene (27.8 mL, 200 mmol) and aluminum chloride (32.0 g, 240 mmol) in dichloromethane (300 mL) were mixed with bromoacetyl bromide ( 19.1 mL, 220 mmol) was added at −10 ° C., and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into ice-cold water and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by a small amount of silica gel column chromatography (ethyl acetate-hexane 1: 9) to obtain 2-bromo-1- (4-isopropylphenyl) ethanone as an oil. The obtained oil was added to an acetone solution (500 mL) of 3,5-dimethylphenol (29.3 g, 240 mmol) and potassium carbonate (33.2 g, 240 mmol), and the mixture was stirred for 12 hours with heating under reflux. The reaction mixture was ice-cooled, poured into cold water and extracted with diethyl ether. The extract was washed with saturated brine, dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4). The obtained oil was crystallized from hexane to obtain 39.4 g (yield 75%) of the title compound. Melting point 68-69 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6.9 Hz), 2.27 (3H, s), 2.28 (3H, s), 2.98 (1H, septet, J = 6.9 Hz), 5.22 ( 2H, s), 6.57 (2H, s), 6.63 (1H, s), 7.35 (2H, d, J = 8.4 Hz), 7.95 (2H, d, J = 8.4 Hz).
[Reference Example 143]

3- (4-Isopropylphenyl) -4,6-dimethylbenzofuran 1- (4-isopropylphenyl) -2- (3,5-dimethylphenoxy) ethanone (38.1 g, 135 mmol) obtained in Reference Example 142 A toluene solution (400 mL) of montmorillonite KSF (57.2 g) was heated to 95 ° C. and reacted for 16 hours. After cooling the reaction solution to room temperature, montmorillonite KSF was removed by filtration. The filtrate was purified by a small amount of silica gel column chromatography (ethyl acetate-hexane 1: 9) and the solvent was distilled off under reduced pressure to obtain 35.6 g (yield 100%) of the title compound as an oil. The oil was crystallized from methanol as needed. Melting point 44-45 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 6.9 Hz), 2.30 (3H, s), 2.43 (3H, s), 2.96 (1H, septet, J = 6.9 Hz), 6.83 ( 1H, s), 7.18 (1H, s), 7.25 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.6 Hz).
[Reference Example 144]

3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran 3- (4-isopropylphenyl) -4,6-dimethyl-1-benzofuran obtained in Reference Example 143 ( 36.5 g, 135 mmol) and 10% -palladium carbon (containing 50% water, 3.7 g) were suspended in ethanol (400 mL) and subjected to a reduction reaction at 60 ° C. for 6 hours in a hydrogen atmosphere of 5 atm. The reaction solution was cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained oil was crystallized from methanol to obtain 27.5 g (yield 77%) of the title compound. Melting point 48-50 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.29 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.35- 4.53 (2H, m), 4.83 (1H, t, J = 8.1 Hz), 6.47 (1H, s), 6.56 (1H, s), 7.04 (2H, d, J = 8.2 Hz), 7.13 (2H, d , J = 8.2 Hz).
[Reference Example 145]

3- (4-Methoxyphenyl) -N- (2,2,6,7-tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) -propionamide Reference In the same manner as in Example 359, 2,2,6,7-tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 139 and 3- (4 The title compound was obtained using -methoxyphenyl) propionic acid. Yield 64%. Melting point 149-150 ° C. (Ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, s), 1.55 (3H, s), 1.98 (3H, s), 2.15 (3H, s), 2.32 (3H, s), 2.58 (2H, d , J = 7.5 Hz), 2.94 (2H, d, J = 7.5 Hz), 3.73 (3H, s), 4.28 (1H, s), 6.63-6.98 (6H, m), 7.03-7.18 (4H, m) .
[Reference Example 146]

2-hydroxy-4,6-dimethylbenzaldehyde 3,5-dimethylphenol (20.0 g, 164 mmol), paraformaldehyde (14.8 g, 492 mmol), magnesium chloride (23.4 g, 246 mmol), and triethylamine (80 mL, 573 mmol) in acetonitrile (500 mL) was heated to reflux for 4 hours. The reaction solution was acidified with hydrochloric acid and extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 9) to obtain 20.8 g (yield 84%) of the title compound. Melting point 48-49 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 2.55 (3H, s), 6.53 (1H, s), 6.62 (1H, s), 10.23 (1H, s), 11.95 (1H, s ).
[Reference Example 147]

2- (Hydroxy (4-isopropylphenyl) methyl) -3,5-dimethylphenol To a solution of 1-bromo-4-isopropylbenzene (3.32 g, 16.7 mmol) in THF (30 mL) was added n-butyllithium (1.59 M hexane). Solution, 9.2 mL, 14.7 mmol) was added dropwise at −78 ° C. under an argon atmosphere. After stirring the reaction solution for 30 minutes, a solution of 2-hydroxy-4,6-dimethylbenzaldehyde (1.0 g, 6.7 mmol) obtained in Reference Example 146 in THF (10 mL) was added dropwise at −78 ° C. and stirred for 30 minutes. . The reaction mixture was warmed to room temperature, water was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to give the title compound 1 Obtained .64 g (yield 91%). Melting point 103-104 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.13 (3H, s), 2.26 (3H, s), 2.77 (1H, d, J = 2.4 Hz), 2.88 ( 1H, septet, J = 6.9 Hz), 6.14 (1H, d, J = 2.4 Hz), 6.50 (1H, s), 6.62 (1H, s), 7.17 (2H, d, J = 8.1 Hz), 7.28 ( 2H, d, J = 8.1 Hz), 8.56 (1H, s).
[Reference Example 148]

2- (4-Isopropylbenzyl) -3,5-dimethylphenol 2- (hydroxy (4-isopropylphenyl) methyl) -3,5-dimethylphenol (12.3 g, 45.5 mmol) obtained in Reference Example 147 and 10% -A mixture of palladium on carbon (containing 50% water, 1.23 g) in acetic acid (90 mL) was heated at 90 ° C for 16 hours in a hydrogen atmosphere. After removing the catalyst, the reaction solution is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. did. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 3) to obtain 10.5 g (yield 90%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.24 (3H, s), 2.25 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.97 ( 2H, s), 4.58 (1H, s), 6.50 (1H, s), 6.62 (1H, s), 7.05-7.12 (4H, m).
[Reference Example 149]

2-Bromo-3,5-dimethylphenol N-bromosuccinimide (21.9 g, 123 mmol) was added to a carbon disulfide (330 mL) solution of 3,5-dimethylphenol (15.0 g, 123 mmol) under ice-cooling. Slowly added in several portions and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the precipitated crystals were filtered and washed with ethyl acetate-hexane (10: 1). The filtrate was concentrated, and the residue was purified by silica gel chromatography (ethyl acetate-hexane 1: 9) to obtain 16.3 g (yield 66%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.24 (3H, s), 2.34 (3H, s), 5.52 (1H, s), 6.62 (1H, s), 6.68 (1H, s).
[Reference Example 150]

2-Bromo-6- (4-isopropylbenzyl) -3,5-dimethylphenol In the same manner as in Reference Example 149, 2- (4-isopropylbenzyl) -3,5-dimethylphenol obtained in Reference Example 148 was used. The title compound was synthesized. Yield 75%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 2.20 (3H, s), 2.34 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.04 ( 2H, s), 5.66 (1H, s), 6.68 (1H, s), 7.09 (4H, s).
[Reference Example 151]

2-Bromo-5-isopropylphenol 2-bromo-3-isopropylphenol 3-isopropylphenol (10.0 g, 73.4 mmol) in carbon disulfide (200 mL) was added with N-bromosuccinimide (13.1 g, 73.4 mmol) was slowly added and stirred for 1 hour. The reaction mixture was stirred at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 15:85), and 11.0 g (yield) of a 3: 1 mixture of 2-bromo-5-isopropylphenol and 2-bromo-3-isopropylphenol. Rate 70%).
[Reference Example 152]

1-Bromo-4-isopropyl-2-methoxybenzene A mixture of 2-bromo-5-isopropylphenol and 2-bromo-3-isopropylphenol obtained in 2-bromo-1-isopropyl-3-methoxybenzene Reference Example 151 ( 10.0 g, 51.3 mmol), methyl iodide (7.28 g, 51.3 mmol), and a mixture of potassium carbonate (7.08 g, 51.3 mmol) in acetone (200 mL) were heated to reflux for 8 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-bromo-4-isopropyl-2-methoxybenzene and 2-bromo-1-isopropyl-3-methoxybenzene. 9.81 g (yield 83%) of the mixture was obtained.
[Reference Example 153]

2- (2- (4-Isopropylbenzyl) -3,5-dimethylphenoxy) -2-methylpropanoic acid ethyl 2- (4-isopropylbenzyl) -3,5-dimethylphenol (5.0 g) obtained in Reference Example 148 , 19.7 mmol), a solution of ethyl 2-bromoisobutyrate (11.5 g, 59.0 mmol) and potassium carbonate (8.13 g, 59.0 mmol) in dimethyl sulfoxide (20 mL) was stirred at 50 ° C. for 40 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to synthesize 6.64 g (yield 92%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.28 (9H, m), 1.47 (6H, s), 2.19 (3H, s), 2.22 (3H, s), 2.83 (1H, septet, J = 6.9 Hz ), 3.97 (2H, s), 4.23 (2H, q, J = 6.9 Hz), 6.33 (1H, s), 6.61 (1H, s), 7.07 (4H, s).
[Reference Example 154]

(2- (4-Isopropylbenzyl) -3,5-dimethylphenoxy) ethyl acetate In the same manner as in Reference Example 153, 2- (4-isopropylbenzyl) -3,5-dimethylphenol and bromo obtained in Reference Example 148 were used. The title compound was synthesized using ethyl acetate. Yield 95%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 1.27 (3H, t, J = 7.5 Hz), 2.22 (3H, s), 2.27 (3H, s), 2.83 ( 1H, septet, J = 6.9 Hz), 4.04 (2H, s), 4.24 (2H, q, J = 7.5 Hz), 4.58 (2H, s), 6.46 (1H, s), 6.66 (1H, s), 7.03-7.13 (4H, m).
[Reference Example 155]

(2,3,5-Trimethylphenoxy) ethyl acetate In the same manner as in Reference Example 153, the title compound was synthesized using 2,3,5-trimethylphenol and ethyl bromoacetate. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.5 Hz), 2.17 (3H, s), 2.23 (3H, s), 2.36 (3H, s), 4.26 (2H, q, J = 7.5 Hz), 4.60 (2H, s), 6.42 (1H, s), 6.65 (1H, s).
[Reference Example 156]

2- (2- (4-Isopropylbenzyl) -3,5-dimethylphenoxy) -2-methylpropanoic acid 2- (2- (4-isopropylbenzyl) -3,5-dimethylphenoxy) obtained in Reference Example 153 A mixture of ethyl 2-methylpropanoate (6.65 g, 18.1 mmol) and 8N aqueous sodium hydroxide solution (4.5 mL) in methanol (40 mL) -THF (20 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified with hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (5.59 g, yield 91%). Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 1.49 (6H, s), 2.22 (3H, s), 2.26 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.97 (2H, s), 6.50 (1H, s), 6.71 (1H, s), 7.01 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz), 1H unconfirmed.
[Reference Example 157]

(2- (4-Isopropylbenzyl) -3,5-dimethylphenoxy) acetic acid (2- (4-Isopropylbenzyl) -3,5-dimethylphenoxy) acetic acid obtained in Reference Example 154 in the same manner as Reference Example 156 The title compound was synthesized using ethyl. Yield 75%. Melting point 104-105 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.26 (3H, s), 2.30 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 4.02 ( 2H, s), 4.57 (2H, s), 6.48 (1H, s), 6.73 (1H, s), 7.04 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz), 1H unconfirmed.
[Reference Example 158]

(2,3,5-Trimethylphenoxy) acetic acid In the same manner as in Reference Example 156, the title compound was synthesized using (2,3,5-dimethylphenoxy) ethyl acetate obtained in Reference Example 155. Yield 92%. Melting point 129-130 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 2.16 (3H, s), 2.24 (3H, s), 2.27 (3H, s), 4.67 (2H, s), 6.44 (1H, s), 6.68 (1H, s ) 1H unconfirmed.
[Reference Example 159]

1- (2- (4-Isopropylbenzyl) -3,5-dimethylphenoxy) acetone 2- (4-Isopropylbenzyl) -3,5-dimethylphenol (1.0 g, 3.93 mmol) obtained in Reference Example 148, carbonic acid A mixture of potassium (1.30 g, 9.44 mmol), chloroacetone (436 mg, 4.72 mmol), and potassium iodide (100 mg) in acetone (15 mL) was heated to reflux for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to give the title compound 888 mg. (Yield 73%) was obtained. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.10 (3H, s), 2.24 (3H, s), 2.28 (3H, s), 2.80-2.90 (1H, septet , J = 6.9 Hz), 4.04 (2H, s), 4.42 (2H, s), 6.40 (1H, s), 6.68 (1H, s), 7.02 (2H, d, J = 8.1 Hz), 7.07 (2H , d, J = 8.1 Hz).
[Reference Example 160]

1- (2- (4-Isopropylbenzyl) -3,5-dimethylphenoxy) butan-2-one In the same manner as in Reference Example 159, 2- (4-isopropylbenzyl) -3,5 obtained in Reference Example 148 The title compound was synthesized using dimethylphenol and 1-bromobutan-2-one. Yield 88%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.2 Hz), 1.20 (6H, d, J = 6.9 Hz), 2.45 (3H, s), 2.88 (3H, s), 2.42 ( 2H, q, J = 7.2 Hz), 2.84 (1H, septet, J = 6.9 Hz), 4.05 (2H, s), 4.45 (2H, s), 6.42 (1H, s), 6.69 (1H, s), 7.04 (2H, d, J = 8.1 Hz), 7.08 (2H, d, J = 8.1 Hz).
[Reference Example 161]

1- (3-Bromophenyl) -2- (2,3,5-trimethylphenoxy) ethanone In the same manner as in Reference Example 159, 2,3,5-trimethylphenol and 2-bromo-1- (3-bromophenyl The title compound was synthesized using ethanone. Yield 52%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.16 (3H, s), 2.24 (3H, s), 2.26 (3H, s), 5.16 (2H, s), 6.46 (1H, s), 6.66 (1H, s ), 7.37 (1H, t, J = 8.0 Hz), 7.70-7.76 (1H, m), 7.91-7.96 (1H, m), 8.15-8.17 (1H, m).
[Reference Example 162]

1- (3-methoxyphenyl) -2- (2,3,5-trimethylphenoxy) ethanone In the same manner as in Reference Example 159, 2,3,5-trimethylphenol and 2-bromo-1- (3-methoxyphenyl) The title compound was synthesized using ethanone. Yield 88%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.18 (3H, s), 2.23 (3H, s), 2.25 (3H, s), 3.86 (3H, s), 5.22 (2H, s), 6.46 (1H, s ), 6.65 (1H, s), 7.13-7.20 (1H, m), 7.40 (1H, t, J = 7.5 Hz), 7.53-7.61 (2H, m).
[Reference Example 163]

1- (4-Methylphenyl) -2- (2,3,5-trimethylphenoxy) ethanone In the same manner as in Reference Example 159, 2,3,5-trimethylphenol and 2-bromo-1- (4-methylphenyl) The title compound was synthesized using ethanone. Yield 75%. Melting point 94-95 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 2.23 (3H, s), 2.25 (3H, s), 2.42 (3H, s), 5.18 (2H, s), 6.45 (1H, s ), 6.63 (1H, s), 7.27 (2H, d, J = 8.1 Hz), 7.91 (2H, d, J = 8.1 Hz).
[Reference Example 164]

Bromoacetyl bromide (33.5 mL, 385 mmol) was added to a dichloromethane solution (500 mL) of 2-bromo-1- (4-isopropylphenyl) ethanone cumene (42 g, 350 mmol) and aluminum chloride (56.0 g, 420 mmol). The mixture was added at −40 ° C. over 40 minutes and stirred while raising the temperature to −10 ° C. in 2 hours. The reaction solution was poured into ice-cold water and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 84 g (yield 99%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6.9 Hz), 2.98 (1H, septet, J = 6.9 Hz), 4.44 (2H, s), 7.34 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz).
[Reference Example 165]

4-Bromo-1- (4-isopropylphenyl) -2- (2,3,5-trimethylphenoxy) ethanone In the same manner as in Reference Example 23, using 2,3,5-trimethylphenol, 4-bromo- 2,3,5-trimethylphenol was synthesized. Using this compound and 2-bromo-1- (4-isopropylphenyl) ethanone obtained in Reference Example 164, the title compound was synthesized in the same manner as in Reference Example 159. Yield 51%. Melting point 71-72 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6.6 Hz), 2.28 (3H, s), 2.35 (3H, s), 2.40 (3H, s), 2.98 (1H, septet, J = 6.6 Hz), 5.23 (2H, s), 6.55 (1H, s), 7.35 (2H, d, J = 8.1 Hz), 7.94 (2H, d, J = 8.1 Hz).
[Reference Example 166]

1-((2- (4-Isopropylbenzyl) -3,5-dimethylphenoxy) acetyl) -2-methylaziridine (2- (4-isopropylbenzyl) -3,5-dimethylphenoxy) obtained in Reference Example 157 Oxalyl chloride (3.77 mL, 43.2 mmol) was added dropwise to a solution of acetic acid (9.00 g, 28.8 mmol) in THF (90 mL) under ice cooling, and then DMF (4 drops) was added and stirred for 30 minutes. The reaction solution was stirred at room temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. A solution of the obtained acid chloride in THF (10 mL) was added dropwise to a solution of propyleneimine (1.97 g, 34.6 mmol) and triethylamine (4.82 mL, 34.6 mmol) in THF (80 mL) under ice cooling. After stirring for 30 minutes, the temperature was raised to room temperature, and the reaction mixture was added to water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 2: 3) to obtain 10.0 g (yield 99%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, d, J = 5.7 Hz), 1.20 (6H, d, J = 6.9 Hz), 1.86 (1H, d, J = 3.6 Hz), 2.23 (3H, s), 2.26-2.30 (4H, m), 2.40-2.50 (1H, m), 2.84 (1H, septet, J = 6.9 Hz), 4.05 (2H, s), 4.56 (1H, d, J = 15.6 Hz ), 4.63 (1H, d, J = 15.6 Hz), 6.53 (1H, s), 6.69 (1H, s), 7.05-7.10 (4H, m).
[Reference Example 167]

(2,3,5-Trimethylphenoxy) acetyl) -2-methylaziridine In the same manner as in Reference Example 166, the title compound was obtained using (2,3,5-trimethylphenoxy) acetic acid obtained in Reference Example 158. . Yield 77%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, d, J = 5.4 Hz), 2.03-2.05 (1H, m), 2.18 (3H, s), 2.24 (3H, s), 2.26 (3H, s ), 2.45 (1H, d, J = 5.4 Hz), 2.60-2.69 (1H, m), 4.63 (2H, s),
6.46 (1H, s), 6.65 (1H, s).
[Reference Example 168]

1- (5-Methylpyridin-2-yl) -2- (2,3,5-trimethylphenoxy) ethanone 2-bromo-5-methylpyridine (958 mg, 5.57 mmol) in THF (3 mL) -ether ( 10 ml), n-butyllithium (1.56 M hexane solution, 3.9 mL, 6.13 mmol) was added dropwise at −78 ° C. under an argon atmosphere. After stirring the reaction solution for 30 minutes, a solution of (2,3,5-trimethylphenoxy) acetyl) -2-methylaziridine (1.43 g, 6.13 mmol) obtained in Reference Example 167 in THF (5 ml) was added dropwise at the same temperature. did. The reaction mixture was warmed to room temperature, added to ice, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 795 mg (yield 53%) of the title compound. Melting point 94-95 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 2.25 (9H, s), 2.45 (3H, s), 5.60 (2H, s), 6.52 (1H, s), 6.64 (1H, s), 7.65-7.70 (1H , m), 8.00 (1H, d, J = 7.8 Hz), 8.49-8.51 (1H, m).
[Reference Example 169]

1- (2- (4-Isopropylbenzyl) -3,5-dimethylphenoxy) pentan-2-one 1-((2- (4-isopropylbenzyl) -3,5-dimethylphenoxy) obtained in Reference Example 166 Acetyl) -2-methylaziridine (1.0 g, 2.85 mmol) in THF (20 mL) was added dropwise with n-propylmagnesium bromide (2.0 M THF solution, 1.43 mL, 2.85 mmol) under ice-cooling in an argon atmosphere. And stirred for 30 minutes. The reaction solution was warmed to room temperature, added to water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 920 mg (yield 95%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.83 (3H, t, J = 7.5 Hz), 1.20 (6H, d, J = 6.9 Hz), 1.40-1.59 (2H, m), 2.25 (3H, s), 2.29 (3H, s), 2.39 (2H, t, J = 7.5 Hz), 2.84 (1H, septet, J = 6.9 Hz), 4.05 (2H, s), 4.43 (2H, s), 6.41 (1H, s ), 6.69 (1H, s), 7.03 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz).
[Reference Example 170]

1- (2- (4-Isopropylbenzyl) -3,5-dimethylphenoxy-3-methylbutan-2-one In the same manner as in Reference Example 169, 1-((2- (4-Isopropyl) obtained in Reference Example 166 was used. The title compound was synthesized using (benzyl) -3,5-dimethylphenoxy) acetyl) -2-methylaziridine and isopropylmagnesium bromide Yield 24%.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (6H, d, J = 7.8 Hz), 1.20 (6H, d, J = 6.9 Hz), 2.25 (3H, s), 2.29 (3H, s), 2.75- 2.89 (2H, m), 4.05 (2H, s), 4.51 (2H, s), 6.42 (1H, s), 6.69 (1H, s), 7.03 (2H, d, J = 8.1 Hz), 7.08 (2H , d, J = 8.1 Hz).
[Reference Example 171]

1- (2-Isopropyl-6-methoxyphenyl) -2- (2,3,5-trimethylphenoxy) ethanone 1- (4-Isopropyl-2-methoxyphenyl) -2- (2,3,5-trimethylphenoxy) ) To a solution of 1-bromo-4-isopropyl-2-methoxybenzene and 2-bromo-1-isopropyl-3-methoxybenzene (5.73 g, 25.0 mmol) obtained in Ethanon Reference Example 152 in THF (100 mL) Then, n-butyllithium (1.60 M hexane solution, 17.2 mL, 27.5 mmol) was added dropwise at −70 ° C. under an argon atmosphere. After stirring the reaction solution for 30 minutes, a solution of 2-methyl-1-((2,3,5-trimethylphenoxy) acetyl) aziridine (5.84 g, 25.0 mmol) obtained in Reference Example 167 in THF (20 mL) was added dropwise. The mixture was stirred at -70 ° C for 30 minutes and then warmed to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 6.27 g (yield 77%) of the title compound mixture.
[Reference Example 172]

Acetic acid 4-hydroxy-2-methyl-1-naphthyl acetate To a solution of 4- (acetyloxy) -2-methyl-1-naphthyl acetate (25 g, 96.8 mmol) in methanol (300 mL) was added potassium carbonate (58.1 g, 420 mmol), and stirred at room temperature for 15 minutes under an argon atmosphere. The mixture was poured into water, neutralized with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (21 g, yield: quantitative). Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.48 (3H, s), 5.90 (1H, br s), 6.43 (1H, s), 7.34-7.51 (2H, m), 7.63 ( 1H, d, J = 8.4 Hz), 8.00 (1H, d, J = 9.6 Hz).
[Reference Example 173]

To a suspension of 3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl acetate hydride (60% liquid paraffin dispersion, 1.8 g, 40 mmol) in DMF (60 mL) at 0 ° C. -Methyl-4-phosphonocrotonate triethyl (11 g, 41.6 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Cyclohexanone (3.93 g, 40 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the product was extracted with diisopropyl ether. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product of oily ethyl 4-cyclohexylidene-3-methyl-2-butenoate. To a mixed solution of this compound in THF (160 mL) and methanol (40 mL), 12N aqueous sodium hydroxide solution (4.0 mL) was added at room temperature, stirred for 16 hours, and concentrated under reduced pressure. The residue was acidified with water and hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of 4-cyclohexylidene-3-methyl-2-butenoic acid. Sodium acetate (12 g, 33.8 mmol) was added to a mixture of this compound (6.1 g, 33.8 mmol) in acetic acid (150 mL) at room temperature, and the mixture was heated to reflux for 24 hours under an argon atmosphere. The solvent was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1:10) to obtain 5.1 g (yield 63%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.68-1.87 (4H, m), 2.27 (3H, s), 2.29 (3H, s), 2.44-2.58 (2H, m), 2.68-2.79 (2H, m) , 6.64 (1H, s), 6.78 (1H, s).
[Reference Example 174]

6-Methyl-2,3-dihydro-1H-inden-4-yl acetate In the same manner as in Reference Example 173, the title compound was synthesized using cyclopentanone. Yield 21%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.00-2.14 (2H, m), 2.28 (3H, s), 2.31 (3H, s), 2.73 (2H, t, J = 7.5 Hz), 2.90 (2H, t , J = 7.5 Hz), 6.65 (1H, s), 6.91 (1H, s).
[Reference Example 175]

3-methyl-5,6,7,8-tetrahydro-1-naphthalenol THF synthesized in 3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl acetate (5.1 g, 25.1 mmol) synthesized in Reference Example 173 (120 mL) and methanol (30 mL) were mixed with 12N aqueous sodium hydroxide solution (2.5 mL) at room temperature, stirred for 30 minutes, and concentrated under reduced pressure. The residue was acidified with water and hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized from ethyl acetate-hexane to obtain 4.1 g (yield 99%) of the title compound. Melting point 95-96 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.68-1.87 (4H, m), 2.23 (3H, s), 2.58 (2H, t, J = 6.0 Hz), 2.70 (2H, t, J = 6.0 Hz), 4.67 (1H, br s), 6.42 (1H, s), 6.50 (1H, s).
[Reference Example 176]

6-Methyl-4-indanol In the same manner as in Reference Example 175, the title compound was synthesized using 6-methyl-2,3-dihydro-1H-inden-4-yl acetate synthesized in Reference Example 174. Yield 81%. Melting point 82-83 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 2.02-2.14 (2H, m), 2.27 (3H, s), 2.80 (2H, t, J = 7.5 Hz), 2.87 (2H, t, J = 7.5 Hz), 4.62 (1H, br s), 6.43 (1H, s), 6.65 (1H, s).
[Reference Example 177]

2- (3,4,5-trimethylphenoxy) -1- (4-isopropylphenyl) ethanone 2-bromo-1- (4-isopropylphenyl) ethanone obtained in Reference Example 164 (20 g, 82.9 mmol), 3 , 4,5-Trimethylphenol (10.3 g, 75.4 mmol) and potassium carbonate (12.5 g, 90.5 mmol) in acetonitrile (200 mL) were added and stirred for 6 hours with heating under reflux. The reaction mixture was ice-cooled, poured into cold water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane 1:10). The obtained oil was crystallized from hexane-ethyl acetate to obtain 21.5 g (yield 96%) of the title compound. Mp 96-98 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6.9 Hz), 2.09 (3H, s), 2.23 (6H, s), 2.97 (1H, septet, J = 6.9 Hz), 5.19 ( 2H, s), 6.61 (2H, s), 7.33 (2H, d, J = 8.4 Hz), 7.93 (2H, d, J = 8.4 Hz).
[Reference Example 178]

4- (2- (4-Isopropylphenyl) -2-oxoethoxy) -2-methyl-1-naphthyl acetate Acetic acid 4-hydroxy-2-methyl-1 synthesized in Reference Example 172 in the same manner as Reference Example 177 -The title compound was synthesized using naphthyl. Yield 65%. Melting point 105-106 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6.9 Hz), 2.27 (3H, s), 2.45 (3H, s), 2.98 (1H, septet, J = 6.9 Hz), 5.36 ( 2H, s), 6.60 (1H, s), 7.35 (2H, d, J = 8.1 Hz), 7.40-7.56 (2H, m), 7.66 (1H, d, J = 8.7 Hz), 7.99 (2H, d , J = 8.1 Hz), 8.30 (1H, d, J = 8.7 Hz).
[Reference Example 179]

1- (4-Isopropylphenyl) -2-((3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl) oxy) ethanone In the same manner as in Reference Example 177, synthesized in Reference Example 175 The title compound was synthesized using methyl-5,6,7,8-tetrahydro-1-naphthalenol. Yield 65%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6.9 Hz), 1.65-1.82 (4H, m), 2.25 (3H, s), 2.62-2.75 (4H, m), 2.98 (1H , septet, J = 6.9 Hz), 5.20 (2H, s), 6.39 (1H, s), 6.55 (1H, s), 7.33 (2H, d, J = 8.1 Hz), 7.95 (2H, d, J = 8.1 Hz).
[Reference Example 180]

1- (4-Isopropylphenyl) -2-((6-methyl-2,3-dihydro-1H-inden-4-yl) oxy) ethanone The 6-synthesized in Reference Example 176 in the same manner as Reference Example 177. The title compound was synthesized using methyl-4-indanol. Yield 91%. Melting point 68-69 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6.9 Hz), 1.65-1.82 (2H, quintet, J = 7.5 Hz), 2.27 (3H, s), 2.82-3.05 (5H, m ), 5.22 (2H, s), 6.38 (1H, s), 6.70 (1H, s), 7.34 (2H, d, J = 8.4 Hz), 7.96 (2H, d, J = 8.4 Hz).
[Reference Example 181]

2-((3,5-Dimethylphenyl) thio) -1- (4-isopropylphenyl) ethanone In the same manner as in Reference Example 177, the title compound was synthesized using 3,5-dimethylthiophenol. Yield 81%. Melting point 46-47 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 6.9 Hz), 2.26 (6H, s), 2.97 (1H, septet, J = 6.9 Hz), 4.24 (2H, s), 6.85 ( 1H, s), 7.01 (2H, s), 7.31 (2H, d, J = 8.1 Hz), 7.88 (2H, d, J = 8.1 Hz).
[Reference Example 182]

7- (4-Isopropylbenzyl) -3,4,6-trimethyl-1-benzofuran In the same manner as in Reference Example 143, 1- (2- (4-isopropylbenzyl) -3,5- Dimethylphenoxy) acetone was used to give the title compound. Yield 76%. Melting point 106-107 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.9 Hz), 2.30 (3H, s), 2.36 (3H, s), 2.58 (3H, s), 2.80-2.90 (1H, septet , J = 6.9 Hz), 4.19 (2H, s), 6.79 (1H, s), 7.07 (4H, s), 7.29 (1H, s).
[Reference Example 183]

3-ethyl-7- (4-isopropylbenzyl) -4,6-dimethyl-1-benzofuran In the same manner as in Reference Example 143, 1- (2- (4-isopropylbenzyl) -3, The title compound was obtained using 5-dimethylphenoxy) butan-2-one. Yield 98%. Melting point 62-64 ° C. (diisopropyl ether-methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.6 Hz), 1.31 (3H, t, J = 7.6 Hz), 2.31 (3H, s), 2.76 (3H, s), 2.77- 2.89 (3H, m), 4.19 (2H, s), 6.79 (1H, s), 7.07 (4H, s), 7.29 (1H, s).
[Reference Example 184]

7- (4-Isopropylbenzyl) -4,6-dimethyl-3-propyl-1-benzofuran 1- (2- (4-isopropylbenzyl) -3, obtained in Reference Example 169 in the same manner as Reference Example 143. The title compound was obtained using 5-dimethylphenoxy) pentan-2-one. Yield 92%. Melting point 89-90 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.5 Hz), 1.19 (6H, d, J = 6.9 Hz), 1.70 (2H, m), 2.31 (3H, s), 2.57 ( 3H, s), 2.74 (2H, t, J = 7.5 Hz), 2.83 (1H, septet, J = 6.9 Hz), 4.20 (2H, s), 6.80 (1H, s), 7.08 (4H, s), 7.30 (1H, s).
[Reference Example 185]

3-Isopropyl-7- (4-isopropylbenzyl) -4,6-dimethyl-1-benzofuran 1- (2- (4-isopropylbenzyl) -3, obtained in Reference Example 170 in the same manner as Reference Example 143. The title compound was synthesized using 5-dimethylphenoxy-3-methylbutan-2-one Yield 87%.
¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.9 Hz), 1.33 (6H, d, J = 6.9 Hz), 2.32 (3H, s), 2.59 (3H, s), 2.83 ( 1H, septet, J = 6.9 Hz), 3.28 (1H, septet, J = 6.9 Hz), 4.20 (2H, s), 6.81 (1H, s), 7.08 (4H, s), 7.30 (1H, s).
[Reference Example 186]

3- (3-Bromophenyl) -4,6,7-trimethyl-1-benzofuran 1- (3-bromophenyl) -2- (2,3,3) obtained in Reference Example 161 in the same manner as Reference Example 143. The title compound was synthesized using 5-trimethylphenoxy) ethanone. Yield 82%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.36 (3H, s), 2.43 (3H, s), 6.84 (1H, s), 7.28 (1H, t, J = 8.1 Hz), 7.35-7.39 (1H, m), 7.48-7.53 (2H, m), 7.59-7.60 (1H, m).
[Reference Example 187]

3- (3-methoxyphenyl) -4,6,7-trimethyl-1-benzofuran 1- (3-methoxyphenyl) -2- (2,3,3) obtained in Reference Example 162 in the same manner as Reference Example 143. The title compound was synthesized using 5-trimethylphenoxy) ethanone. Yield 82%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 2.36 (3H, s), 2.43 (3H, s), 3.83 (3H, s), 6.84 (1H, s), 6.90-7.04 (3H , m), 7.32 (1H, t, J = 7.5 Hz), 7.51 (1H, s).
[Reference Example 188]

3- (4-Isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-1-benzofuran 1- (2-isopropyl-6-methoxyphenyl) -2- (2,3,3) obtained in Reference Example 171 5-trimethylphenoxy) ethanone, 1- (4-isopropyl-2-methoxyphenyl) -2- (2,3,5-trimethylphenoxy) ethanone mixture (6.27 g, 19.2 mmol), montmorillonite KSF (9.40 g ) In toluene (100 mL) was stirred at 90 ° C. for 5 hours under an argon atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate-hexane 15:85) to obtain 2.34 g (yield 40%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 6.9 Hz), 2.10 (3H, s), 2.34 (3H, s), 2.41 (3H, s), 3.00 (1H, septet, J = 6.9 Hz), 3.76 (3H, s), 6.77-6.80 (2H, m), 6.83-6.86 (1H, m), 7.17 (1H, d, J = 7.8 Hz), 7.44 (1H, s).
[Reference Example 189]

1- (4-Bromo-2- (4-isopropylbenzyl) -3,5-dimethylphenoxy) acetone 1- (2- (4-isopropylbenzyl)-obtained in Reference Example 159 in the same manner as Reference Example 23. The title compound was synthesized using 3,5-dimethylphenoxy) acetone. Yield 73%. Melting point 93-94 ° C. (methanol-THF).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.12 (3H, s), 2.39 (6H, s), 2.84 (1H, septet, J = 6.9 Hz), 4.13 ( 2H, s), 4.44 (2H, s), 6.51 (1H, s), 7.00 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz).
[Reference Example 190]

5-Bromo-7- (4-isopropylbenzyl) -3,4,6-trimethyl-1-benzofuran In the same manner as in Reference Example 143, 1- (4-bromo-1- (2- The title compound was synthesized using (4-isopropylbenzyl) -3,5-dimethylphenoxy) acetone Yield 84% Melting point 76-77 ° C. (methanol-THF).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.37 (3H, s), 2.44 (3H, s), 2.71 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 4.28 (2H, s), 7.04 (2H, d, J = 8.7 Hz), 7.08 (2H, d, J = 8.7 Hz), 7.32 (1H, s).
[Reference Example 191]

4,6,7-Trimethyl-3- (4-methylphenyl) -1-benzofuran 1- (4-methylphenyl) -2- (2,3,5-trimethylphenoxy) ethanone (1.0) obtained in Reference Example 163 g, 3.73 mmol) and polyphosphoric acid (6.0 g) were stirred at 80 ° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 770 mg (yield 83%) of the title compound. Melting point 112-113 ° C. (ethyl acetate-methanol).
¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.35 (3H, s), 2.41 (3H, s), 2.42 (3H, s), 6.81 (1H, s), 7.20 (2H, d , J = 7.8 Hz), 7.31 (2H, d, J = 7.8 Hz), 7.46 (1H, s).
[Reference Example 192]

5-methyl-2- (4,6,7-trimethyl-1-benzofuran-3-yl) pyridine 1- (5-methylpyridin-2-yl) obtained in Reference Example 168 in the same manner as Reference Example 191 The title compound was synthesized using -2- (2,3,5-trimethylphenoxy) ethanone. Yield 87%. Melting point 134-135 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 2.30 (3H, s), 2.36 (3H, s), 2.39 (3H, s), 2.42 (3H, s), 6.85 (1H, s), 7.37 (1H, d , J = 8.1 Hz), 7.53 (1H, dd, J = 2.1, 8.1 Hz), 7.67 (1H, s), 8.54 (1H, d, J = 2.1 Hz).
[Reference Example 193]

5-Bromo-3- (4-isopropyl) -4,6,7-trimethyl-1-benzofuran 4-bromo-1- (4-isopropylphenyl)-obtained in Reference Example 165 in the same manner as Reference Example 143. The title compound was synthesized using 2- (2,3,5-trimethylphenoxy) ethanone. Yield 86%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 7.0 Hz), 2.30 (3H, s), 2.51 (6H, s), 2.97 (1H, septet, J = 7.0 Hz), 7.24- 7.35 (4H, m), 7.48 (1H, s).
[Reference Example 194]

3- (4-Isopropylphenyl) -4,5,6-trimethyl-1-benzofuran In the same manner as in Reference Example 143, 2- (3,4,5-trimethylphenoxy) -1- ( The title compound was synthesized using 4-isopropylphenyl) ethanone. Yield 96%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 6.9 Hz), 2.18 (3H, s), 2.21 (3H, s), 2.39 (3H, s), 2.96 (1H, septet, J = 6.9 Hz), 7.19 (1H, s), 7.25 (2H, d, J = 8.1 Hz), 7.33 (2H, d, J = 8.1 Hz), 7.39 (1H, s).
[Reference Example 195]

3- (4-Isopropylphenyl) acetic acid 4- (2- (4-isopropylphenyl) acetic acid 4- (2- (4-isopropylphenyl) acetate obtained in Reference Example 178 in the same manner as Reference Example 143 The title compound was synthesized using) -2-oxoethoxy) -2-methyl-1-naphthyl. Yield 88%. Melting point 118-119 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 6.9 Hz), 2.15 (3H, s), 2.47 (3H, s), 2.98 (1H, septet, J = 6.9 Hz), 7.28 ( 2H, d, J = 8.4 Hz), 7.39 (2H, d, J = 8.4 Hz), 7.47-7.59 (2H, m), 7.67 (1H, s), 7.77 (1H, d, J = 8.7 Hz), 8.31 (1H, d, J = 8.7 Hz).
[Reference Example 196]

3- (4-Isopropylphenyl) -4-methyl-6,7,8,9-tetrahydronaphtho [1,2-b] furan In the same manner as in Reference Example 143, 1- (4- The title compound was synthesized using isopropylphenyl) -2-((3-methyl-5,6,7,8-tetrahydro-1-naphthalenyl) oxy) ethanone. Yield 56%. Melting point 97-98 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 6.9 Hz), 1.75-1.98 (4H, m), 2.20 (3H, s), 2.75-3.02 (5H, m), 6.74 (1H , s), 7.26 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.48 (1H, s).
[Reference Example 197]

3- (4-Isopropylphenyl) -4-methyl-7,8-dihydro-6H-indeno [4,5-b] furan 1- (4-Isopropyl) obtained in Reference Example 180 in the same manner as Reference Example 143. The title compound was synthesized using (phenyl) -2-((6-methyl-2,3-dihydro-1H-inden-4-yl) oxy) ethanone. Yield 77%. Melting point 70-72 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 6.9 Hz), 2.11-2.24 (5H, m), 2.90-3.06 (3H, m), 3.13 (2H, t, J = 7.5 Hz ), 6.91 (1H, s), 7.24 (2H, d, J = 8.1 Hz), 7.34 (2H, d, J = 8.1 Hz), 7.46 (1H, s).
[Reference Example 198]

3- (4-Isopropylphenyl) -4,6-dimethyl-1-benzothiophene In the same manner as in Reference Example 143, 2-((3,5-dimethylphenyl) thio) -1- ( The title compound was synthesized using 4-isopropylphenyl) ethanone. Yield 86%. Melting point 83-84 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 6.9 Hz), 2.06 (3H, s), 2.43 (3H, s), 2.97 (1H, septet, J = 6.9 Hz), 6.91 ( 1H, s), 7.10 (1H, s), 7.22 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.53 (1H, s).
[Reference Example 199]

3-ethyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran 3-ethyl-7- (4-isopropylbenzyl) -4,6 obtained in Reference Example 183 -Triethylsilane (0.94 mL, 5.87 mmol) was added dropwise to a mixture of dimethyl-3-propyl-1-benzofuran (941 mg, 2.94 mmol) in trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 940 mg (yield 99%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.6 Hz), 1.19 (6H, d, J = 6.9 Hz), 1.48-1.64 (2H, m), 2.16 (3H, s), 2.24 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.30-3.36 (1H, m), 3.90 (2H, s), 4.36 (1H, dd, J = 3.6, 8.7 Hz), 4.50 (1H, t, J = 8.7 Hz), 4.52 (1H, s), 7.08 (4H, s).
[Reference Example 200]

7- (4-Isopropylbenzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran 7- (4-Isopropylbenzyl) -3 obtained in Reference Example 182 in the same manner as Reference Example 199 , 4,6-Trimethyl-1-benzofuran was used to synthesize the title compound. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 1.28 (3H, d, J = 6.9 Hz), 2.16 (3H, s), 2.24 (3H, s), 2.80- 2.90 (1H, septet, J = 6.9 Hz), 3.40-3.55 (1H, m), 3.90 (2H, s), 3.17 (1H, dd, J = 4.2, 8.4 Hz), 4.56 (1H, t, J = 4.2, 8.4 Hz), 6.48 (1H, s), 7.07 (4H, s).
[Reference Example 201]

7- (4-Isopropylbenzyl) -4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran 7- (4-Isopropylbenzyl) obtained in Reference Example 184 in the same manner as Reference Example 199. The title compound was synthesized using -4,6-dimethyl-3-propyl-1-benzofuran. Yield 99%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.5 Hz), 1.15 (6H, d, J = 6.9 Hz), 1.37 (2H, m), 1.47-1.69 (2H, m), 2.16 (3H, s), 2.24 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.30-3.90 (1H, m), 3.89 (2H, s), 4.34 (1H, dd, J = 3.3, 8.7 Hz), 4.48 (1H, t, J = 8.7 Hz), 6.48 (1H, s), 7.06 (4H, s).
[Reference Example 202]

3-isopropyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran In the same manner as in Reference Example 199, 3-isopropyl-7- (4 The title compound was synthesized using -isopropylbenzyl) -4,6-dimethyl-1-benzofuran. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.73 (3H, d, J = 6.9 Hz), 0.99 (3H, d, J = 6.9 Hz), 1.19 (6H, d, J = 6.9 Hz), 2.05-2.17 ( 1H, m), 2.15 (3H, s), 2.24 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.33-3.38 (1H, m), 3.84 (1H, d, J = 15.6 Hz ), 3.95 (1H, d, J = 15.6 Hz), 4.36 (1H, t, J = 9.0 Hz), 4.50 (1H, dd, J = 2.7, 9.0 Hz), 6.49 (1H, s), 7.06 (4H , s).
[Reference Example 203]

3- (3-Bromophenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran 3- (3-Bromophenyl) -4 obtained in Reference Example 186 in the same manner as Reference Example 199 , 6,7-Trimethyl-1-benzofuran was used to synthesize the title compound. Yield 82%. Melting point 73-74 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.90 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 4.39 (1H, dd, J = 4.8, 9.0 Hz), 4.50 (1H, dd , J = 4.8, 9.0 Hz), 4.83 (1H, t, J = 9.0 Hz), 6.50 (1H, s), 7.06 (1H, d, J = 7.5 Hz), 7.15 (1H, t, J = 7.7 Hz ), 7.30 (1H, s), 7.35 (1H, d, J = 7.7 Hz).
[Reference Example 204]

3- (3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran 3- (3-methoxyphenyl) -4 obtained in Reference Example 187 in the same manner as Reference Example 199 , 6,7-Trimethyl-1-benzofuran was used to synthesize the title compound. Yield 82%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.91 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 3.76 (3H, s), 4.42 (1H, dd, J = 4.8, 8.7 Hz ), 4.52 (1H, dd, J = 4.8, 8.7 Hz), 4.84 (1H, t, J = 8.7 Hz), 6.48 (1H, s), 6.68-6.77 (3H, m), 7.20 (1H, t, J = 7.8 Hz).
[Reference Example 205]

3- (4-Isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran 3- (4-isopropyl) obtained in Reference Example 188 in the same manner as Reference Example 199 The title compound was synthesized using 2-methoxyphenyl) -4,6,7-trimethyl-1-benzofuran. Yield 79%. Melting point 102-103 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.95 (3H, s), 2.14 (3H, s), 2.24 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.87 (3H, s), 4.34 (1H, dd, J = 3.3, 7.5 Hz), 4.78-4.88 (2H, m), 6.52 (1H, s), 6.66 (2H, s), 6.73 (1H, s).
[Reference Example 206]

4,6,7-Trimethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran In the same manner as in Reference Example 144, 4,6,7-trimethyl-3- 3 obtained in Reference Example 191 was obtained. The title compound was synthesized using (4-methylphenyl) -1-benzofuran. Yield 81%. Melting point 65-66 ° C. (THF-methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.88 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 2.31 (3H, s), 4.39 (1H, dd, J = 5.2, 8.8 Hz ), 4.51 (1H, dd, J = 5.2, 8.8 Hz), 4.84 (1H, t, J = 8.8 Hz), 6.48 (1H, s), 7.02 (2H, d, J = 8.4 Hz), 7.09 (2H , d, J = 8.4 Hz).
[Reference Example 207]

5-Methyl-2- (4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) pyridine 5-methyl-2-methyl ester obtained in Reference Example 192 was prepared in the same manner as Reference Example 144. The title compound was synthesized using (4,6,7-trimethyl-1-benzofuran-3-yl) pyridine. Yield 89%. Melting point 69-70 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.92 (3H, s), 2.14 (3H, s), 2.22 (3H, s), 2.29 (3H, s), 4.55 (1H, dd, J = 4.5, 9.0 Hz ), 4.72 (1H, dd, J = 4.5, 9.0 Hz), 4.88 (1H, t, J = 9.0 Hz), 6.49 (1H, s), 6.89 (1H, d, J = 7.8 Hz), 7.37 (1H , dd, J = 2.1, 7.8 Hz), 8.37 (1H, d, J = 2.1 Hz).
[Reference Example 208]

3- (4-Isopropylphenyl) -4,5,6-trimethyl-2,3-dihydro-1-benzofuran 3- (4-Isopropylphenyl) -4 obtained in Reference Example 194 in the same manner as Reference Example 199 , 5,6-Trimethyl-1-benzofuran was used to synthesize the title compound. Yield 74%. Melting point 70-71 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.93 (3H, s), 2.06 (3H, s), 2.26 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.38 (1H, dd, J = 8.7, 4.5 Hz), 4.49 (1H, dd, J = 9.0, 4.2 Hz), 4.78 (1H, t, J = 8.7 Hz), 6.59 (1H, s ), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.0 Hz).
[Reference Example 209]

Acetic acid 3- (4-Isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan-5-yl In the same manner as in Reference Example 199, acetic acid 3- (3- The title compound was synthesized using 4-isopropylphenyl) -4-methylnaphtho [1,2-b] furan-5-yl. Yield 74%. Melting point 109-110 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.93 (3H, s), 2.42 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.63 ( 1H, dd, J = 8.7, 5.1 Hz), 4.74 (1H, dd, J = 9.3, 5.1 Hz), 5.06 (1H, t, J = 9.0 Hz), 7.05 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.38-7.50 (2H, m), 7.66 (1H, d, J = 8.7 Hz), 7.97 (1H, d, J = 8.7 Hz).
[Reference Example 210]

3- (4-Isopropylphenyl) -4-methyl-2,3,6,7,8,9-hexahydronaphtho [1,2-b] furan obtained in Reference Example 196 in the same manner as in Reference Example 199. The title compound was synthesized using 3- (4-isopropylphenyl) -4-methyl-6,7,8,9-tetrahydronaphtho [1,2-b] furan. Yield 80%. Melting point 54-55 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.70-1.98 (7H, m), 2.57-2.76 (4H, m), 2.87 (1H, septet, J = 6.9 Hz ), 4.43 (1H, dd, J = 8.4, 5.4 Hz), 4.50 (1H, dd, J = 9.0, 5.7 Hz), 4.85 (1H, t, J = 8.7 Hz), 6.40 (1H, s), 7.07 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).
[Reference Example 211]

3- (4-Isopropylphenyl) -4-methyl-3,6,7,8-tetrahydro-2H-indeno [4,5-b] furan In the same manner as in Reference Example 199, 3- The title compound was synthesized using (4-isopropylphenyl) -4-methyl-7,8-dihydro-6H-indeno [4,5-b] furan. Yield 59%. Melting point 77-78 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.93 (3H, s), 2.10 (2H, quintet, J = 7.5 Hz), 2.75-2.95 (5H, m), 4.40-4.54 (2H, m), 4.86 (1H, t, J = 8.1 Hz), 6.57 (1H, s), 7.06 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz) ).
[Reference Example 212]

3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothiophene In the same manner as in Reference Example 199, 3- (4-isopropylphenyl) -4, obtained in Reference Example 198, The title compound was synthesized using 6-dimethyl-1-benzothiophene. Yield 85%. Melting point 74-75 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 1.96 (3H, s), 2.28 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.15 ( 1H, dd, J = 11.1, 2.4 Hz), 3.90 (1H, dd, J = 11.1, 8.4 Hz), 4.64 (1H, dd, J = 8.4, 2.4 Hz), 6.63 (1H, s), 6.95 (1H , s), 7.02 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).
[Reference Example 213]

2- (4-Isopropylbenzyl) -1-methoxy-3,5-dimethylbenzene Sodium hydride (60% liquid paraffin dispersion, 757 mg, 18.9 mmol) in DMF (50 mL) mixture under argon atmosphere At 0 ° C., a DMF (15 mL) solution of 2- (4-isopropylbenzyl) -3,5-dimethylphenol (4.01 g, 15.8 mmol) obtained in Reference Example 148 was added dropwise and stirred for 30 minutes. To the reaction solution, a solution of methyl iodide (2.69 mL, 18.9 mmol) in DMF (8 mL) was added dropwise at the same temperature and stirred for 30 minutes. The reaction mixture was warmed to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 8: 1) to obtain 3.49 g (yield 82%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.19 (3H, s), 2.31 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.78 ( 3H, s), 3.97 (2H, s), 6.59 (1H, s), 6.61 (1H, s), 7.03 (2H, d, J = 8.1 Hz), 7.06 (2H, d, J = 8.1 Hz).
[Reference Example 214]

1- (Allyloxy) -3,5-dimethylbenzene In the same manner as in Reference Example 213, the title compound was synthesized using 3,5-dimethylphenol and allyl bromide. Yield 78%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.28 (6H, s), 4.48-4.52 (2H, m), 5.24-5.29 (1H, m), 5.36-5.43 (1H, m), 5.99-6.10 (1H, m), 6.55 (2H, s), 6.60 (1H, s).
[Reference Example 215]

2-allyl-3,5-dimethylphenol A solution of 1- (allyloxy) -3,5-dimethylbenzene (1.0 g, 6.2 mmol) obtained in Reference Example 214 in N, N-diethylaniline (4 mL) was placed in an argon atmosphere. Under stirring at 210 ° C. for 5 hours. Ethyl acetate was added to the reaction solution, washed with hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 7: 3) to obtain 938 mg (yield 94%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.24 (6H, s), 3.37-3.40 (2H, m), 4.79 (1H, s), 4.98-5.08 (2H, m), 5.88-6.01 (1H, m) , 6.50 (1H, s), 6.50 (1H, s).
[Reference Example 216]

2,4,6-Trimethyl-2,3-dihydro-1-benzofuran To a solution of 2-allyl-3,5-dimethylphenol (935 mg, 5.77 mmol) obtained in Reference Example 215 in methanol (5 mL), concentrated hydrochloric acid (5 mL) was added, and the mixture was heated to reflux for 20 hours under an argon atmosphere. The reaction solution was neutralized with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to give the title compound 472 mg. (Yield 50%) was obtained. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, d, J = 6.3 Hz), 2.18 (3H, s), 2.26 (3H, s), 2.67 (1H, dd, J = 7.5, 15.0 Hz), 3.19 (1H, dd, J = 8.7, 15.0 Hz), 4.86-4.96 (1H, m), 6.41 (1H, s), 6.47 (1H, s).
[Reference Example 217]

1-bromo-2- (2-chloroethoxy) -2,4-dimethylbenzene 2-bromo-3,5-dimethylphenol (16.3 g, 74.6 mmol) obtained in Reference Example 149, benzyl-tri-n-butyl A mixture of ammonium chloride (23.3 g, 7.46 mmol) in 1,2-dichloroethane (150 mL) -8N aqueous sodium hydroxide (26 mL) -water (110 mL) was heated to reflux for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 16.6 g (yield 90%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.28 (3H, s), 2.37 (3H, s), 3.85 (2H, t, J = 6.3 Hz), 4.25 (2H, t, J = 6.3 Hz), 6.57 ( 1H, s), 6.73 (1H, s).
[Reference Example 218]

2-Bromo-3- (2-chloroethoxy) -4- (4-isopropylphenyl) -1,5-dimethylbenzene In the same manner as in Reference Example 217, 2-bromo-6- (4 The title compound was synthesized using -isopropylbenzyl) -3,5-dimethylphenol. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 2.15 (3H, s), 2.37 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.75 ( 2H, t, J = 6.0 Hz), 3.98-4.07 (4H, m), 6.89 (1H, s), 7.00 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz).
[Reference Example 219]

4,6-Dimethyl-2,3-dihydro-1-benzofuran 1-bromo-2- (2-chloroethoxy) -2,4-dimethylbenzene (8.70 g, 33.0 mmol) obtained in Reference Example 217 in THF ( 210 mL) n-butyllithium (1.6 M hexane solution, 31 mL, 49.5 mmol) was quickly added to the solution at 0 ° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. The reaction mixture was warmed to room temperature, added to ice, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 4.70 g (yield 96%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 2.26 (3H, s), 3.06 (2H, t, J = 8.7 Hz), 4.54 (2H, t, J = 8.7 Hz), 6.45 ( 1H, s), 6.48 (1H, s).
[Reference Example 220]

7- (4-Isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran 2-Bromo-3- (2-chloroethoxy) obtained in Reference Example 218 in the same manner as Reference Example 219 The title compound was synthesized using -4- (4-isopropylphenyl) -1,5-dimethylbenzene. Yield 81%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.17 (3H, s), 2.19 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.11 ( 2H, t, J = 8.7 Hz), 3.90 (2H, s), 4.56 (2H, t, J = 8.7 Hz), 6.49 (1H, s), 7.07 (4H, s).
[Reference Example 221]

5-Bromo-7- (4-isopropylbenzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran 7- (4-isopropyl) obtained in Reference Example 200 in the same manner as Reference Example 23. The title compound was synthesized using (benzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran. Yield 87%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 1.28 (3H, d, J = 6.9 Hz), 2.30 (3H, s), 2.35 (3H, s), 2.80- 2.90 (1H, septet, J = 6.9 Hz), 3.40-3.55 (1H, m), 3.98 (2H, s), 4.21 (1H, dd, J = 3.0, 8.7 Hz), 4.54 (1H, t, J = 8.7 Hz), 7.03 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz).
[Reference Example 222]

5-Bromo-3-ethyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran 3-ethyl-obtained in Reference Example 199 in the same manner as Reference Example 23 The title compound was synthesized using 7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran. Yield 99%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.6 Hz), 1.20 (6H, d, J = 6.9 Hz), 1.49-1.64 (2H, m), 2.30 (3H, s), 2.34 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.31-3.37 (1H, m), 3.97 (2H, s), 4.38 (1H, dd, J = 3.0, 8.7 Hz), 4.48 (1H, t, J = 8.7 Hz), 7.04 (2H, d, J = 8.1 Hz), 7.09 (2H, d, J = 8.1 Hz).
[Reference Example 223]

5-Bromo-7- (4-isopropylbenzyl) -4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran 7- (4 obtained in Reference Example 201 in the same manner as Reference Example 23. The title compound was synthesized using -isopropylbenzyl) -4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.5 Hz), 1.20 (6H, d, J = 6.9 Hz), 1.22-1.42 (2H, m), 1.47-1.62 (2H, m ), 2.29 (3H, s), 2.34 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.30-3.40 (1H, m), 3.98 (2H, s), 4.38 (1H, dd, J = 3.3, 9.0 Hz), 4.47 (1H, t, J = 9.0 Hz), 7.04 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz).
[Reference Example 224]

5-Bromo-3-isopropyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran In the same manner as in Reference Example 23, 3-isopropyl- obtained in Reference Example 202 The title compound was synthesized using 7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.73 (3H, d, J = 6.9 Hz), 0.98 (3H, d, J = 6.9 Hz), 1.20 (6H, d, J = 6.9 Hz), 2.01-2.10 ( 1H, m), 2.29 (3H, s), 2.34 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.34-3.39 (1H, m), 3.92 (1H, d, J = 15.3 Hz ), 4.02 (1H, d, J = 15.3 Hz), 4.36 (1H, t, J = 9.0 Hz), 4.50 (1H, dd, J = 2.7, 9.0 Hz), 7.03 (2H, d, J = 8.7 Hz) ), 7.08 (2H, d, J = 8.7 Hz).
[Reference Example 225]

5-Bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran 2,4,6-trimethyl-2,3-dihydro-1 obtained in Reference Example 216 in the same manner as Reference Example 23 -The title compound was synthesized using benzofuran. Yield 89%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, d, J = 6.3 Hz), 2.28 (3H, s), 2.35 (3H, s), 2.74 (1H, dd, J = 7.5, 15.0 Hz), 3.26 (1H, dd, J = 8.7, 15.0 Hz), 4.85-4.97 (1H, m), 6.52 (1H, s).
[Reference Example 226]

5-Bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran In the same manner as in Reference Example 23, the 4,6-dimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 219 was used. The title compound was synthesized. Yield 92%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 2.35 (3H, s), 3.15 (2H, t, J = 8.7 Hz), 4.56 (2H, t, J = 8.7 Hz), 6.56 ( 1H, s).
[Reference Example 227]

5-Bromo-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran 7- (4-isopropylbenzyl) obtained in Reference Example 220 in the same manner as Reference Example 23. The title compound was synthesized using -4,6-dimethyl-2,3-dihydro-1-benzofuran. Yield 92%. Melting point 95-96 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.31 (6H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.19 (2H, t, J = 8.4 Hz), 3.97 (2H, s), 4.56 (2H, t, J = 8.7 Hz), 7.04 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz).
[Reference Example 228]

3-Phenyl-4,6,7-trimethyl-1-benzofuran-2 (3H) -one In the same manner as in Reference Example 2, using 2,3,5-trimethylphenol and hydroxy (phenyl) acetic acid, the title compound was prepared. Synthesized. Yield 37%. Melting point 129-130 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.92 (3H, s), 2.25 (3H, s), 2.30 (3H, s), 4.80 (1H, s), 6.78 (1H, s), 7.16-7.20 (2H , m), 7.27-7.40 (3H, m).
[Reference Example 229]

3- (4-Bromophenyl) -4,6,7-trimethyl-1-benzofuran-2 (3H) -one In the same manner as in Reference Example 2, 2,3,5-trimethylphenol and hydroxy (4-bromophenyl) ) The title compound was synthesized using acetic acid. Yield 43%. Melting point 168-169 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.93 (3H, s), 2.24 (3H, s), 2.30 (3H, s), 4.76 (1H, s), 6.79 (1H, s), 7.06 (2H, d , J = 8.1 Hz), 7.47 (2H, d, J = 8.1 Hz).
[Reference Example 230]

3- (4-Isopropylphenyl) -4,7-dimethyl-1-benzofuran-2 (3H) -one In the same manner as in Reference Example 2, hydroxy (4-isopropylphenyl) acetic acid synthesized in Reference Example 1 and 2, The title compound was synthesized using 5-dimethylphenol. Yield 20%. Melting point 107-109 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 7.0 Hz), 1.97 (3H, s), 2.33 (3H, s), 2.89 (1H, septet, J = 7.0 Hz), 4.77 ( 1H, s), 6.86 (1H, d, J = 7.6 Hz), 7.05-7.13 (3H, m), 7.19 (2H, d, J = 8.0 Hz).
[Reference Example 231]

2- (2-Hydroxy-1- (phenyl) ethyl) -3,5,6-trimethylphenol
In the same manner as in Reference Example 8, the title compound was synthesized using 3-phenyl-4,6,7-trimethyl-1-benzofuran-2 (3H) -one obtained in Reference Example 228. Yield 82%. Melting point 103-104 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 2.15 (3H, s), 2.19 (3H, s), 2.24 (3H, s), 4.26 (1H, d, J = 10.8 Hz), 4.47 (1H, dd, J = 5.1, 10.8 Hz), 4.53 (1H, br), 6.60 (1H, s), 7.20-7.35 (5H, m), 8.00 (1H, br), 1H not confirmed.
[Reference Example 232]

2- (2-Hydroxy-1- (4-bromophenyl) ethyl) -3,5,6-trimethylphenol 3- (4-Bromophenyl) -4 obtained in Reference Example 229 in the same manner as Reference Example 8. , 6,7-Trimethyl-1-benzofuran-2 (3H) -one was used to synthesize the title compound. Yield 93%. Melting point 114-115 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.19 (3H, s), 2.23 (3H, s), 4.20-4.30 (1H, m), 4.40-4.52 (2H, m), 6.60 (1H, s), 7.13 (2H, d, J = 8.4 H), 7.41 (2H, d, J = 8.4 H), 7.72 (1H, s), 1H not confirmed.
[Reference Example 233]

2- (2-Hydroxy-1- (4-isopropylphenyl) ethyl) -3,6-dimethylphenol 3- (4-Isopropylphenyl) -4,7 synthesized in Reference Example 230 in the same manner as Reference Example 8. The title compound was synthesized using -dimethyl-1-benzofuran-2 (3H) -one. Yield 88%. Melting point 88-89 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.21 (3H, s), 2.23 (3H, s), 2.25 (1H, br s), 2.87 (1H, septet, J = 6.9 Hz), 4.20-4.30 (1H, m), 4.32-4.52 (2H, m), 6.65 (1H, d, J = 7.2 Hz), 6.96 (1H, d, J = 7.2 Hz), 7.17 ( 4H, s), 8.18 (1H, br s).
[Reference Example 234]

3-Bromo-6- (2-hydroxy-1- (4-isopropylphenyl) ethyl) -2,4,5-trimethylphenol Hydroxy (4-isopropylphenyl) acetic acid synthesized in Reference Example 1 (10.0 g, 46.5 mmol) ), 70% sulfuric acid (10 mL) was added to a mixture of 3-bromo-2,4,5-trimethylphenol (8.2 g, 42.2 mmol) synthesized in Reference Example 68 at room temperature, and the mixture was stirred at 115 ° C. for 4 hours. . The mixture was added to water and extracted with diisopropyl ether. The extract was washed with water and saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 8) to give 6-bromo-3- (4-isopropylphenyl) -4,5,7-trimethyl. -1-Benzofuran-2 (3H) -one was obtained. To a solution of this compound in THF (80 mL), lithium aluminum hydride (2.40 g, 63.3 mmol) was added at 0 ° C., and the mixture was heated to reflux for 1 hour. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 15.5 g (yield 97%) of the title compound. Melting point 96-97 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.19 (3H, s), 2.38 (3H, s), 2.39 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.24 (1H, dt, J = 11.4, 2.7 Hz), 4.42 (1H, ddd, J = 11.4, 5.4, 2.7 Hz), 4.60 (1H, dd, J = 5.4, 2.7 Hz), 4.93 (1H, d, J = 6.3 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.17 (2H, d, J = 8.7 Hz), 8.27 (1H, br s).
[Reference Example 235]

4,6,7-Trimethyl-3-phenyl-2,3-dihydro-1-benzofuran 2- (2-hydroxy-1- (phenyl) ethyl)-obtained in Reference Example 231 in the same manner as Reference Example 13. The title compound was synthesized using 3,5,6-trimethylphenol. Yield 95%. Melting point 72-73 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.88 (3H, s), 2.16 (3H, s), 2.23 (3H, s), 4.43 (1H, dd, J = 5.1, 9.0 Hz), 4.55 (1H, dd , J = 5.1, 9.0 Hz), 4.86 (1H, t, J = 9.0 Hz), 6.49 (1H, s), 7.13-7.31 (5H, m).
[Reference Example 236]

3- (4-Bromophenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran In the same manner as in Reference Example 13, 2- (2-hydroxy-1- ( The title compound was synthesized using 4-bromophenyl) ethyl) -3,5,6-trimethylphenol. Yield 95%. Melting point 72-73 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.88 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 4.36 (1H, dd, J = 5.1, 9.0 Hz), 4.50 (1H, dd , J = 5.1, 9.0 Hz), 4.83 (1H, t, J = 9.0 Hz), 6.49 (1H, s), 7.01 (2H, d, J = 8.7 Hz), 7.40 (2H, d, J = 8.7 Hz) ).
[Reference Example 237]

3- (4-Isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran 2- (2-hydroxy-1- (4-) synthesized in Reference Example 233 in the same manner as Reference Example 13. The title compound was synthesized using isopropylphenyl) ethyl) -3,6-dimethylphenol. Yield 85%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 7.0 Hz), 1.92 (3H, s), 2.29 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 4.35- 4.53 (2H, m), 4.75-4.90 (1H, m), 6.47 (1H, s), 6.55 (1H, s), 7.05 (2H, d, J = 8.0 Hz), 7.13 (2H, d, J = 8.0 Hz).
[Reference Example 238]

6-bromo-3- (4-isopropylphenyl) -4,5,7-trimethyl-2,3-dihydro-1-benzofuran 3-bromo-6-synthesized in Reference Example 234 in the same manner as Reference Example 13. The title compound was synthesized using (2-hydroxy-1- (4-isopropylphenyl) ethyl) -2,4,5-trimethylphenol. Yield 57%. Melting point 56-57 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.95 (3H, s), 2.28 (3H, s), 2.32 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.42 (1H, dd, J = 8.7, 4.8 Hz), 4.50 (1H, dd, J = 9.0, 4.2 Hz), 4.81 (1H, t, J = 8.7 Hz), 7.01 (2H, d , J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).
[Reference Example 239]

5-Bromo-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran 4,6,7-trimethyl-3-phenyl obtained in Reference Example 235 in the same manner as Reference Example 23 The title compound was synthesized using -2,3-dihydro-1-benzofuran. Yield 79%. Melting point 107-108 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 2.03 (3H, s), 2.24 (3H, s), 2.39 (3H, s), 4.41 (1H, dd, J = 4.5, 9.0 Hz), 4.59 (1H, dd , J = 4.5, 9.0 Hz), 4.84 (1H, t, J = 9.0 Hz), 7.08-7.13 (2H, m), 7.18-7.34 (3H, m).
[Reference Example 240]

5-Bromo-4,6,7-trimethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran 4,6,7- obtained in Reference Example 206 in the same manner as Reference Example 23 The title compound was synthesized using trimethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran. Yield 96%. Melting point 108-109 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 2.03 (3H, s), 2.23 (3H, s), 2.31 (3H, s), 2.38 (3H, s), 4.38 (1H, dd, J = 4.8, 8.4 Hz ), 4.55 (1H, dd, J = 4.8, 8.4 Hz), 4.82 (1H, t, J = 8.4 Hz), 6.99 (2H, d, J = 8.0 Hz), 7.09 (2H, d, J = 8.0 Hz) ).
[Reference Example 241]

5-Bromo-3- (4-isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran 3- (4-isopropylphenyl) obtained in Reference Example 237 in the same manner as Reference Example 23 The title compound was synthesized using -4,7-dimethyl-2,3-dihydro-1-benzofuran. Yield 77%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 7.0 Hz), 1.99 (3H, s), 2.21 (3H, s), 2.87 (1H, septet, J = 7.0 Hz), 4.43 ( 1H, dd, J = 8.2, 4.8 Hz), 4.53 (1H, dd, J = 9.0, 4.4 Hz), 4.85 (1H, t, J = 8.3 Hz), 7.02 (2H, d, J = 8.2 Hz), 7.14 (2H, d, J = 8.2 Hz), 7.19 (1H, s).
[Reference Example 242]

5-Methyl-2- (5-bromo-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) pyridine In the same manner as in Reference Example 23, The title compound was synthesized using methyl-2- (4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) pyridine. Yield 84%. Melting point 105-106 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 2.06 (3H, s), 2.22 (3H, s), 2.29 (3H, s), 2.37 (3H, s), 4.63 (1H, dd, J = 4.5, 9.0 Hz ), 4.76 (1H, dd, J = 4.5, 9.0 Hz), 4.87 (1H, t, J = 9.0 Hz), 6.86 (1H, d, J = 8.1 Hz), 7.37 (1H, d, J = 8.1 Hz) ), 8.37 (1H, s).
[Reference Example 243]

3- (biphenyl-4-yl) -5-bromo-4,6,7-trimethyl-2,3-dihydro-1-benzofuran 3- (4-bromophenyl) -4,6 obtained in Reference Example 236 Of 7-trimethyl-2,3-dihydro-1-benzofuran (1.0 g, 3.15 mmol), phenylboronic acid (500 mg, 4.10 mmol), tetrakis (triphenylphosphine) palladium (0) (73 mg, 0.063 mmol) A 2N aqueous sodium carbonate solution (4 mL) -ethanol (4 mL) -toluene (15 mL) mixture was reacted at 80 ° C. for 5 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to give (3-biphenyl-4- Yl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran (750 mg, yield 76%). Using this compound, 873 mg of the title compound was synthesized in the same manner as in Reference Example 23. Yield 93%. Melting point 153-154 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 2.08 (3H, s), 2.26 (3H, s), 2.40 (3H, s), 4.46 (1H, dd, J = 5.0, 9.0 Hz), 4.62 (1H, dd , J = 5.0, 9.0 Hz), 4.88 (1H, t, J = 9.0 Hz), 7.15-7.60 (9H, m).
[Reference Example 244]

2-Bromo-4- (4-isopropylbenzyl) -5-methoxy-1,3-dimethylbenzene 2- (4-isopropylbenzyl) -1-methoxy-3,5-dimethylbenzene (3.45) obtained in Reference Example 213 g, 12.9 mmol) N-bromosuccinimide (2.29 g, 12.9 mmol) was added to acetonitrile (40 mL) under ice cooling, and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Ethyl acetate-hexane (1: 9) was added to the residue, the precipitated crystals were filtered, and the filtrate was concentrated to obtain 4.50 g (quantitative yield) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.34 (3H, s), 2.42 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.78 ( 3H, s), 4.06 (2H, s), 6.70 (1H, s), 7.00 (2H, d, J = 8.1 Hz), 7.04 (2H, d, J = 8.1 Hz).
[Reference Example 245]

3- (3-Formylphenyl) -4,6,7-trimethyl-1-benzofuran 3- (3-bromophenyl) -4,6,7-trimethyl-2,3-dihydro-1 obtained in Reference Example 203 -N-Butyllithium (1.6 M hexane solution, 4.18 mL, 6.68 mmol) was added dropwise to a solution of benzofuran (1.77 g, 5.57 mmol) in THF (20 mL) at -78 ° C under an argon atmosphere, and the mixture was stirred for 30 minutes. DMF (0.86 mL, 11.14 mmol) was added dropwise to the reaction solution at the same temperature, and the mixture was stirred for 30 minutes and then warmed to room temperature. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.48 g of the title compound (quantitative yield). Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.88 (3H, s), 2.17 (3H, s), 2.24 (3H, s), 4.42 (1H, dd, J = 4.5, 9.0 Hz), 4.63 (1H, dd , J = 4.5, 9.0 Hz), 4.88 (1H, t, J = 9.0 Hz), 6.50 (1H, s), 7.39-7.49 (2H, m), 7.67-7.69 (1H, m), 7.73-7.76 ( 1H, m), 9.98 (1H, s).
[Reference Example 246]

3- (4-Formylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran 3- (4-bromophenyl) -4 obtained in Reference Example 236 in the same manner as Reference Example 245 , 6,7-Trimethyl-2,3-dihydro-1-benzofuran was used to synthesize the title compound. Yield 73%. Melting point 87-88 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.88 (3H, s), 2.17 (3H, s), 2.24 (3H, s), 4.43 (1H, dd, J = 4.5, 9.0 Hz), 4.62 (1H, dd , J = 4.5, 9.0 Hz), 4.88 (1H, t, J = 9.0 Hz), 6.51 (1H, s), 7.32 (2H, d, J = 8.1 Hz), 7.81 (2H, d, J = 8.1 Hz) ), 9.98 (1H, s).
[Reference Example 247]

3- (3- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran 3- (3-formylphenyl) obtained in Reference Example 245 -4,6,7-trimethyl-1-benzofuran (1.48 g, 5.57 mmol), ethylene glycol (0.62 mL, 11.14 mmol) and p-toluenesulfonic acid monohydrate (50 mg) in toluene (20 mL) The solution was heated to reflux using a Dean-Starks apparatus for 16 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.52 g, yield 88%). Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.87 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 3.98-4.13 (4H, m), 4.39 (1H, dd, J = 5.4, 9.0 Hz), 4.57 (1H, dd, J = 5.4, 9.0 Hz), 4.85 (1H, t, J = 9.0 Hz), 5.75 (1H, s), 6.47 (1H, s), 7.08-7.12 (1H, m), 7.25-7.35 (3H, m).
[Reference Example 248]

3- (4- (1,3-Dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 246 in the same manner as Reference Example 247. The title compound was synthesized using 3- (4-formylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran. Yield 73%. Melting point 107-108 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.87 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 3.97-4.16 (4H, m), 4.39 (1H, dd, J = 4.5, 8.4 Hz), 4.56 (1H, dd, J = 4.5, 8.4 Hz), 4.85 (1H, t, J = 8.4 Hz), 5.77 (1H, s), 6.48 (1H, s), 7.17 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz).
[Reference Example 249]

5-Bromo-3- (3- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran In the same manner as in Reference Example 23, Reference Example The title compound was synthesized using 3- (3- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in 247. Yield 73%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.02 (3H, s), 2.24 (3H, s), 2.39 (3H, s), 4.00-4.16 (4H, m), 4.39 (1H, dd, J = 4.5, 9.0 Hz), 4.62 (1H, dd, J = 4.5, 9.0 Hz), 4.84 (1H, t, J = 9.0 Hz), 5.76 (1H, s), 7.05-7.09 (1H, m), 7.26-7.38 ( 3H, m).
[Reference Example 250]

5-Bromo-3- (4- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran In the same manner as in Reference Example 23, Reference Example The title compound was synthesized using 3- (4- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in 248. Yield quantitative. Melting point 146-147 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, s), 2.24 (3H, s), 2.39 (3H, s), 4.00-4.15 (4H, m), 4.38 (1H, dd, J = 4.5, 9.0 Hz), 4.60 (1H, dd, J = 4.5, 9.0 Hz), 4.83 (1H, t, J = 9.0 Hz), 5.77 (1H, s), 7.13 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz).
[Reference Example 251]

5-Bromo-3- (4-isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran In the same manner as in Reference Example 23, 3- The title compound was synthesized using (4-isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran. Yield 96%. Melting point 102-103 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 2.07 (3H, s), 2.22 (3H, s), 2.39 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.87 (3H, s), 4.33 (1H, dd, J = 3.3, 9.0 Hz), 4.82 (1H, t, J = 9.0 Hz), 4.90 (1H, dd, J = 3.3, 9.0 Hz) ), 6.60 (1H, d, J = 7.5 Hz), 6.67 (1H, d, J = 7.5 Hz), 6.74 (1H, s).
[Reference Example 252]

3- (4-Isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan-5-ol Acetic acid synthesized in Reference Example 209 in the same manner as Reference Example 175 3- (4 The title compound was synthesized using -isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan-5-yl. Yield 91%. Mp 94-96 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.04 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.52-4.74 (3H, m), 4.92-5.08 (1H, m), 7.04 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.35-7.53 (2H, m), 7.91-8.12 (2H, m) .
[Reference Example 253]

Tri (trifluoromethanesulfonic acid) 3- (4-isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan-5-yl 3- (4-isopropylphenyl)-obtained in Reference Example 252 To a solution of 4-methyl-2,3-dihydronaphtho [1,2-b] furan-5-ol (2.60 g, 8.17 mmol) and 4-dimethylaminopyridine (2.0 g, 16.3 mmol) in pyridine (30 mL) Trifluoromethanesulfonic anhydride (1.51 mL, 9.00 mmol) was added at 0 ° C at room temperature, and the mixture was stirred at 50 ° C for 8 hours. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2.8 g (yield 76%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 7.0 Hz), 2.16 (3H, s), 2.87 (1H, septet, J = 7.0 Hz), 4.62-4.80 (2H, m), 5.10 (1H, t, J = 9.0 Hz), 7.04 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J = 8.1 Hz), 7.46-7.64 (2H, m), 7.96-8.05 (2H , m).
[Reference Example 254]

3- (4-Isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan trifluoromethanesulfonic acid 3- (4-isopropylphenyl) -4-methyl- obtained in Reference Example 253 2,3-dihydronaphtho [1,2-b] furan-5-yl (2.23 g, 4.96 mmol), dichlorobis (triphenylphosphine) palladium (210 mg, 0.30 mmol), 1,3-bis (diphenylphosphino) ) Formic acid (0.5 mL) was added to a toluene (15 mL) solution of propane (310 mg, 0.750 mmol) and tributylamine (5 mL, 21 mmol) at room temperature, and the mixture was stirred at 90 ° C. for 16 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1:20) to obtain 270 mg (yield 18%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.11 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.64 (1H, dd, J = 8.7 , 4.8 Hz), 4.72 (1H, dd, J = 9.3, 5.1 Hz), 5.06 (1H, t, J = 8.7 Hz), 7.07 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz), 7.14 (1H, s), 7.39-7.48 (2H, m), 7.70-7.76 (1H, m), 7.94-8.02 (1H, m).
[Reference Example 255]

5-Bromo-3- (4-isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan In the same manner as in Reference Example 23, 3- (4- The title compound was synthesized using isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan. Yield 88%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.26 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.64 (1H, dd, J = 8.7 , 4.5 Hz), 4.75 (1H, dd, J = 9.6, 4.5 Hz), 5.05 (1H, t, J = 8.7 Hz), 7.03 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz), 7.40-7.62 (2H, m), 7.98 (1H, d, J = 8.1 Hz), 8.24 (1H, d, J = 8.4 Hz).
[Reference Example 256]

7-Bromo-3- (4-isopropylphenyl) -4,5,6-trimethyl-2,3-dihydro-1-benzofuran 3- (4-isopropyl) obtained in Reference Example 208 in the same manner as Reference Example 23. The title compound was synthesized using (phenyl) -4,5,6-trimethyl-2,3-dihydro-1-benzofuran. Yield 95%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.14 (3H, s), 2.40 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.48 (1H, dd, J = 8.4, 4.5 Hz), 4.63 (1H, dd, J = 9.0, 4.5 Hz), 4.90 (1H, t, J = 9.0 Hz), 7.04 (2H, d , J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).
[Reference Example 257]

5-Bromo-3- (4-isopropylphenyl) -4-methyl-2,3,6,7,8,9-hexahydronaphtho [1,2-b] furan In the same manner as in Reference Example 23, Reference Example The title compound was synthesized using 3- (4-isopropylphenyl) -4-methyl-2,3,6,7,8,9-hexahydronaphtho [1,2-b] furan obtained in 210. Yield 85%. Melting point 108-109 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.68-1.90 (4H, m), 2.03 (3H, s), 2.60-2.89 (4H, m), 2.86 (1H , septet, J = 6.9 Hz), 4.42 (1H, dd, J = 8.7, 4.8 Hz), 4.54 (1H, dd, J = 9.0, 4.5 Hz), 4.83 (1H, t, J = 9.0 Hz), 7.01 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).
[Reference Example 258]

5-Bromo-3- (4-isopropylphenyl) -4-methyl-3,6,7,8-tetrahydro-2H-indeno [4,5-b] furan In the same manner as in Reference Example 23, in Reference Example 211 The title compound was synthesized using the obtained 3- (4-isopropylphenyl) -4-methyl-3,6,7,8-tetrahydro-2H-indeno [4,5-b] furan. Yield 84%. Melting point 127-128 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.01 (3H, s), 2.13 (2H, quintet, J = 7.5 Hz), 2.80-3.03 (5H, m), 4.45 (1H, dd, J = 8.7, 4.8 Hz), 4.53 (1H, dd, J = 9.0, 4.8 Hz), 4.86 (1H, t, J = 8.7 Hz), 7.03 (2H, d, J = 8.1 Hz) ), 7.14 (2H, d, J = 8.1 Hz).
[Reference Example 259]

5-Bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothiophene 3- (4-isopropylphenyl) -4,6-dimethyl-synthesized in Reference Example 212 To a mixture of 2,3-dihydro-1-benzothiophene (4.45 g, 15.8 mmol) and iron powder (59 mg, 1.05 mmol) in methylene chloride (20 mL) was added bromine (0.81 mL, 15.8 mmol) at 0 ° C. Stir at the same temperature for 1 hour. Water was poured into the reaction mixture and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1:10) to obtain 4.6 g (yield 80%) of the title compound. Melting point 98-100 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.12 (3H, s), 2.39 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.15 ( 1H, dd, J = 11.1, 1.8 Hz), 3.93 (1H, dd, J = 11.1, 8.7 Hz), 4.64 (1H, d, J = 8.7 Hz), 7.01 (2H, d, J = 8.1 Hz), 7.05 (1H, s), 7.12 (2H, d, J = 8.1 Hz).
[Reference Example 260]

4,6,7-Trimethyl-1-benzofuran-3 (2H) -one In the same manner as in Reference Example 41, the title compound was synthesized using (2,3,5-trimethylphenoxy) acetic acid obtained in Reference Example 158. did. Yield 75%. Melting point 92-93 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 2.30 (3H, s), 2.53 (3H, s), 4.58 (2H, s), 6.64 (1H, s).
[Reference Example 261]

Tribromomethanesulfonic acid 5-bromo-4,6,7-trimethyl-1-benzofuran-3-yl 4,6,7-trimethyl-1-benzofuran-3 obtained in Reference Example 260 in the same manner as in Reference Example 23 5-Bromo-4,6,7-trimethyl-1-benzofuran-3 (2H) -one was synthesized using (2H) -one. Yield 86%. Diisopropylethylamine (1.14 mL, 6.53 mmol) was added dropwise to a solution of this compound (1.0 g, 5.7 mmol) in methylene chloride (10 mL) at −30 ° C. under an argon atmosphere. Trifluoromethanesulfonic anhydride (0.96 mL, 5.70 mmol) was added dropwise to the reaction solution, and the mixture was warmed to room temperature and stirred for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to give 1.38 g (yield) of the title compound. 63%) was synthesized. Melting point 54-55 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H, s), 2.50 (3H, s), 2.64 (3H, s), 7.77 (1H, s).
[Reference Example 262]

5-Bromo-3- (4-ethylphenyl) -4,6,7-trimethyl-1-benzofuran Trifluoromethanesulfonic acid 5-bromo-4,6,7-trimethyl-1-benzofuran-obtained in Reference Example 261 2N aqueous sodium carbonate solution of 4-yl (1.35 g, 3.49 mmol), 4-ethylphenylboronic acid (523 mg, 3.49 mmol), tetrakis (triphenylphosphine) palladium (0) (81 mg, 0.07 mmol) (4 mL) -ethanol (4 mL) -toluene (15 mL) was reacted at 80 ° C. for 5 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to synthesize 1.10 g of the title compound (yield 92%). did. Oily substance. .
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.5 Hz), 2.30 (3H, s), 2.52 (6H, s), 2.72 (2H, q, J = 7.5 Hz), 7.25 ( 2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.48 (1H, s).
[Reference Example 263]

N-benzyl-7- (4-isopropylbenzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine In the same manner as in Reference Example 24, 5- The title compound was synthesized using bromo-7- (4-isopropylbenzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran. Yield 84%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 1.28 (3H, d, J = 6.9 Hz), 2.16 (3H, s), 2.24 (3H, s), 2.80- 2.90 (1H, septet, J = 6.9 Hz), 3.40-3.55 (1H, m), 3.85-3.95 (4H, m), 4.17 (1H, dd, J = 3.3, 8.7 Hz), 4.53 (1H, t, J = 8.7 Hz), 7.07 (4H, s), 7.25-7.38 (5H, m). 1H unconfirmed.
[Reference Example 264]

N-benzyl-3-ethyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine Obtained in Reference Example 222 in the same manner as in Reference Example 24. The title compound was synthesized using 5-bromo-3-ethyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran. Yield 76%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.5 Hz), 1.20 (6H, d, J = 6.9 Hz), 1.50-1.66 (2H, m), 2.15 (3H, s), 2.21 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 2,88 (1H, br), 3.26-3.37 (1H, m), 3.87-4.00 (4H, m), 4.34 (1H, dd, J = 3.0, 9.0 Hz), 4.46 (1H, t, J = 9.0 Hz), 7.06 (4H, s), 7.25-7.38 (5H, s).
[Reference Example 265]

N-benzyl-7- (4-isopropylbenzyl) -4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-amine Obtained in Reference Example 223 in the same manner as Reference Example 24. The title compound was synthesized using 5-bromo-7- (4-isopropylbenzyl) -4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran. Yield 85%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.2 Hz), 1.21 (6H, d, J = 6.9 Hz), 1.27-1.42 (2H, m), 1.50-1.63 (2H, m ), 2.15 (3H, s), 2.22 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 2.89 (1H, br), 3.30-3.39 (1H, m), 3.93 (2H, s) , 4.34 (1H, dd, J = 3.3, 9.0 Hz), 4.45 (1H, t, J = 9.0 Hz), 7.08 (4H, s), 7.09 (2H, d, J = 8.4 Hz), 7.16-7.40 ( 5H, m).
[Reference Example 266]

N-Benzyl-3-isopropyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine Obtained in Reference Example 224 in the same manner as Reference Example 24. The title compound was synthesized using 5-bromo-3-isopropyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran. Yield 73%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.73 (3H, d, J = 6.9 Hz), 0.99 (3H, d, J = 6.9 Hz), 1.21 (6H, d, J = 6.9 Hz), 2.01-2.10 ( 1H, m), 2.14 (3H, s), 2.19 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 2.90 (1H, br), 3.30-3.35 (1H, m), 3.81-4.01 (4H, m), 4.34 (1H, t, J = 9.0 Hz), 4.47 (1H, dd, J = 2.7, 9.0 Hz), 7.06 (4H, s), 7.24-7.36 (5H, m).
[Reference Example 267]

N-benzyl-3- (4-isopropylbenzyl) -4-methoxy-2,6-dimethylaniline In the same manner as in Reference Example 24, 5-bromo-2,4,6-trimethyl-2 obtained in Reference Example 244 The title compound was synthesized using 1,3-dihydro-1-benzofuran. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.19 (3H, s), 2.28 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.76 ( 3H, s), 3.95 (2H, s), 4.02 (2H, s), 6.63 (1H, s), 7.01 (2H, d, J = 8.1 Hz), 7.07 (2H, d, J = 8.1 Hz), 7.24-7.37 (5H, m) 1H unconfirmed.
[Reference Example 268]

N-benzyl-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine 4-bromo-2- (4-isopropylbenzyl) obtained in Reference Example 225 in the same manner as Reference Example 24. The title compound was synthesized using 1-methoxy-3,5-dimethylbenzene. Yield 70%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, d, J = 6.3 Hz), 2.19 (3H, s), 2.23 (3H, s), 2.70 (1H, dd, J = 7.5, 15.0 Hz), 3.21 (1H, dd, J = 8.7, 15.0 Hz), 3.95 (2H, s), 4.85-4.97 (1H, m), 6.45 (1H, s), 7.25-7.41 (5H, m), 1H not confirmed.
[Reference Example 269]

N-benzyl-7- (4-isopropylbenzyl) -3,4,6-trimethyl-1-benzofuran-5-amine 5-bromo-7- (4 obtained in Reference Example 190 in the same manner as Reference Example 24. -Isopropylbenzyl) -3,4,6-trimethyl-1-benzofuran was used to give the title compound. Yield 93%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.26 (3H, s), 2.38 (3H, s), 2.60 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.11 (1H, br s), 3.98 (2H, s), 4.23 (2H, s), 7.05 (4H, s), 7.24-7.41 (6H, m).
[Reference Example 270]

N-benzyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine 5-bromo-4,6-dimethyl-2,3 obtained in Reference Example 226 in the same manner as Reference Example 24 -The title compound was obtained using dihydro-1-benzofuran. Yield 89%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 2.22 (3H, s), 3.10 (2H, t, J = 8.7 Hz), 3.96 (2H, s), 4.53 (2H, t, J = 8.7 Hz), 6.49 (1H, s), 7.24-7.40 (5H, m), 1H not confirmed.
[Reference Example 271]

N-benzyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine 5-bromo-obtained in Reference Example 227 in the same manner as Reference Example 24 The title compound was obtained using 7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran. Yield 84%. Melting point 115-116 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.15 (3H, s), 2.20 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.14 ( 2H, t, J = 8.7 Hz), 3.92 (2H, s), 3.94 (2H, s), 4.53 (2H, t, J = 8.7 Hz), 7.07 (4H, s), 7.24-7.40 (5H, m ) 1H unconfirmed.
[Reference Example 272]

5- (Benzylamino) -7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-1-benzofuran-3 (2H) -one 2- (2- (4) obtained in Reference Example 156 -Oxalyl chloride (2.13 mL, 24.5 mmol) was added dropwise to a solution of (isopropylbenzyl) -3,5-dimethylphenoxy) -2-methylpropanoic acid (5.55 g, 16.3 mmol) in THF (50 mL) under ice cooling. . After stirring for 20 minutes, DMF (3 drops) was added, stirred for 30 minutes under ice-cooling, and then warmed to room temperature. The solvent was removed by concentration under reduced pressure, and aluminum chloride (3.26 g, 24.5 mmol) was added to the remaining methylene chloride (50 mL) solution at −78 ° C., and the temperature was gradually raised to room temperature. Ice was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4), and 7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-1-benzofuran-3 (2H). -35 g (yield: 64%) was obtained as a crude product. To a solution of this compound (3.35 g, 10.4 mmol) in acetonitrile (40 mL), N-bromosuccinimide (1.85 g, 10.4 mmol) was added under ice-cooling and stirred for 30 minutes. The reaction mixture was warmed to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1:19), and 5-bromo-7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-1-benzofuran- 2.76 g (yield 66%) of 3 (2H) -one as a crude product was obtained. This compound (2.76 g, 6.89 mmol), palladium acetate (31 mg, 0.14 mmol), and BINAP (257 mg, 0.41 mmol) were added at room temperature, and the mixture was stirred for 15 minutes under an argon stream. Sodium tert-butoxide (926 mg, 9.63 mmol) was added to the reaction mixture at room temperature, and the mixture was heated at 110 ° C. under an argon stream for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 9) to obtain 675 mg (23% yield) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 1.57 (6H, s), 2.28 (3H, s), 2.54 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.03 (1H, br s), 3.93 (2H, s), 4.04 (2H, s), 7.10 (4H, s), 7.26-7.47 (5H, m).
[Reference Example 273]

N-benzyl-3- (4-isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine In the same manner as in Example 24, in Reference Example 251, The title compound was synthesized using the obtained 5-bromo-3- (4-isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran. Yield 98%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.18 (3H, s), 2.28 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.00 (1H, br s), 3.87 (3H, s), 3.95 (2H, s), 4.30 (1H, dd, J = 3.3, 8.4 Hz), 4.78 (1H, t, J = 8.4 Hz), 4.85 (1H, dd, J = 3.3, 8.4 Hz), 6.60 (1H, d, J = 7.5 Hz), 6.66 (1H, d, J = 7.5 Hz), 6.73 (1H, s), 7.26- 7.40 (5H, m).
[Reference Example 274]

N-benzyl-3- (3- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine As in Reference Example 24. 5-bromo-3- (3- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 249 was used. The title compound was synthesized. Yield 90%. Melting point 97-99 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.85 (3H, s), 2.17 (3H, s), 2.26 (3H, s), 2.83 (1H, br s), 3.90 (2H, s), 4.00-4.16 ( 4H, m), 4.37 (1H, dd, J = 4.8, 9.0 Hz), 4.59 (1H, dd, J = 4.8, 9.0 Hz), 4.82 (1H, t, J = 9.0 Hz), 5.76 (1H, s ), 7.06-7.10 (1H, m), 7.23-7.36 (8H, m).
[Reference Example 275]

N-benzyl-3- (3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine 3-Reference Example 204 was prepared in the same manner as Reference Example 23. Using (3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran, 5-bromo-3- (3-methoxyphenyl) -4,6,7-trimethyl-2, 3-Dihydro-1-benzofuran was obtained. Using this compound, the title compound was synthesized in the same manner as in Reference Example 24. Yield 76%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.88 (3H, s), 2.19 (3H, s), 2.26 (3H, s), 3.90 (1H, br), 3.77 (3H, s), 3.91 (2H, s ), 4.38 (1H, dd, J = 4.8, 8.7 Hz), 4.53 (1H, dd, J = 4.8, 8.7 Hz), 4.81 (1H, t, J = 8.7 Hz), 6.70-6.77 (3H, m) , 7.17-7.38 (6H, m).
[Reference Example 276]

N-benzyl-4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine 5-bromo-4,6 obtained in Reference Example 239 in the same manner as Reference Example 24 , 7-Trimethyl-3-phenyl-2,3-dihydro-1-benzofuran was used to synthesize the title compound. Yield 91%. Melting point 107-108 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.86 (3H, s), 2.20 (3H, s), 2.27 (3H, s), 2.93 (1H, br s), 3.91 (2H, s), 4.38 (1H, dd, J = 4.5, 9.0 Hz), 4.55 (1H, dd, J = 4.5, 9.0 Hz), 4.83 (1H, t, J = 9.0 Hz), 7.09-7.34 (10H, m).
[Reference Example 277]

5-Benzyl-4,6,7-trimethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine In the same manner as in Reference Example 24, 5- The title compound was synthesized using bromo-4,6,7-trimethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran. Yield 88%. Melting point 99-100 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.87 (3H, s), 2.20 (3H, s), 2.27 (3H, s), 2.31 (3H, s), 2.91 (1H, br s), 3.90 (2H, s), 4.35 (1H, dd, J = 4.5, 9.0 Hz), 4.52 (1H, dd, J = 4.5, 9.0 Hz), 4.81 (1H, t, J = 9.0 Hz), 7.01 (2H, d, J = 8.4 Hz), 7.08 (2H, d, J = 8.4 Hz), 7.23-7.40 (5H, m).
[Reference Example 278]

N-Benzyl-4,6,7-trimethyl-3- (5-methylpyridin-2-yl) -2,3-dihydro-1-benzofuran-5-amine In the same manner as in Reference Example 24, Using the obtained 5-methyl-2- (5-bromo-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) pyridine, the title compound was synthesized. Yield 79%. Melting point 104-105 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.90 (3H, s), 2.19 (3H, s), 2.26 (3H, s), 2.30 (3H, s), 2.92 (1H, br s), 3.91 (2H, s), 4.52 (1H, dd, J = 4.5, 8.4 Hz), 4.73 (1H, dd, J = 4.5, 8.4 Hz), 4.85 (1H, t, J = 8.4 Hz), 6.84 (1H, d, J = 7.8 Hz), 7.25-7.37 (6H, m), 8.36 (1H, s).
[Reference Example 279]

N-benzyl-3- (biphenyl-4-yl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine 5 obtained in Reference Example 243 in the same manner as Reference Example 24 The title compound was synthesized using -bromo-3- (biphenyl-4-yl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran. Yield 85%. Melting point 77-78 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.90 (3H, s), 2.22 (3H, s), 2.28 (3H, s), 2.94 (1H, br s), 3.92 (2H, s), 4.42 (1H, dd, J = 4.4, 8.8 Hz), 4.59 (1H, dd, J = 4.4, 8.8 Hz), 4.85 (1H, t, J = 8.8 Hz), 7.19 (2H, d, J = 8.0 Hz), 7.25- 7.64 (12H, m).
[Reference Example 280]

N-benzyl-3- (4-isopropylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine 5-bromo-3- (4) obtained in Reference Example 193 in the same manner as Reference Example 24. The title compound was synthesized using -isopropylphenyl) -4,6,7-trimethyl-1-benzofuran. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 6.9 Hz), 2.18 (3H, s), 2.39 (3H, s), 2.47 (3H, s), 2.97 (1H, septet, J = 6.9 Hz), 3.13 (1H, br s), 3.99 (2H, s), 7.25-7.44 (10H, m).
[Reference Example 281]

N-benzyl-3- (4-ethylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine 5-bromo-3- (4) obtained in Reference Example 262 in the same manner as Reference Example 24. The title compound was synthesized using -ethylphenyl) -4,6,7-trimethyl-1-benzofuran. Yield 93%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.5 Hz), 2.17 (3H, s), 2.38 (3H, s), 2.47 (3H, s), 2.71 (2H, q, J = 7.5 Hz), 3.13 (1H, br s), 3.99 (2H, s), 7.20-7.47 (10H, m).
[Reference Example 282]

N-benzyl-3- (4-isobutylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine Trifluoromethanesulfonic acid 5-bromo- obtained in Reference Example 261 in the same manner as Reference Example 262 Using 4,6,7-trimethyl-1-benzofuran-3-yl and (4-isobutylphenyl) boronic acid, 5-bromo-3- (4-isobutylphenyl) -4,6,7-trimethyl-1- Benzofuran was synthesized. Using this compound, the title compound was synthesized in the same manner as in Reference Example 24. Yield 74%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.94 (6H, d, J = 7.0 Hz), 1.91 (1H, septet, J = 6.9 Hz), 2.16 (3H, s), 2,38 (3H, s), 2.47 (3H, s), 2.53 (2H, d, J = 7.0 Hz), 3.12 (1H, br), 3.99 (2H, s), 7.15-7.47 (10H, m).
[Reference Example 283]

N-benzyl-3- (4-cyclohexylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine Trifluoromethanesulfonic acid 5-bromo- obtained in Reference Example 261 in the same manner as Reference Example 262 Using 4,6,7-trimethyl-1-benzofuran-3-yl and (4-cyclohexylphenyl) boronic acid, 5-bromo-3- (4-cyclohexylphenyl) -4,6,7-trimethyl-1- Benzofuran was synthesized. Using this compound, the title compound was synthesized in the same manner as in Reference Example 24. Yield 61%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.26-1.52 (4H, m), 1.73-2.00 (6H, m), 2.17 (3H, s), 2.38 (3H, s), 2.47 (3H, s), 2.50 -2.60 (1H, m), 3.15 (1H, br), 3.99 (2H, s), 7.20-7.48 (10H, m).
[Reference Example 284]

N-benzyl-3- (4- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine As in Reference Example 24. 5-bromo-3- (4- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 250 was used. The title compound was synthesized. Yield 88%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.85 (3H, s), 1.20 (3H, s), 2.26 (3H, s), 3.89 (2H, s), 3.98-4.17 (4H, m), 4.35 (1H , dd, J = 4.4, 9.0 Hz), 4.56 (1H, dd, J = 4.4, 9.0 Hz), 4.82 (1H, t, J = 9.0 Hz), 5.77 (1H, s), 7.l4 (2H, d, J = 8.0 Hz), 7.25-7.41 (7H, m). 1H unconfirmed.
[Reference Example 285]

N-benzyl-3- (4-isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine 5-Bromo- synthesized in Reference Example 241 in the same manner as Reference Example 24 The title compound was synthesized using 3- (4-isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran. Yield 96%. Melting point 82-83 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.27 (3H, s), 2.67-3.02 (2H, m), 3.93 (2H, s ), 4.38 (1H, dd, J = 8.4, 4.5 Hz), 4.49 (1H, dd, J = 9.0, 4.5 Hz), 4.75-4.83 (1H, m), 6.59 (1H, s), 7.02 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.19-7.39 (5H, m).
[Reference Example 286]

N-benzyl-3- (4-isopropylphenyl) -4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6-amine 6-synthesized in Reference Example 238 in the same manner as Reference Example 24 The title compound was synthesized using bromo-3- (4-isopropylphenyl) -4,5,7-trimethyl-2,3-dihydro-1-benzofuran. Yield 76%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.13 (3H, s), 2.17 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.05 (2H, s), 4.38 (1H, dd, J = 8.7, 4.5 Hz), 4.52 (1H, dd, J = 9.0, 4.5 Hz), 4.79 (1H, t, J = 9.0 Hz ), 7.03 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.21-7.42 (5H, m), 1H Not confirmed.
[Reference Example 287]

N-benzyl-3- (4-isopropylphenyl) -4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-amine 7- synthesized in Reference Example 256 in the same manner as Reference Example 24 The title compound was synthesized using bromo-3- (4-isopropylphenyl) -4,5,6-trimethyl-2,3-dihydro-1-benzofuran. Yield 81%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.07 (3H, s), 2.19 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.23-4.52 (4H, m), 4.75 (1H, t, J = 8.7 Hz), 6.99 (2H, d, J = 7.8 Hz), 7.12 (2H, d, J = 7.8 Hz), 7.19-7.39 (5H, m), 1H Not confirmed.
[Reference Example 288]

N-benzyl-3- (4-isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan-5-amine 5 synthesized in Reference Example 255 in the same manner as Reference Example 24 The title compound was synthesized using -bromo-3- (4-isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan. Yield 53%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.95 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.25 (1H, br s), 4.14 (2H, s), 4.60 (1H, dd, J = 8.7, 4.8 Hz), 4.70 (1H, dd, J = 9.3, 4.8 Hz), 5.02 (1H, t, J = 9.0 Hz), 7.03 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.20-7.57 (7H, m), 7.98-8.04 (1H, m), 8.13-8.18 (1H, m).
[Reference Example 289]

N-benzyl-3- (4-isopropylphenyl) -4-methyl-2,3,6,7,8,9-hexahydronaphtho [1,2-b] furan-5-amine As in Reference Example 24. Then, 5-bromo-3- (4-isopropylphenyl) -4-methyl-2,3,6,7,8,9-hexahydronaphtho [1,2-b] furan synthesized in Reference Example 257 was used. The title compound was synthesized. Yield 84%. Melting point 98-99 ° C. (hexane-ethyl acetate). ¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.72-1.87 (4H, m), 1.91 (3H, s), 2.60-2.78 (4H, m), 2.87 (1H , septet, J = 6.9 Hz), 3.92 (2H, s), 4.41 (1H, dd, J = 8.7, 5.1 Hz), 4.52 (1H, dd, J = 9.3, 5.1 Hz), 4.82 (1H, t, J = 9.0 Hz), 7.06 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz), 7.20-7.40 (5H, m), 1H Not confirmed.
[Reference Example 290]

N-benzyl-3- (4-isopropylphenyl) -4-methyl-3,6,7,8-tetrahydro-2H-indeno [4,5-b] furan-5-amine In the same manner as in Reference Example 24, Using 5-bromo-3- (4-isopropylphenyl) -4-methyl-3,6,7,8-tetrahydro-2H-indeno [4,5-b] furan synthesized in Reference Example 258, the title compound was Synthesized. Yield 76%. Melting point 95-96 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.87 (3H, s), 2.10 (2H, quintet, J = 7.5 Hz), 2.76-2.93 (6H, m), 4.05 (2H, s), 4.41 (1H, dd, J = 8.7, 4.8 Hz), 4.50 (1H, dd, J = 9.0, 4.8 Hz), 4.83 (1H, t, J = 8.7 Hz), 7.04 (2H , d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz), 7.20-7.37 (5H, m).
[Reference Example 291]

3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothiophen-5-amine 5-bromo-3- (4-isopropylphenyl) -4 obtained in Reference Example 259, To a solution of 6-dimethyl-2,3-dihydro-1-benzothiophene (870 mg, 2.41 mmol) and benzophenone imine (0.76 mL, 2.89 mmol) in toluene (15 mL), tris (dibenzylideneacetone) dipalladium (22 mg, 0.024 mmol) and BINAP (45 mg, 0.072 mmol) were added at room temperature, and the mixture was stirred under an argon atmosphere for 15 minutes. Sodium tert-butoxide (324 mg, 3.37 mmol) was added to the reaction solution at room temperature, and the mixture was heated to reflux for 16 hours under an argon stream. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and N- (diphenylmethylene) -3- A crude product of (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-amine was obtained. This compound was dissolved in THF (10 mL), 1N hydrochloric acid (2 mL) was added, and the mixture was heated to reflux for 30 min. The solvent was concentrated under reduced pressure, and the resulting residue was neutralized with 1N aqueous sodium hydroxide solution. The product was extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1:10) to obtain 521 mg (yield 73%) of the title compound. Melting point 121-122 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.17 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.11 ( 1H, dd, J = 11.1, 1.8 Hz), 3.42 (2H, br s), 3.89 (1H, dd, J = 11.1, 8.7 Hz), 4.64 (1H, d, J = 8.7 Hz), 6.90 (1H, s), 7.02 (2H, d, J = 8.1 Hz), 7.09 (2H, d, J = 8.1 Hz).
[Reference Example 292]

7- (4-Isopropylbenzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-7- obtained in Reference Example 263 in the same manner as Reference Example 30 The title compound was synthesized using (4-isopropylbenzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 84%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.9 Hz), 1.27 (3H, d, J = 7.2 Hz), 2.02 (3H, br s), 2.15 (3H, br s), 2.80-2.90 (1H, septet, J = 6.9 Hz), 3.29 (2H, br s), 3.44 (1H, br s), 3.95 (2H, m), 4.15 (1H, br s), 4.74 (1H, br s), 7.06 (4H, s).
[Reference Example 293]

3-ethyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-obtained in Reference Example 264 in the same manner as Reference Example 30 The title compound was synthesized using 3-ethyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 93%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.5 Hz), 1.20 (6H, d, J = 6.9 Hz), 1.50-1.61 (2H, m), 2.02 (3H, s), 2.14 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.23-3.31 (3H, m), 3.94 (2H, s), 4.32 (1H, dd, J = 2.7, 8.7 Hz), 4.40 (1H, t, J = 9.0 Hz), 7.05 (4H, s).
[Reference Example 294]

7- (4-Isopropylbenzyl) -4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-obtained in Reference Example 265 in the same manner as Reference Example 30 The title compound was synthesized using 7- (4-isopropylbenzyl) -4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-amine. Yield 85%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.2 Hz), 1.21 (6H, d, J = 6.9 Hz), 1.30-1.43 (2H, m), 1.50-1.63 (2H, m ), 2.02 (3H, s), 2.14 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.30-3.39 (3H, m), 3.94 (2H, s), 4.31 (1H, dd, J = 3.3, 8.7 Hz), 4.39 (1H, t, J = 8.7 Hz), 7.06 (4H, s).
[Reference Example 295]

3-isopropyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-obtained in Reference Example 266 in the same manner as Reference Example 30. The title compound was synthesized using 3-isopropyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 74%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.72 (3H, d, J = 6.9 Hz), 0.99 (3H, d, J = 6.9 Hz), 1.19 (6H, d, J = 6.9 Hz), 2.01 (3H, s), 2.01-2.08 (1H, m), 2.14 (3H, s), 2.82 (1H, septet, J = 6.9 Hz), 3.23-3.35 (3H, m), 3.88 (1H, d, J = 15.6 Hz ), 3.99 (1H, d, J = 15.6 Hz), 4.29 (1H, t, J = 9.0 Hz), 4.44 (1H, dd, J = 2.4, 9.0 Hz), 7.04 (4H, s).
[Reference Example 296]

7- (4-Isopropylbenzyl) -3,4,6-trimethyl-1-benzofuran-5-amine N-benzyl-7- (4-isopropylbenzyl) obtained in Reference Example 269 in the same manner as Reference Example 30 The title compound was synthesized using -3,4,6-trimethyl-1-benzofuran-5-amine. Yield 87%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.9 Hz), 2.16 (3H, s), 2.38 (3H, s), 2.44 (3H, s), 2.82 (1H, septet, J = 6.9 Hz), 3.46 (2H, br s), 4.24 (2H, s), 7.06 (4H, s), 7.24 (1H, s).
[Reference Example 297]

4,6-Dimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-4,6-dimethyl-2,3-dihydro-1 obtained in Reference Example 270 in the same manner as Reference Example 30 -The title compound was synthesized using benzofuran-5-amine. Yield 86%. Melting point 85-86 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 2.11 (3H, s), 2.15 (3H, s), 3.10 (2H, t, J = 8.7 Hz), 3.27 (2H, br s), 4.48 (2H, t, J = 8.7 Hz), 6.44 (1H, s).
[Reference Example 298]

7- (4-Isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-7- (4 obtained in Reference Example 271 in the same manner as Reference Example 30. The title compound was synthesized using -isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 92%. Melting point 114-115 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.9 Hz), 2.03 (3H, s), 2.11 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.14 ( 2H, t, J = 8.7 Hz), 3.20 (2H, br), 3.95 (2H, s), 4.48 (2H, t, J = 8.7 Hz), 7.06 (4H, s).
[Reference Example 299]

5-Amino- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-1-benzofuran-3 (2H) -one 5- (benzyl) obtained in Reference Example 272 in the same manner as Reference Example 30. The title compound was synthesized using amino) -7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-1-benzofuran-3 (2H) -one. Yield 99%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.43 (6H, s), 2.14 (3H, s), 2.47 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.42 (2H, br s), 4.04 (2H, s), 7.08 (4H, s).
[Reference Example 300]

(3- (4-Isopropylbenzyl) -4-methoxy-2,6-dimethylphenyl) amine In the same manner as in Reference Example 30, N-benzyl-3- (4-isopropylbenzyl) -4 obtained in Reference Example 267 The title compound was synthesized using -methoxy-2,6-dimethylaniline. Yield 86%. Melting point 91-92 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.06 (3H, s), 2.21 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.26 ( 2H, br s), 3.73 (3H, s), 4.04 (2H, s), 6.61 (1H, s), 7.02 (2H, d, J = 8.1 Hz), 7.07 (2H, d, J = 8.1 Hz) .
[Reference Example 301]

3- (3- (1,3-Dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine In the same manner as in Reference Example 30, Reference Example Using N-benzyl-3- (3- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in 274 The title compound was synthesized. Yield 81%. Melting point 138-139 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.81 (3H, s), 2.12 (3H, s), 2.20 (3H, s), 3.26 (2H, br s), 4.00-4.16 (4H, m), 4.32 ( 1H, dd, J = 4.8, 9.0 Hz), 4.59 (1H, dd, J = 4.8, 9.0 Hz), 4.77 (1H, t, J = 9.0 Hz), 5.75 (1H, s), 7.08-7.12 (1H , m), 7.26-7.36 (3H, m).
[Reference Example 302]

3- (3-Methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine In the same manner as in Reference Example 30, N-benzyl-3-ethyl obtained in Reference Example 275 was used. The title compound was obtained using (3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.84 (3H, s), 2.11 (3H, s), 2.20 (3H, s), 3.26 (2H, br s), 3.75 (3H, s), 4.33 (1H, dd, J = 4.8, 8.7 Hz), 4.53 (1H, dd, J = 4.8, 8.7 Hz), 4.76 (1H, t, J = 8.7 Hz), 6.67-6.75 (3H, m), 7.18 (1H, t , J = 7.8 Hz).
[Reference Example 303]

3- (4-Isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine N--obtained in Reference Example 273 in the same manner as Reference Example 30 The title compound was synthesized using benzyl-3- (4-isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 87%. Melting point 120-121 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.13 (3H, s), 2.19 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.29 (2H, br s), 3.88 (3H, s), 4.27 (1H, dd, J = 3.3, 8.7 Hz), 4.73 (1H, t, J = 8.7 Hz), 4.86 (1H, dd, J = 3.3, 8.7 Hz), 6.65 (2H, s), 6.73 (1H, s).
[Reference Example 304]

2,4,6-Trimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-2,4,6-trimethyl-2,3 obtained in Reference Example 268 in the same manner as Reference Example 30 -The title compound was obtained using dihydro-1-benzofuran-5-amine. Yield 71%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, d, J = 6.3 Hz), 2.09 (3H, s), 2.15 (3H, s), 2.71 (1H, dd, J = 7.5, 15.0 Hz), 3.18-3.27 (3H, m), 4.80-4.91 (1H, m), 6.42 (1H, s).
[Reference Example 305]

3- (4-Isopropylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine N-benzyl-3- (4-isopropylphenyl) obtained in Reference Example 280 in the same manner as Reference Example 30 The title compound was synthesized using -4,6,7-trimethyl-1-benzofuran-5-amine. Yield 80%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 6.9 Hz), 2.08 (3H, s), 2.24 (3H, s), 2.47 (3H, s), 2.97 (1H, septet, J = 6.9 Hz), 3.49 (2H, br s), 7.27 (2H, d, J = 7.8 Hz), 7.36 (2H, d, J = 7.8 Hz), 7.42 (1H, s).
[Reference Example 306]

4,6,7-Trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-4,6,7-trimethyl obtained in Reference Example 276 in the same manner as Reference Example 30 The title compound was synthesized using -3-phenyl-2,3-dihydro-1-benzofuran-5-amine. Yield 72%. Melting point 94-95 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.82 (3H, s), 2.11 (3H, s), 2.21 (3H, s), 3.26 (2H, br s), 4.33 (1H, dd, J = 4.5, 9.0 Hz), 4.56 (1H, dd, J = 4.5, 9.0 Hz), 4.77 (1H, t, J = 9.0 Hz), 7.11-7.29 (5H, m).
[Reference Example 307]

4,6,7-Trimethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine N-benzyl-4, obtained in Reference Example 277 in the same manner as Reference Example 30 The title compound was synthesized using 6,7-trimethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine. Yield 91%. Melting point 121-122 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.83 (3H, s), 2.12 (3H, s), 2.24 (3H, s), 2.31 (3H, s), 3.26 (2H, s), 4.31 (1H, dd , J = 4.5, 9.0 Hz), 4.53 (1H, dd, J = 4.5, 9.0 Hz), 4.76 (1H, t, J = 9.0 Hz), 7.13 (2H, d, J = 8.1 Hz), 7.08 (2H , d, J = 8.1 Hz).
[Reference Example 308]

4,6,7-Trimethyl-3- (5-methylpyridin-2-yl) -2,3-dihydro-1-benzofuran-5-amine N--obtained in Reference Example 278 in the same manner as Reference Example 30 The title compound was synthesized using benzyl-4,6,7-trimethyl-3- (5-methylpyridin-2-yl) -2,3-dihydro-1-benzofuran-5-amine. Yield 85%. Melting point 125-127 [deg.] C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.87 (3H, s), 2.11 (3H, s), 2.19 (3H, s), 2.29 (3H, s), 3.27 (2H, br s), 4.48 (1H, dd, J = 3.9, 9.0 Hz), 4.73 (1H, dd, J = 3.9, 9.0 Hz), 4.81 (1H, t, J = 9.0 Hz), 6.87 (1H, d, J = 7.8 Hz), 7.35 ( 1H, dd, J = 1.8, 7.8 Hz), 8.36 (1H, d, J = 1.8 Hz).
[Reference Example 309]

3- (biphenyl-4-yl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-3 obtained in Reference Example 279 in the same manner as Reference Example 30 The title compound was synthesized using-(biphenyl-4-yl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 89%. Melting point 149-150 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.88 (3H, s), 2.13 (3H, s), 2.22 (3H, s), 3.29 (2H, br s), 4.38 (1H, dd, J = 4.4, 8.8 Hz), 4.60 (1H, dd, J = 4.4, 8.8 Hz), 4.81 (1H, t, J = 8.8 Hz), 7.20 (2H, d, J = 8.2 Hz), 7.28-7.59 (7H, m).
[Reference Example 310]

3- (4- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine In the same manner as in Reference Example 30, Reference Example Using N-benzyl-3- (4- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in 284 The title compound was synthesized. Yield 87%. Melting point 125-136 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.81 (3H, s), 2.11 (3H, s), 2.20 (3H, s), 3.26 (2H, br s), 3.97-4.17 (4H, m), 4.30 ( 1H, dd, J = 4.8, 9.0 Hz), 4.57 (1H, dd, J = 4.8, 9.0 Hz), 4.77 (1H, t, J = 9.0 Hz), 5.77 (1H, s), 7.15 (2H, d , J = 8.0 Hz), 7.42 (2H, d, J = 8.0 Hz).
[Reference Example 311]

3- (4-Ethylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine N-benzyl-3- (4-ethylphenyl) obtained in Reference Example 281 in the same manner as Reference Example 30 The title compound was synthesized using -4,6,7-trimethyl-1-benzofuran-5-amine. Yield 85%. Melting point 68-69 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.5 Hz), 2.07 (3H, s), 2.24 (3H, s), 2.47 (3H, s), 2.72 (2H, q, J = 7.5 Hz), 3.48 (2H, br s), 7.24 (2H, d, J = 8.1 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.42 (1H, s).
[Reference Example 312]

3- (4-Isobutylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine N-benzyl-3- (4-isobutylphenyl) obtained in Reference Example 282 in the same manner as Reference Example 30 The title compound was synthesized using -4,6,7-trimethyl-1-benzofuran-5-amine. Yield 88%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.95 (6H, d, J = 6.9 Hz), 1.94 (1H, septet, J = 6.9 Hz), 2.05 (3H, s), 2.24 (3H, s), 2.47 ( 3H, s), 2.53 (2H, d, 6.9 Hz), 3.48 (2H, br s), 7.18 (2H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.43 (1H , s).
[Reference Example 313]

3- (4-Cyclohexylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine N-benzyl-3- (4-cyclohexylphenyl) obtained in Reference Example 283 in the same manner as Reference Example 30. The title compound was synthesized using -4,6,7-trimethyl-1-benzofuran-5-amine. Yield 79%. Melting point: 139-140 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.26-1.50 (4H, m), 1.74-1.92 (6H, m), 1.95 (3H, s), 2.23 (3H, s), 2.47 (3H, s), 2.50 -2.60 (1H, m), 3.48 (2H, br s), 7.24 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.41 (1H, s).
[Reference Example 314]

3- (4-Ethylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine 3- (4-ethyl) obtained in Reference Example 311 in the same manner as Reference Example 144. The title compound was synthesized using (phenyl) -4,6,7-trimethyl-1-benzofuran-5-amine. Yield 80%. Melting point 88-89 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.5 Hz), 1.84 (3H, s), 2.12 (3H, s), 2.21 (3H, s), 2.61 (2H, q, J = 7.5 Hz), 3.27 (2H, br s), 4.53 (1H, dd, J = 4.8, 8.4 Hz), 4.53 (1H, dd, J = 4.8, 8.4 Hz), 4.76 (1H, t, J = 8.4 Hz), 7.05 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).
[Reference Example 315]

3- (4-Isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-3- (4) synthesized in Reference Example 285 in the same manner as Reference Example 30 The title compound was synthesized using -isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 92%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.79 (3H, s), 2.18 (3H, s), 2.73 (2H, br s), 2.86 (1H, septet, J = 6.9 Hz), 4.36 (1H, dd, J = 8.7, 4.5 Hz), 4.49 (1H, dd, J = 9.0, 4.5 Hz), 4.77 (1H, t, J = 8.7 Hz), 6.40 (1H, s), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).
[Reference Example 316]

3- (4-Isopropylphenyl) -4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6-amine N-benzyl-3-synthesized in Reference Example 286 in the same manner as Reference Example 30 The title compound was synthesized using (4-isopropylphenyl) -4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6-amine. Yield 83%. Melting point 88-89 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.00 (3H, s), 2.11 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.59 (2H, br s), 4.36 (1H, dd, J = 8.7, 4.5 Hz), 4.50 (1H, dd, J = 9.0, 4.2 Hz), 4.77 (1H, t, J = 8.7 Hz), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).
[Reference Example 317]

3- (4-Isopropylphenyl) -4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-amine N-benzyl-3-synthesized in Reference Example 287 in the same manner as Reference Example 30 The title compound was synthesized using (4-isopropylphenyl) -4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-amine. Yield 80%. Melting point 122-123 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.09 (3H, s), 2.13 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.40 (2H, br s), 4.42 (1H, dd, J = 8.7, 4.5 Hz), 4.53 (1H, dd, J = 9.3, 4.5 Hz), 4.81 (1H, t, J = 9.3 Hz), 7.04 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).
[Reference Example 318]

3- (4-Isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan-5-amine N-benzyl-3 synthesized in Reference Example 288 in the same manner as Reference Example 30 The title compound was synthesized using-(4-isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan-5-amine. Yield 83%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 2.01 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.54 (2H, br s), 4.47 -4.58 (2H, m), 4.90-5.03 (1H, m), 7.04 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz), 7.30-7.50 (2H, m), 7.74-7.85 (1H, m), 7.89-8.05 (1H, m).
[Reference Example 319]

3- (4-Isopropylphenyl) -4-methyl-2,3,6,7,8,9-hexahydronaphtho [1,2-b] furan-5-amine In the same manner as in Reference Example 30, Reference Example N-benzyl-3- (4-isopropylphenyl) -4-methyl-2,3,6,7,8,9-hexahydronaphtho [1,2-b] furan-5-amine synthesized in 289 The title compound was synthesized. Yield 76%. Melting point 106-107 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.59-1.92 (7H, m), 2.49 (2H, t, J = 7.5 Hz), 2.67 (2H, t, J = 7.5 Hz), 2.86 (1H, septet, J = 6.9 Hz), 3.20 (2H, br s), 4.36 (1H, dd, J = 8.7, 5.1 Hz), 4.52 (1H, dd, J = 9.0, 4.5 Hz), 4.77 (1H, t, J = 8.7 Hz), 7.06 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).
[Reference Example 320]

3- (4-Isopropylphenyl) -4-methyl-3,6,7,8-tetrahydro-2H-indeno [4,5-b] furan-5-amine In a similar manner to Reference Example 30, in Reference Example 290 Using the synthesized N-benzyl-3- (4-isopropylphenyl) -4-methyl-3,6,7,8-tetrahydro-2H-indeno [4,5-b] furan-5-amine, the title compound was Synthesized. Yield 91%. Melting point 112-113 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.83 (3H, s), 2.10-2.25 (2H, m), 2.68-2.98 (5H, m), 3.22 (2H , br s), 4.38 (1H, dd, J = 8.4, 4.5 Hz), 4.49 (1H, dd, J = 8.7, 4.5 Hz), 4.79 (1H, t, J = 8.7 Hz), 7.05 (2H, d , J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).
[Reference Example 321]

3- (5-amino-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) ethyl propanoate sodium hydride (60% liquid paraffin dispersion, To a DMF (50 mL) suspension of 430 mg, 10.8 mmol) was added triethyl phosphonoacetate (2.19 g, 9.78 mmol) at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide (3.0 g, 8.89 mmol) obtained in Example 60 in the reaction solution. ) Was added and stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted with diisopropyl ether. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give oily (2E) -3- (5- (formylamino) -3- (4-isopropylphenyl) -4,6- A crude product of ethyl dimethyl-2,3-dihydro-1-benzofuran-7-yl) -2-propenoate was obtained. A mixture of this compound, 10% -palladium carbon (containing 50% water, 300 mg) and ammonium formate (1.26 g, 20 mmol) in ethanol (50 mL) was heated to reflux for 2 hours. The solid was removed and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and ethyl 3- (5- (formylamino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) propanoate A crude product was obtained. A mixture of this compound and concentrated hydrochloric acid (10 mL) -ethanol (30 mL) was heated to reflux for 1.5 hours under a nitrogen atmosphere. The solvent was concentrated under reduced pressure, and the resulting residue was neutralized with 12N aqueous sodium hydroxide solution. The product was extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 1.55 g of the title compound (yield 46%). Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.84 (3H, s), 2.14 (3H, s), 2.53 ( 2H, dd, J = 9.6, 6.0 Hz), 2.86 (1H, septet, J = 6.9 Hz), 2.99 (2H, dd, J = 9.3, 7.2 Hz), 3.26 (2H, br s), 4.14 (2H, q, J = 7.2 Hz), 4.33 (1H, dd, J = 8.7, 4.8 Hz), 4.50 (1H, dd, J = 9.3, 4.8 Hz), 4.74 (1H, t, J = 9.0 Hz), 7.02 ( 2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).
[Reference Example 322]

3- (5-amino-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) propan-1-ol 3- (synthesized in Reference Example 321) To a suspension of ethyl 5-amino-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) propanoate (1.28 g, 3.36 mmol) in THF was added. Lithium aluminum hydride (255 mg, 6.72 mmol) was added at ° C, stirred at the same temperature for 30 minutes, and heated to reflux for 30 minutes. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 750 mg (yield 66%) of the title compound. Mp 110-111 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 7.0 Hz), 1.70-1.90 (5H, m), 2.13 (3H, s), 2.70-2.91 (3H, m), 3.24 (2H , br s), 3.56 (2H, t, J = 5.4 Hz), 4.36 (1H, dd, J = 8.4, 4.0 Hz), 4.53 (1H, dd, J = 8.8, 4.4 Hz), 4.75 (1H, t , J = 8.6 Hz), 7.02 (2H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.0 Hz), 1H Not confirmed.
[Reference Example 323]

(4-Bromo-3- (4-isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) amine 3- (4-isopropylphenyl)-synthesized in Reference Example 31 N-bromosuccinimide (3.76 g, 21.1 mmol) in a solution of 6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine (5.62 g, 21.1 mmol) in acetonitrile (60 mL) at −20 ° C. And stirred at the same temperature for 10 minutes. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 0.90 g of the title compound (yield 34%). Melting point 191-193 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 2.13 (3H, s), 2.17 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.68 ( 2H, br s), 4.42 (1H, dd, J = 8.4, 3.9 Hz), 4.50 (1H, dd, J = 8.7, 3.9 Hz), 4.76 (1H, t, J = 8.7 Hz), 7.07 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz).
[Reference Example 324]

Cyclopentanecarbonyl chloride (20 g, 151 mmol) was added to a solution of cyclopentyl (4-isopropylphenyl) methanone cumene (16.4 g, 137 mmol) and aluminum chloride (21.9 g, 164 mmol) in dichloromethane (200 mL) at -50 ° C ( (Internal temperature) and stirred for 2 hours until it reached -10 ° C (internal temperature). The reaction solution was poured into ice-cold water and the organic layer was separated. The organic layer was washed with 12N aqueous sodium hydroxide solution and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 22.5 g (yield 80%) of the title compound as an oil. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 6.9 Hz), 1.57-1.92 (8H, m), 2.96 (1H, septet, J = 6.9 Hz), 3.69 (1H, quartet, J = 7.8 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.90 (2H, d, J = 8.4 Hz).
[Reference Example 325]

3- (4-Isopropylphenyl) -4,6,7-trimethyl-3H-spiro (1-benzofuran-2,1′-cyclopentane) -5-amine 3-bromo-4-methoxy synthesized in Reference Example 129 To a THF (20 mL) solution of tert-butyl 2,5,6-trimethylphenylcarbamate (2.0 g, 5.81 mmol) at −78 ° C. was added n-butyllithium (1.6 M hexane solution, 8 mL, 12.8 mmol). In addition, the mixture was stirred at the same temperature for 20 minutes. A solution of cyclopentyl (4-isopropylphenyl) methanone (1.38 g, 6.39 mmol) synthesized in Reference Example 324 in THF (5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to give 3- (cyclopentyl (hydroxy) (4-isopropylphenyl) methyl) -4-methoxy-2,5,6-trimethylphenyl. A tert-butyl carbamate was obtained. A mixture of this compound and 47% hydrobromic acid (50 mL) was heated to reflux for 3 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and neutralized with 12N aqueous sodium hydroxide solution. The product was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 400 mg (yield 22%) of the title compound. Melting point 132-133 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11-1.35 (7H, m), 1.45-1.92 (9H, m), 1.96-2.22 (7H, m), 2.84 (1H, septet, J = 6.9 Hz), 3.21 (2H, br s), 4.13 (1H, s), 6.88 (2H, d, J = 8.1 Hz), 7.05 (2H, d, J = 8.1 Hz).
[Reference Example 326]

(S) -3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine 3- (4 obtained in Reference Example 32 in the same manner as Reference Example 141. The title compound was synthesized using -isopropylphenyl) -3,5-dimethyl-2,3-dihydro-1-benzofuran-5-amine and (2R, 3R)-(4′-methyl) -terthranilic acid. Yield 40%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.18 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.07 ( 2H, br s), 4.35 (1H, dd, J = 8.4, 4.5 Hz), 4.49 (1H, dd, J = 9.0, 4.5 Hz), 4.71-4.80 (1H, m), 6.54 (1H, s), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).
[Reference Example 327]

3- (4-Isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine Synthesized in Example 59 (7-bromo-3- (4-isopropylphenyl) ) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide (800 mg, 2.06 mmol), copper (I) bromide (296 mg, 2.06 mmol), ethyl acetate (0.402 mL) , 4.12 mmol) and a 28% sodium methoxide-methanol solution (20 mL) were heated to reflux for 6 hours. 1N Hydrochloric acid was added to the reaction mixture, and the product was extracted with ethyl acetate to give (3- (4-isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5 Il) A crude product of formamide was obtained. This compound was dissolved in methanol (6 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was heated to reflux for 24 hours. The solvent was concentrated under reduced pressure, and the resulting residue was neutralized with 12N aqueous sodium hydroxide solution. The product was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 310 mg (yield 48%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.81 (3H, s), 2.12 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.28 ( 2H, br s), 3.88 (3H, s), 4.39 (1H, dd, J = 4.5, 8.7 Hz), 4.50 (1H, dd, J = 4.2, 9.0 Hz), 4.79 (1H, t, J = 8.7 Hz), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).
[Reference Example 328]

7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine methylmagnesium bromide (1.0 M in THF, 10 mL, 10 mmol) in THF (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide obtained in Example 60 (600 mg, 1.78 mmol) Was added at 0 ° C., and the reaction solution was stirred at room temperature for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Triethylsilane (0.27 mL, 2.46 mmol) was added to a mixture of the obtained trifluoroacetic acid (5 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, the aqueous layer was made alkaline, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (6 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was heated to reflux for 24 hours. The solvent was concentrated under reduced pressure, and the resulting residue was neutralized with 12N aqueous sodium hydroxide solution. The product was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 250 mg (yield 45%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.5 Hz), 1.22 (6H, d, J = 6.9 Hz), 1.84 (3H, s), 2.14 (3H, s), 2.67 ( 2H, q, J = 7.5 Hz), 2.86 (1H, septet, J = 6.9 Hz), 4.20-4.60 (2H, m), 4.61-4.82 (1H, m), 7.04 (2H, d, J = 8.1 Hz ), 7.11 (2H, d, J = 8.1 Hz), 2H, unconfirmed.
[Reference Example 329]

3- (4-Isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-amine (7-bromo-3- (4-isopropylphenyl) obtained in Example 59 ) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide (1.0 g, 2.58 mmol), phenylboronic acid (345 mg, 2.83 mmol), tetrakis (triphenylphosphine) palladium ( 99 mg, 0.086 mmol) 2N aqueous sodium carbonate solution (30 mL) -1,2-dimethoxyethane (15 mL) was heated to reflux for 16 hours under a nitrogen atmosphere. The reaction mixture is diluted with ethyl acetate, the insoluble material is collected by filtration, the filtrate is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure to give (3- (4-isopropylphenyl). ) -4,6-Dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) formamide was obtained. This compound was dissolved in methanol (18 mL), concentrated hydrochloric acid (6 mL) was added, and the mixture was heated to reflux for 2 hours. The solvent was concentrated under reduced pressure, and the resulting residue was neutralized with 12N aqueous sodium hydroxide solution. The product was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 642 mg (yield 70%) of the title compound. Melting point 101-102 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.03 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.34 ( 2H, br s), 4.31 (1H, dd, J = 4.2, 9.0 Hz), 4.55 (1H, dd, J = 4.8, 9.3 Hz), 4.72 (1H, t, J = 8.7 Hz), 7.09 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz), 7.28-7.45 (5H, m).
[Reference Example 330]

N- (7- (4-Isopropylbenzyl) -2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Reference In the same manner as in Example 63, using 5-amino-7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-1-benzofuran-3 (2H) -one obtained in Reference Example 299, The title compound was synthesized. Yield 86%. Melting point 193-194 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.44 (6H, s), 2.20 (3H, s), 2.29 (2H, s), 2.49 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 4.02 (2H, s), 6.56 (1H, br s), 7.09 (4H, s).
[Reference Example 331]

N- (7- (4-isopropylbenzyl) -3,4,6-trimethyl-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Reference Example 296 in the same manner as Reference Example 63. The title compound was synthesized using 7- (4-isopropylbenzyl) -3,4,6-trimethyl-1-benzofuran-5-amine. Yield 90%. Melting point 171-172 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.16 (9H, s), 1.19 (6H, d, J = 6.9 Hz), 2.21 (3H, s), 2.32 (2H, s), 2.36 (3H, s), 2.56 (3H, s), 2.82 (1H, septet, J = 6.9 Hz), 4.22 (2H, br s), 6.64 (1H, s), 7.04 (4H, s), 7.29 (1H, s).
[Reference Example 332]

N-benzyl-N- (3- (4-isopropylbenzyl) -4-methoxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide N obtained in Reference Example 267 in the same manner as in Example 63 The title compound was obtained using -benzyl-3- (4-isopropylbenzyl) -4-methoxy-2,6-dimethylaniline. Yield 94%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.61 (3H, s), 1.73 (2H, s), 1.91 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.79 (3H, s), 3.89 (1H, d, J = 15.6 Hz), 4.00 (1H, d, J = 15.6 Hz), 4.55 (1H, d, J = 13.5 Hz), 4.83 (1H, d, J = 13.5 Hz), 6.63 (1H, s), 6.89 (2H, d, J = 7.8 Hz), 7.07 (2H, d, J = 7.8 Hz), 7.11- 7.20 (5H, m).
[Reference Example 333]

N- (3- (4-Isopropylbenzyl) -4-methoxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide In the same manner as in Example 63, the compound obtained in Reference Example 300 (3- (4 The title compound was synthesized using -isopropylbenzyl) -4-methoxy-2,6-dimethylphenyl) amine. Yield 94%. Melting point 181-182 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 2.10 (3H, s), 2.25 (3H, s), 2.27 (2H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.78 (3H, s), 4.00 (2H, s), 6.55 (1H, br s), 6.67 (1H, s), 7.01 (2H, d, J = 8.1 Hz), 7.06 (2H, d, J = 8.1 Hz).
[Reference Example 334]

(7- (1- (4-Isopropylphenyl) vinyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) amine (7- (1-hydroxy-) obtained in Example 223 1- (4-Isopropylphenyl) ethyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl (306 mg, 0.72 mmol) in ethyl acetate (5 mL) A 4N hydrochloric acid-ethyl acetate (5 mL) solution was added dropwise to the solution under ice-cooling, and the reaction solution was stirred for 30 minutes. The reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 221 mg (quantitative yield) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.97 (3H, s), 2.16 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.14 ( 2H, t, J = 8.4 Hz), 3.34 (2H, br s), 4.44 (2H, t, J = 8.4 Hz), 5.14 (1H, s), 5.94 (1H, s), 7.10 (2H, d, J = 8.1 Hz), 7.25 (2H, d, J = 8.1 Hz).
[Reference Example 335]

N- (3- (4-Isopropylbenzyl) -4-hydroxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide N- (3- (4-isopropylbenzyl) -4 obtained in Reference Example 333 To a solution of -methoxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide (1.99 g, 5.21 mmol) in methylene chloride (25 mL) at -78 ° C under argon atmosphere, boron tribromide (1.0 M chloride) Methylene solution, 10.4 mL, 10.4 mmol) was added dropwise and stirred for 30 minutes. The reaction was warmed to room temperature and stirred for 14 hours. The reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. All organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.83 g (97% yield) of the title compound. Melting point 202-203 [deg.] C (ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.19 (6H, d, J = 6.9 Hz), 2.11 (3H, s), 2.12 (3H, s), 2.29 (2H, s), 2.82 (1H, septet, J = 6.9 Hz), 3.93 (2H, s), 6.34 (1H, s), 6.37 (1H, br), 6.62 (1H, s), 7.06 (4H, s).
[Reference Example 336]

N-benzyl-N- (3- (4-isopropylbenzyl) -4-hydroxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide N obtained in Reference Example 332 was prepared in the same manner as Reference Example 335. The title compound was synthesized using -benzyl-N- (3- (4-isopropylbenzyl) -4-methoxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide. Yield 83%. Melting point 167-168 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.66 (3H, s), 1.80 (2H, s), 1.87 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.90 (1H, d, J = 16.2 Hz), 3.97 (1H, d, J = 16.2 Hz), 4.54 (1H, d, J = 13.5 Hz), 4.57 ( 1H, d, J = 13.5 Hz), 4.98 (1H, br), 6.59 (1H, s), 6.94 (2H, d, J = 7.8 Hz), 7.11 (2H, d, J = 7.8 Hz), 7.10- 7.16 (5H, m).
[Reference Example 337]

N-benzyl-N- (3-bromo-5- (4-isopropylbenzyl) -4-hydroxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide Reference Example 336 was prepared in the same manner as Reference Example 66. The title compound was synthesized from N-benzyl-N- (3- (4-isopropylbenzyl) -4-hydroxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide obtained in 1 above. Yield 98%. Melting point 107-108 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.66 (3H, s), 1.76 (2H, s), 2.00 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.96 (1H, d, J = 15.6 Hz), 4.08 (1H, d, J = 15.6 Hz), 4.49 (1H, d, J = 13.5 Hz), 4.87 ( 1H, d, J = 13.5 Hz), 5.76 (1H, s), 6.93 (2H, d, J = 8.4 Hz), 7.09-7.21 (7H, m).
[Reference Example 338]

N-benzyl-N- (3-bromo-4- (2-chloroethoxy) -5- (4-isopropylbenzyl) -2,6-dimethylphenyl) -3,3-dimethylbutanamide In the same manner as in Reference Example 217. Using N-benzyl-N- (3-bromo-5- (4-isopropylbenzyl) -4-hydroxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide obtained in Reference Example 337, The title compound was synthesized. Yield 87%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 0.98 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.54 (3H, s), 1.73 (2H, s), 2.07 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.75 (2H, t, J = 6.0 Hz), 3.99-4.13 (4H, m), 4.42 (1H, d, J = 13.5 Hz), 4.96 (1H, d , J = 13.5 Hz), 6.84 (2H, d, J = 8.1 Hz), 7.00-7.20 (7H, m).
[Reference Example 339]

N- (3- (4-Isopropylbenzyl) -2,6-dimethyl-4-((2-methylprop-2-en-1-yl) oxy) phenyl) -3,3-dimethylbutanamide In Reference Example 335 N- (3- (4-Isopropylbenzyl) -4-methoxy-2,6-dimethyl) -amino-2- (4-isopropylbenzyl) -1-hydroxy-3,5-dimethylphenyl) -3, A mixture of 3-dimethylbutanamide (300 mg, 0.82 mmol), methallyl chloride (89 mg, 0.98 mmol) and potassium carbonate (135 mg, 0.98 mmol) in DMF (5 mL) at 80 ° C. for 18 hours under an argon atmosphere. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 2: 3) to obtain 280 mg (yield 81%) of the title compound. Melting point 129-130 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.19 (6H, d, J = 6.9 Hz), 1.72 (3H, s), 2.12 (3H, s), 2.22 (3H, s), 2.26 (2H, s), 2.82 (1H, septet, J = 6.9 Hz), 4.03 (2H, s), 4.38 (2H, s), 4.90 (1H, s), 5.02 (1H, s), 6.53 (1H , s), 6.63 (1H, br), 7.04 (4H, s).
[Reference Example 340]

N- (4- (allyloxy) -3-bromo-5- (4-isopropylbenzyl) -2,6-dimethylphenyl) -3,3-dimethylbutanamide obtained in Reference Example 335 in the same manner as Reference Example 66. N- (3- (4-isopropylbenzyl) -4-hydroxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide and N- (3-bromo-5- (4-isopropylbenzyl) -4-Hydroxy-2,6-dimethylphenyl) -3,3-dimethylbutanamide was synthesized. Using this compound, the title compound was synthesized in the same manner as in Reference Example 213. Yield 33%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 2.06 (3H, s), 2.28 (2H, s), 2.37 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 4.08 (2H, br s), 4.29 (2H, br s), 5.20 (1H, d, J = 10.5 Hz), 5.28-5.36 (1H, m), 5.98 -6.20 (1H, m), 6.65 (1H, s), 7.00 (2H, d, J = 8.1 Hz), 7.08 (2H, d, J = 8.1 Hz).
[Reference Example 341]

N- (4-hydroxy-3- (4-isopropylbenzyl) -2,6-dimethyl-5- (2-methylprop-2-en-1-yl) phenyl) -3,3-dimethylbutanamide Reference Example 215 In the same manner as described above, N- (3- (4-isopropylbenzyl) -2,6-dimethyl-4-((2-methylprop-2-en-1-yl) oxy) phenyl)-obtained in Reference Example 339 The title compound was synthesized using 3,3-dimethylbutanamide. Yield 93%. Melting point 124-125 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.78 (3H, s), 2.15 (3H, s), 2.16 (3H, s), 2.29 (2H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.38 (2H, s), 4.03 (2H, br s), 4.65 (1H, s), 4.84 (1H, s), 5.05 ( 1H, s), 6.60 (1H, s), 7.04 (2H, d, J = 8.1 Hz), 7.09 (2H, d, J = 8.1 Hz).
[Reference Example 342]

3,3-Dimethyl-N- (2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide In the same manner as in Example 1, Reference Example 55 Using the 5-amino-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-3 (2H) -one obtained in 1 above, the title compound was synthesized. Yield 91%. Melting point 181-182 ° C (THF-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.42 (6H, s), 2,30-2.32 (5H, m), 2.49 (3H, s), 6.55 (1H, br s), 6.79 (1H, s).
[Reference Example 343]

3,3-Dimethyl-N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-1-benzofuran-5-yl) butanamide 3 obtained in Reference Example 305 in the same manner as in Example 63 The title compound was synthesized using-(4-isopropylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine. Yield 50%. Melting point 229-230 ° C. (THF-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.30 (6H, d, J = 6.9 Hz), 2.11 (3H, s), 2.27 (3H, s), 2.31 (2H, s), 2.45 (3H, s), 2.96 (1H, septet, J = 6.9 Hz), 6.67 (1H, br s), 7.24 (2H, d, J = 8.4 Hz), 7.33 (2H, d, J = 8.4 Hz) , 7.48 (1H, s).
[Reference Example 344]

7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine N- (7-acetyl-3- (4) obtained in Example 203 -Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide (808 mg, 2.3 mmol) was added to a solution of methanol (10 mL) and concentrated hydrochloric acid (5 mL). The mixture was stirred for 2 hours with heating under reflux. The reaction solution was cooled to room temperature, poured into cold sodium bicarbonate water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 1: 1) to give the title compound as an oil.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.87 (3H, s), 2.18 (3H, s), 2.60 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.34 (2H, br), 4.36-4.43 (1H, m), 4.48-4.56 (1H, m), 4.76-4.85 (1H, m), 7.03 (2H, d, J = 8.1Hz) , 7.12 (2H, d, J = 8.1 Hz).
[Reference Example 345]

2-Bromo-1- (4-isopropylphenyl) propan-1-one The title compound was synthesized in the same manner as in Reference Example 164 using 2-bromopropanoyl chloride. Yield 97%. Oily substance.
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.28 (6H, d, J = 7.0 Hz), 1.90 (3H, d, J = 7.0 Hz), 2.98 (1H, septet, J = 7.0 Hz), 5.28 (1H, q, J = 7.0 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.97 (2H, d, J = 8.0 Hz).
[Reference Example 346]

1- (4-Isopropylphenyl) -2- (2,3,5-trimethylphenoxy) propan-1-one In the same manner as in Reference Example 159, 2-bromo-1- (4-isopropyl) obtained in Reference Example 345 The title compound was synthesized using (phenyl) propan-1-one and 2,3,5-trimethylphenol. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7.0 Hz), 1.69 (3H, d, J = 7.0 Hz), 2.16 (3H, s), 2.19 (3H, s), 2.21 ( 3H, s), 2.95 (1H, septet, J = 7.0 Hz), 5.37 (1H, q, J = 7.0 Hz), 6.40 (1H, s), 6.59 (1H, s), 7.29-7.32 (2H, m ), 8.00-8.04 (2H, m).
[Reference Example 347]

3- (4-Isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran 1- (4-isopropylphenyl) -2- (2,3,5-trimethylphenoxy) obtained in Reference Example 346 A toluene (200 mL) mixture of propan-1-one (61.3 g, 194 mmol), Amberlyst 15 (61.0 g), and molecular sieve MS4A (30 g) was heated to reflux at 80 ° C. for 2 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate-hexane 1: 100) to obtain the title compound (54.4 g, yield 96%). Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 7.0 Hz), 2.06 (3H, s), 2.32 (3H, s), 2.34 (3H, s), 2.41 (3H, s), 2.96 (1H, septet, J = 7.0 Hz), 6.75 (1H, s), 7.25 (4H, s).
[Reference Example 348]

2-Bromo-1- (4-isopropylphenyl) propane-1-obtained in Reference Example 345 in the same manner as 3- (4-isopropylphenyl) -2,6,7-trimethyl-1-benzofuran Reference Example 159 Using 1- and 2,3-dimethylphenol, 1- (4-isopropylphenyl) -2- (2,3-dimethylphenoxy) propan-1-one was obtained. The title compound was obtained in the same manner as in Reference Example 143. Yield 81%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 7.0 Hz), 2.38 (3H, s), 2.44 (3H, s), 2.53 (3H, s), 2.97 (1H, septet, J = 7.0 Hz), 7.02 (1H, d, J = 8.0 Hz), 7.29-7.45 (5H, m).
[Reference Example 349]

(Cis) -3- (4-Isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran 3- (obtained in Reference Example 347 in the same manner as Reference Example 144 The title compound was synthesized using 4-isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran. Yield 63%. Melting point 79-80 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.09 (3H, d, J = 7.0 Hz), 1.21 (6H, d, J = 7.0 Hz), 1.90 (3H, s), 2.16 (3H, s), 2.24 ( 3H, s), 2.85 (1H, septet, J = 7.0 Hz), 4.30 (1H, d, J = 7.0 Hz), 4.91-5.05 (1H, m), 6.49 (1H, s), 6.83 (2H, d , J = 8.0 Hz), 7.08 (2H, d, J = 8.0 Hz).
[Reference Example 350]

(Cis) -N-benzyl-3- (4-isopropylphenyl) -2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine In the same manner as in Reference Example 144, in Reference Example 348 Using the obtained 3- (4-isopropylphenyl) -2,6,7-trimethyl-1-benzofuran, 3- (4-isopropylphenyl) -2,6,7-trimethyl-2,3-dihydro-1- Obtained benzofuran. Using this compound, 5-bromo-3- (4-isopropylphenyl) -2,6,7-trimethyl-2,3-dihydro-1-benzofuran was obtained in the same manner as in Reference Example 23. Using this compound, the title compound was synthesized in the same manner as in Reference Example 24. Yield 22%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, d, J = 7.0 Hz), 1.23 (6H, d, J = 7.0 Hz), 2.10 (3H, s), 2.24 (3H, s), 2.87 ( 1H, septet, J = 7.0 Hz), 3.44 (1H, br s), 4.19 (2H, s), 4.44 (1H, d, J = 8.0 Hz), 4.90-4.99 (1H, m), 6.37 (1H, s), 6.90 (2H, d, J = 8.0 Hz), 7.10 (2H, d, J = 8.0 Hz), 7.23-7.36 (5H, m).
[Reference Example 351]

(Cis) -3- (4-Isopropylphenyl) -2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride Obtained in Reference Example 350 in the same manner as Reference Example 30. The title compound was synthesized using (cis) -N-benzyl-3- (4-isopropylphenyl) -2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 96%. Melting point 189-190 [deg.] C. (diisopropyl ether-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, d, J = 6.0 Hz), 1.22 (6H, d, J = 7.0 Hz), 2.09 (3H, s), 2.21 (3H, s), 2.86 ( 1H, sept, J = 7.0 Hz), 3.23 (3H, br), 4.39 (1H, d, J = 8.0 Hz), 4.89-4.99 (1H, m), 6.36 (1H, s), 6.90 (2H, d , J = 8.0 Hz), 7.11 (2H, d, J = 8.0 Hz).
[Reference Example 352]

(Cis) -3- (4-Isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine Obtained in Reference Example 349 in the same manner as Reference Example 23. (Cis) -3- (4-Isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran was used to give (cis) -5-bromo-3- (4 -Isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran was synthesized. Using this compound, in the same manner as in Reference Example 24, (cis) -N-benzyl-3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1- Benzofuran-5-amine was synthesized. Using this compound, the title compound was synthesized in the same manner as in Reference Example 30. Yield 83%.
Melting point 91-92 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, d, J = 7.0 Hz), 1.21 (6H, d, J = 7.0 Hz), 1.84 (3H, s), 2.12 (3H, s), 2.21 ( 3H, s), 2.85 (1H, septet, J = 7.0 Hz), 3.25 (2H, br s), 4.29 (1H, d, J = 8.0 Hz), 4.83-4.96 (1H, m), 6.83 (2H, d, J = 8.0 Hz), 7.07 (2H, d, J = 8.0 Hz).
[Reference Example 353]

2- (3,5-Dimethylphenoxy) -1-phenylethanone In the same manner as in Reference Example 177, the title compound was synthesized using 3,5-dimethylphenol and phenacyl bromide. Yield 86%. Melting point 104-105 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 2.28 (6H, s), 5.23 (2H, s), 6.58 (2H, s), 6.63 (1H, s), 7.46-7.54 (2H, m), 7.58-7.65 (1H, m), 7.98-8.04 (2H, m).
[Reference Example 354]

4,6-Dimethyl-3-phenyl-1-benzofuran In the same manner as in Reference Example 143, the title compound was synthesized using 2- (3,5-dimethylphenoxy) -1-phenylethanone obtained in Reference Example 353. did. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 2.43 (3H, s), 6.83 (1H, s), 7.17 (1H, s), 7.38-7.50 (6H, m).
[Reference Example 355]

4,6-Dimethyl-3-phenyl-2,3-dihydro-1-benzofuran In the same manner as in Reference Example 199, 4,6-dimethyl-3-phenyl-1-benzofuran obtained in Reference Example 354 was used. The compound was synthesized. Yield 91%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.91 (3H, s), 2.29 (3H, s), 4.41 (1H, dd, J = 8.4, 4.8 Hz), 4.51 (1H, dd, J = 9.0, 5.1 Hz ), 4.85 (1H, d, J = 9.0 Hz), 6.48 (1H, s), 6.57 (1H, s), 7.11-7.31 (5H, m).
[Reference Example 356]

5-Bromo-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran
In the same manner as in Reference Example 23, the title compound was synthesized using 4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran obtained in Reference Example 355. Yield 78%. Melting point 135-136 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 2.04 (3H, s), 2.39 (3H, s), 4.41 (1H, dd, J = 9.0, 4.5 Hz), 4.56 (1H, dd, J = 9.3, 4.2 Hz ), 4.85 (1H, d, J = 9.0 Hz), 6.67 (1H, s), 7.07-7.25 (2H, m), 7.19-7.32 (3H, m).
[Reference Example 357]

N-benzyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine 5-bromo-4,6-dimethyl obtained in Reference Example 356 in the same manner as Reference Example 24 The title compound was synthesized using -3-phenyl-2,3-dihydro-1-benzofuran. Yield 72%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.89 (3H, s), 2.26 (3H, s), 2.87 (1H, br s), 3.92 (2H, s), 4.37 (1H, dd, J = 8.4, 4.8 Hz), 4.52 (1H, dd, J = 9.0, 4.2 Hz), 4.82 (1H, d, J = 9.0 Hz), 6.60 (1H, s), 7.05-7.40 (10H, m).
[Reference Example 358]

4,6-Dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine N-benzyl-4,6-dimethyl-3-phenyl obtained in Reference Example 357 in the same manner as Reference Example 30 The title compound was synthesized using -2,3-dihydro-1-benzofuran-5-amine. Yield 84%. Melting point 127-128 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.84 (3H, s), 2.19 (3H, s), 3.26 (2H, br s), 4.33 (1H, dd, J = 8.7, 4.5 Hz), 4.53 (1H, dd, J = 9.0, 4.5 Hz), 4.78 (1H, dd, J = 9.0, 8.7 Hz), 6.56 (1H, s), 7.09-7.29 (5H, m).
[Reference Example 359]

(+)-N-((3R) -2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) -2- ( 4- (Trifluoromethyl) phenyl) acetamide (3R)-(+)-2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro obtained in Reference Example 134 To a DMF solution of -1-benzofuran-5-amine (0.89 g, 3 mmol), triethylamine (0.84 mL, 6 mmol), (4-trifluoromethyl) phenylacetic acid (0.67 g, 3.3 mmol), diethyl cyanophosphate ( 0.46 mL, 3.3 mmol) was added at 0 ° C., and the mixture was warmed to room temperature. After stirring at the same temperature for 1 hour, the reaction solution was poured into cold water (50 mL). The precipitated crystals were collected by filtration, and the crystals were dissolved again in ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was dried under reduced pressure, purified by silica gel column chromatography (ethyl acetate-hexane 1: 1), and crystallized from diethyl ether-hexane to give the title compound (1.19 g, yield 83%). Melting point 187-189 [deg.] C. (diethyl ether-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.47 (3H, s), 1.65 (3H, s), 2.04 (3H, s), 2.13 (3H, s), 2.29 (3H, s ), 3.79 (2H, s), 4.06 (1H, s), 6.44 (1H, br), 7.02 (4H, br), 7.49 (2H, d, J = 8.2 Hz), 7.62 (2H, d, J = 8.2 Hz).
[Reference Example 360]

(+)-2- (4-Methoxyphenyl) -N-((3R) -2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran -5-yl) acetamide Similar to Reference Example 359, (+)-(3R) -2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2, obtained in Reference Example 134 The title compound was synthesized using 3-dihydro-1-benzofuran-5-amine and 4-methoxyphenylacetic acid. Yield 74%. Melting point 186-188 ° C (ethyl acetate-hexane). ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.46 (3H, s), 1.64 (3H, s), 2.04 (3H, s), 2.13 (3H, s), 2.28 (3H, s ), 3.68 (2H, s), 3.80 (3H, s), 4.06 (1H, s), 6.44 (1H, br), 6.89 (2H, d, J = 8.6 Hz), 7.02 (4H, br), 7.25 (2H, d, J = 8.6 Hz).
[Reference Example 361]

(+)-3- (4-Methoxyphenyl) -N-((3R) -2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran -5-yl) propionamide (+)-(3R) -2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2 obtained in Reference Example 134 as in Reference Example 359 The title compound was synthesized using 1,3-dihydro-1-benzofuran-5-amine and 4-methoxyphenylpropionic acid. Yield 21%. Melting point 170-172 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.48 (3H, s), 1.63 (3H, s), 1.99 (3H, s), 2.13 (3H, s), 2.29 (3H, s ), 2.64 (2H, d, J = 7.4 Hz), 2.99 (2H, d, J = 7.4 Hz), 3.76 (3H, s), 4.08 (1H, s), 6.44 (1H, br), 6.81 (2H , d, J = 8.5 Hz), 7.02 (4H, br), 7.16 (2H, d, J = 8.5 Hz).
[Reference Example 362]

3- (4-Methoxyphenyl) -N- (2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) propionamide Reference Analogously to Example 359, 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine and 4-methoxy obtained in Reference Example 130 The title compound was synthesized using phenylpropionic acid. Yield 29%. Melting point 180-183 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.48 (3H, s), 1.63 (3H, s), 1.99 (3H, s), 2.13 (3H, s), 2.29 (3H, s ), 2.64 (2H, d, J = 7.3 Hz), 2.99 (2H, d, J = 7.3 Hz), 3.76 (3H, s), 4.08 (1H, s), 6.45 (1H, br), 6.81 (2H , d, J = 8.5 Hz), 7.02 (4H, br), 7.16 (2H, d, J = 8.5 Hz).
[Reference Example 363]

2- (4-Methoxyphenyl) -N- (2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) acetamide Reference Example Like 2,359, 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine and 4-methoxyphenyl obtained in Reference Example 130 The title compound was synthesized using acetic acid. Yield 62%. Melting point 166-167 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.46 (3H, s), 1.63 (3H, s), 2.03 (3H, s), 2.12 (3H, s), 2.28 (3H, s ), 3.68 (2H, s), 3.79 (3H, s), 4.05 (1H, s), 6.43 (1H, br), 6.87 (2H, d, J = 8.6 Hz), 7.00 (4H, br), 7.25 (2H, d, J = 8.6 Hz).
[Reference Example 364]

4- (4-Methoxyphenyl) -N- (2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) butanamide Reference Example As in 359, 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 130 and 4- (4 The title compound was synthesized using -methoxyphenyl) butanoic acid. Yield 11%. Melting point 166-167 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.46 (3H, s), 1.63 (3H, s), 2.03 (3H, s), 2.12 (3H, s), 2.28 (3H, s ), 3.68 (2H, s), 3.79 (3H, s), 4.05 (1H, s), 6.43 (1H, br), 6.87 (2H, d, J = 8.6 Hz), 7.00 (4H, br), 7.25 (2H, d, J = 8.6 Hz).
[Reference Example 365]

N- (3- (4-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -4-methoxyphenylacetamide As in Reference Example 63. 3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 120 and 4-methoxyphenylacetyl chloride Used to synthesize the title compound. Yield 74%. Melting point 171-173 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 1.20 (6H, d, J = 6.6 Hz), 1.46 (3H, s), 1.64 (3H, s), 2.03 (3H, s), 2.12 (3H, s), 2.84 (1H, septet, J = 6.6 Hz), 3.68 (2H, s), 3.80 (3H, s), 4.06 (1H, s), 6.45 (1H, br), 6.6-6.9 (2H, m), 6.89 (2H, d, J = 8.6 Hz), 7.05 (2H, d, J = 8.0 Hz), 7.26 (d, 2H, J = 8.6 Hz).
[Reference Example 366]

N- (3- (4-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3- (4-methoxyphenyl) propionamide Reference In the same manner as in Example 63, 3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 120 and 4- The title compound was synthesized using methoxyphenylpropionyl chloride. Yield 72%. Melting point 188-191 [deg.] C. (Ethyl acetate-hexane)
¹ H-NMR (CDCl ₃ ) δ: 0.99-1.01 (3H, m), 1.19-1.26 (6H, m), 1.48 (3H, s), 1.64-1.68 (3H, m), 1.99 (3H, s) , 2.05-2.13 (5H, m), 2.65-3.04 (3H, m), 3.72-3.77 (3H, m), 4.08 (1H, s), 6.47-7.19 (9H, m).
[Reference Example 367]

N- (3- (4-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -N- (2- (4-methoxyphenyl) Ethyl) acetamide To a suspension of aluminum chloride (1.23 g, 9.25 mmol) in THF (40 mL) was added lithium aluminum hydride (354 mg, 9.31 mmol) little by little under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. . N- (3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -4-synthesized in Reference Example 365 was added to this mixture. Methoxyphenylacetamide (536 mg, 1.14 mmol) was added and heated to reflux for 3 hours. The reaction mixture was added to ice water, neutralized with 8N aqueous sodium hydroxide solution, and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and reduced pressure. Concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 3: 1) to give 3- (4-isopropylphenyl) -N- (2- (4-methoxyphenyl) ethyl) -2,2,4,6. , 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine was obtained. This compound (537.9 mg, 1.18 mmol) was added to a DMF (25 mL) suspension of sodium hydride (60% paraffin dispersion, 232.1 mg, 5.80 mmol) and stirred at 60 ° C. for 20 minutes. Acetyl chloride (0.5 mL, 7.03 mmol) was added and stirred at the same temperature for 1 hour. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 3: 1) to obtain the target rotamer (Rf = 0.38; hexane-ethyl acetate 3: 1) (yield 43%). It was. Melting point 134-136 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.22 (6H, d, J = 7.0 Hz), 1.54 (3H, s), 1.66 (3H, s), 1.72 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 2.77-2.89 (3H, m), 3.59-3.70 (2H, m), 3.77 (3H, s), 4.11 (1H, s), 6.77-7.13 ( 8H, m).
[Reference Example 368]

N- (3- (4-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -N- (2- (4-methoxyphenyl) Ethyl) acetamide The residue operated in the same manner as in Reference Example 367 was purified by silica gel column chromatography (hexane-ethyl acetate 3: 1), and the target rotational isomer (Rf = 0.25; hexane-ethyl acetate 3: 1) (yield 34%) was obtained. Amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.23 (6H, d, J = 6.8 Hz), 1.53 (3H, s), 1.73 (3H, s), 1.75 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 2.67-2.75 (2H, m), 2.80-2.94 (1H, septet, J = 6.8 Hz), 3.57-3.74 (2H, m), 3.77 (3H, s), 4.14 (1H, s), 6.77-7.13 (8H, m).

N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide 3-obtained in Reference Example 30 Chlorination of (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine (430 mg, 1.46 mmol) and tert-butylacetyl chloride (0.22 mL, 1.53 mmol) Triethylamine (0.22 mL, 1.61 mmol) was added to the methylene (10 mL) solution at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 8: 1) to obtain 400 mg (yield 70%) of the title compound. Melting point 171-173 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.81 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.41 (1H, dd, J = 8.7, 4.8 Hz), 4.52 (1H, dd, J = 8.7, 4.8 Hz), 4.82 (1H , t, J = 8.7 Hz), 6.49 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.4 Hz).

N- (3- (4-Isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, Reference Example The title compound was synthesized using 3- (4-isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in 31. Yield 54%. Melting point 177-178 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.09 (9H, s), 1.24 (6H, d, J = 7.2 Hz), 2.13 (3H, s), 2.18 (2H, s), 2.20 (3H, s), 2.87 (1H, septet, J = 7.2 Hz), 4.28 (1H, dd, J = 9.0, 7.5 Hz), 4.56-4.63 (1H, m), 4.84 (1H, t, J = 9.0 Hz), 6.69 (1H , br s), 6.94 (1H, s), 7.11 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, Reference Example Using the 3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in 32, the title compound was synthesized. Yield 67%. Melting point 130-131 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.21 (3H, s), 2.23 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.40 (1H, dd, J = 8.4, 4.8 Hz), 4.49 (1H, dd, J = 9.0, 4.8 Hz), 4.77-4.85 (1H, m), 6.48 (1H, br s), 6.62 (1H, s), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide 3-methylbutanamide obtained in Reference Example 33 in the same manner as in Example 1. The title compound was synthesized using (4-isopropylphenyl) -2,3-dihydro-1-benzofuran-5-amine. Yield 71%. Melting point 119-120 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.06 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 2.13 (2H, s), 2.88 (1H, septet, J = 6.9 Hz), 4.40 ( 1H, dd, J = 9.0, 7.5 Hz), 4.56-4.64 (1H, m), 4.87 (1H, t, J = 9.0 Hz), 6.79 (1H, d, J = 8.7 Hz), 6.89 (1H, br s), 7.08-7.23 (6H, m).

N- (3- (4-Isopropylphenyl) -3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 1 The title compound was synthesized using 3- (4-isopropylphenyl) -3,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 34. . Yield 37%. Melting point 194-195 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.72 (3H, s), 1.74 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.24 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.37 (1H, d, J = 8.4 Hz), 4.42 (1H, d, J = 8.4 Hz), 6.48 (1H, br s), 7.13 (2H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz).

N- (3- (4-Isopropylphenyl) -3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, The title compound was synthesized using 3- (4-isopropylphenyl) -3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 35. Yield 59%. Melting point 132-133 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.71 (3H, s), 2.14 (3H, s), 2.19 (3H, s), 2.20 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.40 (1H, d, J = 8.7 Hz), 4.57 (1H, d, J = 8.7 Hz), 6.72 (1H, br s) , 6.97 (1H, s), 7.13 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz).

(+)-N-((3R) -3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 1 was obtained. High performance liquid chromatography (instrument: GIGAPREP SK-1 manufactured by Shiseido Co., Ltd., column: CHIRALCEL OD (50 (i, d) x 500 mm) manufactured by Daicel Chemical Industries, Ltd.), moving bed: hexane: ethanol = 95: 5, flow rate: 60 mL / min, column temperature: 35 ° C., injection amount: 30 mg / time, detection: UV 220 nm), and the one with the smaller retention time was fractionated. Recovery 44%. Melting point 186-187 [deg.] C. (ethyl acetate-hexane). [α] _D ²⁰ = + 64.0 ° (c = 0.44, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.84 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.40 (1H, dd, J = 8.7, 4.8 Hz), 4.51 (1H, dd, J = 9.3, 4.8 Hz), 4.81 (1H , t, J = 9.0 Hz), 6.47 (1H, br s), 7.03 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.4 Hz).

(-)-N-((3S) -3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 1 was obtained. High performance liquid chromatography (instrument: GIGAPREP SK-1 manufactured by Shiseido Co., Ltd., column: CHIRALCEL OD (50 (i, d) x 500 mm) manufactured by Daicel Chemical Industries, Ltd.), moving bed: hexane: ethanol = 95: 5, flow rate: 60 mL / min, column temperature: 35 ° C., injection amount: 30 mg / time, detection: UV 220 nm), and the one with the longer retention time was fractionated. Recovery rate 42%. Melting point 185-186 ° C. (Ethyl acetate-hexane). [α] _D = −61.2 ° (c = 0.42, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.84 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.24 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.40 (1H, dd, J = 8.7, 4.8 Hz), 4.51 (1H, dd, J = 9.0, 4.8 Hz), 4.81 (1H , t, J = 8.7 Hz), 6.49 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) propionamide obtained in Reference Example 30 in the same manner as in Example 1. The title compound was synthesized using 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine and propionyl chloride. Yield 74%. Melting point 164-165 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.00-1.37 (9H, m), 1.82 (3H, s), 2.09-2.45 (8H, m), 2.85 (1H, septet, J = 6.9 Hz), 4.37-4.60 (2H, m), 4.77-4.89 (1H, m), 6.54 (1H, br s), 6.99-7.19 (4H, m).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide
In the same manner as in Example 1, using 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine and butyryl chloride obtained in Reference Example 30 The title compound was synthesized. Yield 80%. Melting point 177-178 [deg.] C. (THF-diisopropyl ether).
¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.5 Hz), 1.22 (6H, d, J = 6.9 Hz), 1.71-1.87 (5H, m), 2.13 (3H, s), 2.18 (3H, s), 2.35 (2H, t, J = 7.5 Hz), 2.86 (1H, septet, J = 6.9 Hz), 4.42 (1H, dd, J = 9.0, 4.5 Hz), 4.53 (1H, dd , J = 9.0, 4.5 Hz), 4.83 (1H, t, J = 9.0 Hz), 6.54 (1H, br s), 6.99-7.06 (2H, m), 7.11-7.15 (2H, m).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) pentanamide obtained in Reference Example 30 in the same manner as in Example 1. The title compound was synthesized using 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine and pentanoyl chloride. Yield 72%. Melting point 128-129 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.72-1.00 (3H, m), 1.21 (6H, d, J = 6.9 Hz), 1.36-1.90 (7H, m), 2.11-2.42 (8H, m), 2.85 (1H, septet, J = 6.9 Hz), 4.37-4.59 (2H, m), 4.77-4.89 (1H, m), 6.53 (1H, br s), 6.99-7.17 (4H, m).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -2- (4-methoxyphenyl) acetamide
Similarly to Example 1, 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine and (4-methoxyphenyl) obtained in Reference Example 30 The title compound was synthesized using acetyl chloride. Yield 62%. Melting point 166-167 [deg.] C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 1.72 (3H, s), 2.02 (3H, s), 2.14 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.69 (2H, s), 3.80 (3H, s), 4.39 (1H, dd, J = 9.0, 4.5 Hz), 4.48 (1H, dd, J = 9.0, 4.5 Hz), 4.80 (1H , t, J = 9.0 Hz), 6.46 (1H, br s), 6.90 (2H, d, J = 8.4 Hz), 7.01 (2H, d, J = 8.4 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.26 (2H, d, J = 8.4 Hz).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3- (4-methoxyphenyl) propionamide Same as Example 1 3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine and 3- (4-methoxyphenyl) propionyl chloride obtained in Reference Example 30 Was used to synthesize the title compound. Yield 83%. Melting point 119-120 ° C. (ethyl acetate-hexane). ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 7.2 Hz), 1.66-1.75 (3H, m), 1.97-2.20 (6H, m), 2.61-3.02 (5H, m), 3.71 -3.78 (3H, m), 4.35-4.56 (2H, m), 4.77-4.85 (1H, m), 6.45 (1H, br s), 6.62-7.20 (8H, m).

N- (tert-butyl) -N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) urea obtained in Reference Example 30 To a solution of 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine (300 mg, 1.02 mmol) in methylene chloride (5 mL) tert-isocyanate Butyl (0.14 mL, 1.22 mmol) was added and refluxed for 20 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 2: 1) and recrystallized from THF-hexane to obtain 283 mg (yield 70%) of the title compound. Melting point 201-202 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.40 (15H, m), 1.87 (3H, s), 2.19 (6H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.00 (1H, br s), 4.45 (1H, dd, J = 8.7, 4.5 Hz), 4.55 (1H, dd, J = 8.7, 4.5 Hz), 4.86 (1H, t, J = 8.7 Hz), 5.31 (1H, br s) , 7.00 (2H, d, J = 8.0 Hz), 7.12 (2H, d, J = 8.0 Hz).

(3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) ethyl oxamate
In the same manner as in Example 1, 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine and ethyl oxalyl chloride obtained in Reference Example 30 were used. The title compound was synthesized. Yield 76%. Melting point 83-84 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.42 (3H, t, J = 7.2 Hz), 1.83 (3H, s), 2.13 (3H, s), 2.19 ( 3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.37-4.46 (3H, m), 4.54 (1H, dd, J = 9.0, 4.5 Hz), 4.85 (1H, t, J = 9.0 Hz ), 7.04 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz), 8.27 (1H, br s).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl-2-oxobutanamide
THF of (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) oxamate (100 mg, 0.25 mmol) obtained in Example 15 To the (3 mL) solution, tert-butylmagnesium chloride (2.0 M THF solution, 0.26 mL, 0.5 mmol) was added dropwise at 0 ° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour, added to ice, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) and recrystallized from ethyl acetate-hexane to obtain 29 mg (yield 28%) of the title compound. Mp 142-143 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.37 (9H, s), 1.81 (3H, s), 2.10 (3H, s), 2.18 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.42 (1H, dd, J = 9.0, 4.5 Hz), 4.52 (1H, dd, J = 9.0, 4.5 Hz), 4.82 (1H, t, J = 9.0 Hz ), 7.03 (2H, d, J = 7.8 Hz), 7.12 (2H, d, J = 7.8 Hz), 8.00 (1H, br s).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -2-oxobutanamide
Oxalyl chloride (0.33 mL, 3.80 mmol) was added dropwise to a solution of 2-oxobutanoic acid (259 mg, 2.54 mmol) in THF (5 mL) under ice-cooling, DMF (3 drops) was added, and the mixture was stirred for 30 min. The reaction solution was warmed to room temperature and stirred for 1 hour, and then the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (5 mL), and 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine (500 mg) obtained in Reference Example 30 was obtained. , 1.69 mmol) and triethylamine (0.24 mL, 1.69 mmol) in THF (5 mL) were added dropwise under ice cooling and stirred for 30 minutes. After raising the temperature to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 2: 1) to give 363 mg of the title compound ( Yield 57%) was synthesized. Yield 57%. Melting point 97-98 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 1.22 (6H, d, J = 6.9 Hz), 1.79 (3H, s), 2.09 (3H, s), 2.18 ( 3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.01 (2H, q, J = 7.2 Hz), 4.42 (1H, dd, J = 9.0, 4.5 Hz), 4.53 (1H, dd, J = 9.0, 4.5 Hz), 4.83 (1H, t, J = 9.0 Hz), 7.03 (2H, d, J = 7.8 Hz), 7.12 (2H, d, J = 7.8 Hz), 8.13 (1H, s).

2-Hydroxy-N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide
N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -2-oxobutanamide obtained in Example 17 (237 mg, 0.62 mmol) in methanol (5 mL) was added sodium borohydride (24 mg, 0.62 mmol) at 0 ° C. and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 170 mg (yield 72%) of the title compound. Melting point 146-147 [deg.] C.
¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, t, J = 7.5 Hz), 1.22 (6H, d, J = 6.9 Hz), 1.70-1.88 (4H, m), 1.88-2.05 (1H, m ), 2.12 (3H, s), 2.18 (3H, s), 2.50-2.60 (2H × 0.5, m), 2.86 (1H, septet, J = 6.9 Hz), 4.22-4.28 (2H × 0.5, m), 4.41 (1H, dd, J = 9.0, 4.5 Hz), 4.52 (1H, dd, J = 9.0, 4.5 Hz), 4.82 (1H, t, J = 9.0 Hz), 7.03 (2H, d, J = 7.5 Hz) ), 7.11 (2H, d, J = 7.5 Hz), 7.58 (1H x 0.5, br s), 7.60 (1H x 0.5, br s).

2-Hydroxy-N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide
Ethyl (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) oxamate (500 mg, 1.26 mmol) obtained in Example 15 in THF (10 mL) To the solution, tert-butylmagnesium chloride (2.0 M THF solution, 1.9 mL, 3.78 mmol) was added dropwise at 0 ° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. The reaction mixture was warmed to room temperature, stirred for 1 hour, added to ice, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) and recrystallized from ethyl acetate-hexane to obtain 194 mg (yield 38%) of the title compound as a diastereomer mixture. Melting point 165-166 [deg.] C.
¹ H-NMR (CDCl ₃ ) δ: 1.09 (9H, s), 1.20-1.26 (6H, m), 1.84 (3H, s), 2.14 (3H, s), 2.18 (3H, s), 2.64 (1H × 0.5, d, J = 5.1 Hz), 2.70 (1H × 0.5, d, J = 5.1 Hz), 2.80-2.92 (1H, m), 3.91 (1H × 0.5, d, J = 5.1 Hz), 3.92 ( 1H × 0.5, d, J = 5.1 Hz), 4.41 (1H, dd, J = 9.0, 4.5 Hz), 4.52 (1H, dd, J = 9.0, 4.5 Hz), 4.82 (1H, t, J = 9.0 Hz ), 7.03 (2H, d, J = 7.8 Hz), 7.12 (2H, d, J = 7.8 Hz), 7.36 (1H x 0.5, br s), 7.47 (1H x 0.5, br s).

N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 3 N- (3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (650 mg, 1.71 mmol) and 1, To a solution of 1-dichloromethyl methyl ether (237 mg, 2.06 mmol) in methylene chloride (5 mL) was added titanium tetrachloride (0.34 mL, 3.07 mmol) in an argon atmosphere under ice-cooling, followed by 20 at the same temperature. Stir for minutes. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 520 mg (yield 75%) of the title compound. Melting point 177-178 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.26 (2H, s), 2.51 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.49-4.61 (2H, m), 4.92-5.05 (1H, m), 6.55 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz), 10.4 (1H, s).

N- (7- (hydroxymethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Example 20 N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (370) mg, 0.91 mmol) in methanol (5 mL) was added sodium borohydride (34 mg, 0.91 mmol) at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain 290 mg (yield 78%) of the title compound. Melting point 274-275 [deg.] C.
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.86 (3H, s), 2.00 (1H, br s), 2.26 (5H, s) , 2.86 (1H, septet, J = 6.9 Hz), 4.43 (1H, dd, J = 8.1, 4.8 Hz), 4.52 (1H, dd, J = 9.3, 4.8 Hz), 4.64-4.93 (3H, m), 6.54 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

N- (7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide methyl To magnesium bromide (2.0 M THF solution, 5.0 mL, 10.0 mmol), N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro- obtained in Example 20 was used. 1-Benzofuran-5-yl) -3,3-dimethylbutanamide (780 mg, 1.91 mmol) was added at 0 ° C., and the reaction solution was stirred at the same temperature for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 590 mg (yield 73%) of the title compound as a diastereomer mixture. Melting point 156-157 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.87-1.32 (15H, m), 1.50-1.62 (3H, m), 1.86 (3H, s), 2.17-2.25 (5H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.42-3.52 (1H, m), 4.47-4.52 (2H, m), 4.82-5.09 (2H, m), 6.50 (1H, br s), 7.00-7.05 (2H, m), 7.03-7.15 (2H, m).

N- (7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 22 N- (7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide ( To a mixture of 200 mg, 0.47 mmol) trifluoroacetic acid (3 mL), triethylsilane (0.5 mL, 3.2 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, the aqueous layer was made alkaline, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 10: 1) and crystallized from hexane to obtain 100 mg of the title compound (yield 52%). Melting point 135-136 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.90-1.25 (18H, m), 1.84 (3H, s), 2.18 (3H, s), 2.24 (2H, s), 2.65 (2H, q, J = 7.5 Hz ), 2.85 (1H, septet, J = 6.9 Hz), 4.40 (1H, dd, J = 8.7, 4.8 Hz), 4.50 (1H, dd, J = 9.0, 4.8 Hz), 4.81 (1H, t, J = 9.0 Hz), 6.50 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -N, 3,3-trimethylbutanamide Synthesized in Example 1 Of N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (200 mg, 0.51 mmol) Sodium hydride (60% liquid paraffin dispersion, 24 mg, 0.6 mmol) was added to the DMF (3 mL) solution at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (78 mg, 0.55 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with diisopropyl ether. The extract was washed with water, dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to give two rotamers of the title compound. Among them, 25 mg (yield 12%) of a low-polar target product was obtained. Melting point 122-123 ° C. (petroleum ether).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.75 (3H, s), 1.79 (2H, s), 2.06 (3H, s), 2.18 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.00 (3H, s), 4.44 (1H, dd, J = 8.7, 4.8 Hz), 4.55 (1H, dd, J = 9.0, 4.8 Hz), 4.87 (1H, t, J = 9.0 Hz), 7.02 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -N, 3,3-trimethylbutanamide Silica gel column of Example 24 Chromatography (hexane-ethyl acetate 4: 1) gave 28 mg (14% yield) of the highly polar title compound of the two rotamers. Melting point 80-82 ° C. (petroleum ether).
¹ H-NMR (CDCl ₃ ) δ: 0.91 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.72 (2H, s), 1.73 (3H, s), 2.07 (3H, s), 2.19 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.06 (3H, s), 4.43 (1H, dd, J = 8.7, 4.8 Hz), 4.55 (1H, dd, J = 9.0, 4.8 Hz), 4.86 (1H, t, J = 9.0 Hz), 6.95 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7- (1-pyrrolidinylmethyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane Amide pyrrolidine (0.20 mL, 2.4 mmol) in methanol (5 mL) in titanium tetraisopropoxide (0.36 mL, 1.20 mmol), N- (7-formyl-3- (4-isopropylphenyl) obtained in Example 20 ) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (250 mg, 0.61 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 14 hours. Sodium borohydride (23.2 mg, 0.61 mol) was added to the reaction solution at room temperature, and the mixture was stirred for 1.5 hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (hexane-ethyl acetate 2: 1) to obtain 140 mg (yield 49%) of the title compound. Amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.09 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.62-1.87 (7H, m), 2.22 (2H, s), 2.26 (3H, s ), 2.47-2.62 (4H, m), 2.85 (1H, septet, J = 6.9 Hz), 3.58 (1H, d, J = 12.0 Hz), 3.67 (1H, d, J = 12.0 Hz), 4.38 (1H , dd, J = 8.4, 4.5 Hz), 4.48 (1H, dd, J = 9.0, 4.5 Hz), 4.78 (1H, t, J = 9.0 Hz), 6.65 (1H, br s), 7.01 (2H, d , J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

N- (7-((dimethylamino) methyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 26, N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) obtained in Example 20 The title compound was synthesized using -3,3-dimethylbutanamide and dimethylamine. Yield 37%. Amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.20-2.32 (11H, m), 2.85 (1H, septet , J = 6.9 Hz), 3.39 (1H, d, J = 12.3 Hz), 3.45 (1H, d, J = 12.3 Hz), 4.40 (1H, dd, J = 8.7, 4.8 Hz), 4.51 (1H, dd , J = 9.0, 4.8 Hz), 4.80 (1H, t, J = 8.7 Hz), 6.51 (1H, br s), 7.01 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

N- (7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide methyl To magnesium bromide (2.0 M THF solution, 5.0 mL, 10.0 mmol), N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro- obtained in Example 20 was used. 1-Benzofuran-5-yl) -3,3-dimethylbutanamide (1.0 g, 1.91 mmol) was added at 0 ° C., and then the reaction solution was stirred at the same temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and 1N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 192 mg (yield 19%) of the title compound as a low polar substance. Melting point 147-148 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.51 (3H, d, J = 6.6 Hz), 1.86 (3H, s), 2.17 ( 3H, s), 2.25 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.51 (1H, d, J = 10.5 Hz), 4.43-4.58 (2H, m), 4.82-5.11 (2H , m), 6.51 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

N- (7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide The residue operated in the same manner as in Example 28 was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 122 mg (yield 12%) of the title compound as a highly polar substance. Melting point 169-170 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.55 (3H, d, J = 6.6 Hz), 1.85 (3H, s), 2.18 ( 3H, s), 2.25 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.49 (1H, d, J = 9.9 Hz), 4.43-4.58 (2H, m), 4.82-5.12 (2H , m), 6.53 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

N- (7- (1-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide ethyl Magnesium chloride (2.0 M THF solution, 5.0 mL, 10.0 mmol) was added to N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-) obtained in Example 20. 1-Benzofuran-5-yl) -3,3-dimethylbutanamide (0.7 g, 1.72 mmol) was added at 0 ° C., and then the reaction solution was stirred at the same temperature for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and 1N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 264 mg (yield 35%) of the title compound as a low polar substance. Melting point 145-146 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.90-1.05 (3H, m), 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.69-1.95 (5H, m), 2.17 (3H , s), 2.25 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.32 (1H, d, J = 10.2 Hz), 4.41-4.57 (2H, m), 4.72-4.90 (2H, m), 6.51 (1H, br s), 7.01 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.4 Hz).

N- (7- (1-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide The residue operated in the same manner as in Example 30 was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 160 mg (yield 21%) of the title compound as a highly polar substance. Melting point 165-167 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.87-1.09 (3H, m), 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.77-1.93 (5H, m), 2.17 (3H , s), 2.24 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.36 (1H, d, J = 10.2 Hz), 4.40-4.52 (2H, m), 4.72-4.90 (2H, m), 6.56 (1H, br s), 7.01 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz).

N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 22 N- (7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide ( A mixture of 580 mg, 1.37 mmol) and manganese dioxide (1.43 g, 16.4 mmol) was stirred at 100 ° C. for 2 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 440 mg (yield 76%) of the title compound. Melting point 200-201 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.8 Hz), 1.89 (3H, s), 2.23 (3H, s), 2.26 (2H, s), 2.58 (3H, s), 2.87 (1H, septet, J = 6.8 Hz), 4.41-4.58 (2H, m), 4.78-4.96 (1H, m), 6.47 (1H, br s), 7.03 (2H, d , J = 8.2 Hz), 7.14 (2H, d, J = 8.2 Hz).

N- (7- (1-hydroxy-1-methylethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- Dimethylbutanamide In the same manner as in Example 22, N- (7-acetyl-3- (4-isopropylphenyl)))-4,6-dimethyl-2,3-dihydro-1-benzofuran obtained in Example 32 -5-yl))-3,3-dimethylbutanamide was used to synthesize the title compound. Yield 34%. Melting point 133-134 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.21 (6H, d, J = 6.8 Hz), 1.68 (3H, s), 1.70 (3H, s), 1.86 (3H, s), 2.26 (2H, s), 2.35 (3H, s), 2.86 (1H, septet, J = 6.8 Hz), 4.37-4.55 (3H, m), 4.75-4.88 (1H, m), 6.47 (1H, br s ), 7.03 (2H, d, J = 8.2 Hz), 7.13 (2H, d, J = 8.2 Hz).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7-propyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 23. N- (7- (1-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-- obtained during the synthesis of Examples 30 and 31 The title compound was synthesized using a diastereo mixture of benzofuran-5-yl) -3,3-dimethylbutanamide. Yield 86%. Melting point 145-148 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.80-1.35 (18H, m), 1.45-1.65 (2H, m), 1.80 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.57 -2.68 (2H, m), 2.85 (1H, septet, J = 6.8 Hz), 4.40 (1H, dd, J = 8.4, 6.6 Hz), 4.50 (1H, dd, J = 8.8, 6.6 Hz), 4.80 ( 1H, t, J = 8.4 Hz), 6.49 (1H, br s), 7.04 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz).

N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide synthesized in Example 3 N- (3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (1.0 g, 2.63 mmol) in acetonitrile ( 30 mL) To the solution was added N-bromosuccinimide (468 mg, 2.63 mmol) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized from ethanol to obtain 1.10 g (yield 91%) of the title compound. Melting point: 191-193 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.82 (3H, s), 2.24 (2H, s), 2.33 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.51 (1H, dd, J = 9.0, 4.8 Hz), 4.63 (1H, dd, J = 9.0, 4.8 Hz), 4.93 (1H, t, J = 9.3 Hz) ), 6.54 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Synthesized in Example 35 N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (250 mg, 0.545 mmol) ), Copper (I) bromide (78 mg, 0.545 mmol), ethyl acetate (88 mg, 1.00 mmol) and 28% sodium methoxide-methanol solution (20 mL) were heated to reflux for 6 hours. 1N Hydrochloric acid was added to the reaction mixture, and the product was extracted with diisopropyl ether. The extract was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) and crystallized from hexane-ethyl acetate to obtain 130 mg (yield 58%) of the title compound. Melting point: 191-193 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.83 (3H, s), 2.16 (3H, s), 2.25 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.89 (3H, s), 4.44-4.55 (2H, m), 4.87 (1H, t, J = 8.1 Hz), 6.47 (1H, br s), 7.05 ( 2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

(+)-N-((3R) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples 1 and (+)-(3R) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 141 was used. The title compound was synthesized. Yield 93%. Melting point 148-149 [deg.] C. (ethyl acetate-hexane). [α] _D ²⁰ = + 93.2 ° (c = 0.54, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.86 (3H, s), 2.22 (3H, s), 2.24 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.41 (1H, dd, J = 9.0, 4.8 Hz), 4.50 (1H, dd, J = 9.0, 4.8 Hz), 4.83 (1H, t, J = 9.0 Hz ), 6.47 (1H, br s), 6.63 (1H, s), 7.04 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

(+)-N-((3R) -7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide (+)-N-((3R) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 37 , 3-Dimethylbutanamide (933 mg, 2.46 mmol) in methylene chloride (20 mL) was added with aluminum chloride (721 mg, 5.40 mmol) at −70 ° C. in an argon atmosphere and stirred for 20 minutes. Acetyl chloride (424 mg, 5.40 mmol) was added dropwise to the reaction solution at the same temperature, and the temperature was gradually raised to 10 ° C. The reaction solution was added to ice, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 2: 1) to synthesize 873 mg (yield 84%) of the title compound. Melting point 176-177 ° C (ethyl acetate-hexane). [α] _D ²⁰ = + 6.2 ° (c = 0.53, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.22 (3H, s), 2.25 (2H, s), 2.58 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.46-4.55 (2H, m), 4.89 (1H, t, J = 8.4 Hz), 6.53 (1H, br s), 7.03 ( 2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz).

(-)-N-((3R) -7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 20, (+)-N-((3R) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-) obtained in Example 37 was used. The title compound was synthesized using benzofuran-5-yl) -3,3-dimethylbutanamide. Yield 83%. Melting point 179-180 ° C. (ethyl acetate-hexane). [α] _D ²⁰ = −25.8 ° (c = 0.48, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.23 (2H, s), 2.52 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.45-4.60 (2H, m), 4.97 (1H, t, J = 10.8 Hz), 6.49 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz), 10.43 (1H, s).

(+)-N-((3R) -7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)- 3,3-Dimethylbutanamide (-)-N-((3R) -7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl obtained in Example 39 in the same manner as in Example 28. The compound obtained using -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to give low polarity The title compound was obtained as a product. Yield 33%. Melting point 188-189 ° C. (ethyl acetate-hexane). [α] _D ²⁰ = + 63.4 ° (c = 0.49, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.52 (3H, d, J = 6.6 Hz), 1.85 (3H, s), 2.18 ( 3H, s), 2.25 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.50 (1H, br d), 4.45-4.54 (2H, m), 4.85-4.94 (1H, m), 5.00-5.10 (1H, m), 6.50 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

(+)-N-((3R) -7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)- 3,3-Dimethylbutanamide (-)-N-((3R) -7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl obtained in Example 39 in the same manner as in Example 28. The compound obtained using -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) The title compound was obtained as a product. Yield 49%. Melting point 149-150 ° C. (ethyl acetate-hexane). [α] _D ²⁰ = + 15.2 ° (c = 0.49, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.55 (3H, d, J = 6.6 Hz), 1.85 (3H, s), 2.19 ( 3H, s), 2.25 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.47 (1H, br d), 4.40-4.55 (2H, m), 4.83-4.91 (1H, m), 5.01-5.11 (1H, m), 6.50 (1H, br s), 7.03 (2H, d, J = 7.8 Hz), 7.13 (2H, d, J = 7.8 Hz).

(+)-N-((3R) -7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide (+)-N-((3R) -7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro obtained in Examples 40 and 41 A solution of -1-benzofuran-5-yl) -3,3-dimethylbutanamide (746 mg, 1.77 mmol) and 10% palladium carbon (50% water content, 75 mg) in ethanol (8 mL) was heated to reflux for 2 hours. . After removing the catalyst, the reaction solution was concentrated under reduced pressure. The obtained residue was recrystallized from THF-hexane to obtain 589 mg (yield 96%) of the title compound. Melting point 156-157 ° C. [α] _D ²⁰ = + 50.7 ° (c = 0.46, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.14 (3H, t, J = 7.5 Hz), 1.22 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.18 ( 3H, s), 2.25 (2H, s), 2.66 (2H, q, J = 7.5 Hz), 2.85 (1H, septet, J = 6.9 Hz), 4.41 (1H, dd, J = 9.0, 4.5 Hz), 4.51 (1H, dd, J = 9.0, 4.5 Hz), 4.82 (1H, t, J = 9.0 Hz), 6.47 (1H, br s), 7.04 (2H, d, J = 7.8 Hz), 7.12 (2H, d, J = 7.8 Hz).

(+)-N-((3R) -7- (1-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)- 3,3-Dimethylbutanamide (-)-N-((3R) -7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl obtained in Example 39 in the same manner as in Example 30 The compound obtained using -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to give low polarity The title compound was obtained as a product. Yield 25%. Mp 205-206 ° C (ethyl acetate-hexane). [α] _D ²⁰ = + 54.8 ° (c = 0.44, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, t, J = 7.5 Hz), 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.70-1.93 (5H, m), 2.17 (3H, s), 2.23 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.31 (1H, br d), 4.42-4.52 (2H, m), 4.74-4.80 (1H, m ), 4.85 (1H, t, J = 8.1 Hz), 6.49 (1H, br s), 7.01 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.4 Hz).

(+)-N-((3R) -7- (1-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)- 3,3-Dimethylbutanamide (-)-N-((3R) -7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl obtained in Example 39 in the same manner as in Example 30 The compound obtained using -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) The title compound was obtained as a product. Yield 38%. Amorphous powder. [α] _D ²⁰ = + 16.1 ° (c = 0.54, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, t, J = 7.5 Hz), 1.09 (9H, s), 1.24 (6H, d, J = 6.9 Hz), 1.76-1.95 (5H, m), 2.15 (3H, s), 2.23 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.41 (1H, br d), 4.41-4.49 (2H, m), 4.73-4.88 (2H, m ), 6.85 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

(+)-N-((3R) -3- (4-isopropylphenyl) -4,6-dimethyl-7-propyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide (+)-N-((3R) -7- (1-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro obtained in Examples 43 and 44 A solution of -1-benzofuran-5-yl) -3,3-dimethylbutanamide (620 mg, 1.42 mmol) in 10% palladium on carbon (50% water content, 62 mg) in acetic acid (3 mL) The reaction was carried out at 2 ° C for 2 hours. After removing the catalyst, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain 423 mg (yield 71%) of the title compound. Melting point 184-185 ° C. [α] _D ²⁰ = + 41.6 ° (c = 0.51, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, t, J = 7.5 Hz), 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.50-1.60 (2H, m), 1.85 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.57-2.63 (2H, m), 2.85 (1H, septet, J = 6.9 Hz), 4.40 (1H, dd, J = 9.0, 4.5 Hz), 4.50 (1H, dd, J = 9.0, 4.5 Hz), 4.80 (1H, t, J = 9.0 Hz), 6.46 (1H, br s), 7.04 (2H, d, J = 8.1 Hz) ), 7.12 (2H, d, J = 8.1 Hz).

(+)-N-((3R) -7- (1-hydroxy-1-methylethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5 -Yl) -3,3-dimethylbutanamide (+)-N-((3R) -7-acetyl-3- (4-isopropylphenyl) -4 obtained in Example 38 in the same manner as in Example 22. , 6-Dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide was used to synthesize the title compound. Yield 82%. Melting point 141-142 ° C. (ethyl acetate-hexane). [α] _D ²⁰ = + 40.8 ° (c = 0.46, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.68 (3H, s), 1.70 (3H, s), 1.86 (3H, s), 2.25 (2H, s), 2.35 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.37 (1H, s), 4.37-4.50 (2H, m), 4.75-4.87 (1H, m) , 6.52 (1H, br s), 7.03 (2H, d, J = 8.0 Hz), 7.13 (2H, d, J = 8.0 Hz).

(+)-N- (tert-butyl) -N ′-((3R) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) urea (+)-(3R) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine (1.0 g, 3.55 mmol) obtained in Reference Example 141 To the THF (10 mL) solution, 2,2,2-trichloroethyl chloroformate (0.49 mL, 3.55 mmol) was added dropwise under ice-cooling, triethylamine (0.52 mL, 3.73 mmol) was added, and the mixture was stirred for 30 min. The temperature was raised to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting (3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl (1.60 g, 3.50 mmol) And tert-butylamine (779 mg, 10.65 mmol) in dimethyl sulfoxide (20 mL) were stirred at 45 ° C. for 5 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 2: 1) to obtain 1.19 g (yield 88%) of the title compound. Mp 205-206 ° C (ethyl acetate-hexane). [α] _D ²⁰ = + 81.0 ° (c = 0.51, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.30 (15H, m), 1.89 (3H, s), 2.25 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.00 (1H, br s), 4.45 (1H, dd, J = 8.7, 4.8 Hz), 4.53 (1H, dd, J = 8.7, 4.8 Hz), 4.88 (1H, t, J = 8.7 Hz), 5.25 (1H, br s) , 6.66 (1H, s), 7.00 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz).

(-)-N- (tert-butyl) -N '-((3R) -7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5 -Yl) urea In the same manner as in Example 20, (+)-N- (tert-butyl) -N '-((3R) -3- (4-isopropylphenyl) -4,6 obtained in Example 47 The title compound was synthesized using -dimethyl-2,3-dihydro-1-benzofuran-5-yl) urea. Yield 78%. Melting point 209-210 ° C. (ethyl acetate-hexane). [α] _D ²⁰ = −31.2 ° (c = 0.48, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.40 (15H, m), 1.96 (3H, s), 2.57 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.97 (1H, br s), 4.50-4.63 (2H, m), 4.95-5.05 (1H, m), 5.40 (1H, br s), 7.01 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J = 8.1 Hz), 10.47 (1H, s).

(+)-N- (tert-butyl) -N ′-((3R) -7- (hydroxymethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1- (Benzofuran-5-yl) urea In the same manner as in Example 21, (-)-N- (tert-butyl) -N '-((3R) -7-formyl-3- (4- The title compound was synthesized using (isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) urea. Yield 97%. Melting point 187-188 [deg.] C. (ethyl acetate-hexane). [α] _D ²⁰ = + 34.0 ° (c = 0.43, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.12-1.28 (15H, m), 1.89 (3H, s), 2.05 (1H, br s), 2.31 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.99 (1H, br s), 4.48 (1H, dd, J = 9.0, 4.5 Hz), 4.56 (1H, dd, J = 9.0, 4.5 Hz), 4.72-4.82 (2H, m), 4.88 ( 1H, t, J = 9.0 Hz), 5.30 (1H, br s), 6.97 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

(+)-N- (tert-butyl) -N ′-((3R) -3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl ) Urea In the same manner as in Example 45, (+)-N- (tert-butyl) -N ′-((3R) -7- (hydroxymethyl) -3- (4-isopropylphenyl) obtained in Example 49 ) -4,6-Dimethyl-2,3-dihydro-1-benzofuran-5-yl) urea was used to synthesize the title compound. Yield 57%. Melting point 209-210 ° C. (ethyl acetate-hexane). [α] _D ²⁰ = + 53.2 ° (c = 0.47, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.38 (15H, m), 1.87 (3H, s), 2.19 (6H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.99 (1H, br s), 4.44 (1H, dd, J = 9.0, 4.5 Hz), 4.54 (1H, dd, J = 9.0, 4.5 Hz), 4.86 (1H, t, J = 9.0 Hz), 5.29 (1H, br s) , 6.99 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

(-)-N-((3R) -7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide (+)-N-((3R) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-- obtained in Example 37 in the same manner as in Example 35. The title compound was synthesized using benzofuran-5-yl) -3,3-dimethylbutanamide. Yield 90%. Melting point 118-119 ° C. (ethyl acetate-hexane). [α] _D ²⁰ = -13.0 ° (c = 0.52, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.82 (3H, s), 2.24 (2H, s), 2.32 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.51 (1H, dd, J = 9.0, 4.5 Hz), 4.62 (1H, dd, J = 9.0, 4.5 Hz), 4.93 (1H, t, J = 9.0 Hz ), 6.56 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

(+)-N-((3R) -3- (4-isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 36, (-)-N-((3R) -7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3- The title compound was synthesized using dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide. Yield 98%. Melting point 150-151 [deg.] C. (ethyl acetate-hexane). [α] _D ²⁰ = + 55.9 ° (c = 0.50, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.82 (3H, s), 2.15 (3H, s), 2.24 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.88 (3H, s), 4.44-4.53 (2H, m), 4.86 (1H, t, J = 8.1 Hz), 6.48 (1H, br s), 7.03 ( 2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) methanesulfonamide 3- (4-Isopropylphenyl) obtained in Reference Example 30 ) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine (200 mg, 0.68 mmol) and triethylamine (0.09 mL, 0.68 mmol) in THF (4 mL) at 0 ° C. Methanesulfonyl chloride (0.06 mL, 0.81 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes, added to water, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate-hexane 3: 2) to obtain 185 mg (yield 73%) of the title compound. Melting point: 139-140 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.02 (3H, s), 2.18 (3H, s), 2.33 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 2.99 (3H, s), 4.44 (1H, dd, J = 4.5, 9.0 Hz), 4.53 (1H, dd, J = 4.5, 9.0 Hz), 4.84 (1H, t, J = 9.0 Hz ), 5.66 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) butane-1-sulfonamide 3- (4 obtained in Reference Example 30 -Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine (200 mg, 0.68 mmol) in pyridine (10 mL) to 1-butanesulfonyl chloride (0.11 mL) , 0.82 mmol) was added dropwise at 0 ° C., 4-dimethylaminopyridine (91 mg, 0.75 mmol) was added, and the mixture was stirred for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate-hexane 3: 7) to obtain 174 mg (yield 64%) of the title compound. Melting point 96-97 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.5 Hz), 1.22 (6H, d, J = 6.9 Hz), 1.44 (2H, sixtet, J = 7.5 Hz), 1.81-1.82 ( 2H, m), 2.01 (3H, s), 2.18 (3H, s), 2.32 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.03-3.09 (2H, m), 4.43 (1H , dd, J = 4.5, 9.0 Hz), 4.52 (1H, dd, J = 4.5, 9.0 Hz), 4.84 (1H, t, J = 9.0 Hz), 5.58 (1H, s), 7.02 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

4,4,4-trifluoro-N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) butan-1-sulfonamide In the same manner as in Example 53, 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 30 and 4,4,4- The title compound was synthesized using trifluoro-1-butanesulfonyl chloride. Yield 62%. Melting point 149-150 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 2.00 (3H, s), 2.10-2.40 (10H, m), 2.86 (1H, septet, J = 6.9 Hz), 3.14 (2H, t, J = 7.3 Hz), 4.40-4.56 (2H, m), 4.84 (1H, t, J = 8.9 Hz), 5.67 (1H, br s), 7.02 (2H, d, J = 8.0 Hz), 7.14 (2H, d, J = 8.0 Hz).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) ethanesulfonamide Obtained in Reference Example 30 in the same manner as in Example 54. The title compound was synthesized using 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine and ethanesulfonyl chloride. Yield 56%. Melting point 132-133 ° C. (ethanol).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.42 (3H, t, J = 7.5 Hz), 2.02 (3H, s), 2.18 (3H, s), 2.32 ( 3H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.11 (2H, q, J = 7.5 Hz), 4.43 (1H, dd, J = 8.7, 4.8 Hz), 4.52 (1H, dd, J = 9.6, 5.1Hz), 4.83 (1H, t, J = 9.0 Hz), 5.53 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz) .

N- (3- (4- isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) - In the same manner as flop propane-1-sulfonamide Example 54 The title compound was synthesized using 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 30 and 1-propanesulfonyl chloride. . Yield 54%. Melting point 133-134 ° C (ethanol).
¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, t, J = 7.2 Hz), 1.22 (6H, d, J = 6.9 Hz), 1.81-2.05 (5H, m), 2.18 (3H, s), 2.32 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.00-3.09 (2H, m), 4.40-4.58 (2H, m), 4.84 (1H, t, J = 8.7 Hz), 5.55 (1H, br s), 7.02 (2H, d, J = 7.5 Hz), 7.13 (2H, d, J = 7.5 Hz).

(3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide In the same manner as in Reference Example 73, 3- (4- The title compound was synthesized using (isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 81%. Melting point 193-196 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.25 (6H, m), 1.87 (1.5H, s), 1.91 (1.5H, s), 2.22 (1.5H, s), 2.26 (1.5H, s) , 2.79-2.93 (1H, m), 4.39-4.58 (2H, m), 4.79-4.90 (1H, m), 6.59-6.80 (2H, m), 6.98-7.04 (2H, m), 7.10-7.16 ( 2H, m), 7.94 (0.5H, d, J = 12.6 Hz), 8.35 (0.5H, d, J = 1.2 Hz).

(7-Bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide Obtained in Example 58 in the same manner as in Example 35 ( The title compound was synthesized using 3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide. Yield 91%. Melting point 151-152 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.30 (6H, m), 1.82-1.92 (3H, m), 2.32-2.44 (3H, m), 2.80-2.97 (1H, m), 4.45-4.65 ( 2H, m), 4.89-5.00 (1H, m), 6.80 (1H, br s), 7.00-7.17 (4H, m), 7.91 (0.4H, d, J = 12.0 Hz), 8.35 (0.6H, d , J = 1.5 Hz).

(7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide obtained in Example 58 in the same manner as in Example 20 ( The title compound was synthesized using 3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide. Yield 92%. Melting point 123-124 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.25 (6H, m), 1.94 (1.8H, s), 1.97 (1.2H, s), 2.53 (1.8H, s), 2.58 (1.2H, s) , 2.80-2.95 (1H, m), 4.47-4.63 (2H, m), 4.93-5.04 (1H, m), 6.67 (1H, br s), 7.00-7.06 (2H, m), 7.12-7.18 (2H m), 7.91 (0.4H, d, J = 12.0 Hz), 8.39 (0.6H, d, J = 1.2 Hz), 10.4 (0.6H, s), 10.5 (0.4H, s).

Ethyl 3- (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) propanoate In the same manner as in Example 1, 3- (5-amino-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) obtained in Reference Example 321) The title compound was synthesized using ethyl propanoate. Yield 59%. Melting point 150-151 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.26 (3H, t, J = 6.9 Hz), 1.84 (3H, s), 2.19 ( 3H, s), 2.25 (2H, s), 2.54 (2H, dd, J = 9.0, 6.0 Hz), 2.85 (1H, septet, J = 6.9 Hz), 2.96 (2H, dd, J = 10.2, 7.2 Hz ), 4.14 (2H, q, J = 6.9 Hz), 4.40 (1H, dd, J = 8.7, 4.8 Hz), 4.50 (1H, dd, J = 9.3, 4.5 Hz), 4.81 (1H, t, J = 9.3 Hz), 6.47 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

N- (7- (3-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide 3- (5-Amino-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) propane obtained in Reference Example 322 in the same manner as in Example 1. The title compound was synthesized using -1-ol. Yield 36%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.66-1.90 (5H, m), 2.18 (3H, s), 2.24 (2H, s ), 2.56 (1H, br s), 2.77 (2H, t, J = 6.9 Hz), 2.86 (1H, septet, J = 6.9 Hz), 3.50-3.65 (2H, m), 4.43 (1H, dd, J = 8.7, 4.5 Hz), 4.53 (1H, dd, J = 8.7, 4.5 Hz), 4.81 (1H, t, J = 8.7 Hz), 6.59 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

N- (4-Bromo-3- (4-isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 1. The title compound was synthesized using (4-bromo-3- (4-isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) amine obtained in Reference Example 323. did. Yield 51%. Melting point 150-151 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 2.17 (3H, s), 2.18 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.44-4.57 (2H, m), 4.83 (1H, t, J = 7.5 Hz), 6.64 (1H, br s), 7.06 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz).

N- (3- (4-Isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, Reference Example The title compound was synthesized using 3- (4-isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in 315. Yield 61%. Melting point 135-136 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.84 (3H, s), 2.19 (2H, s), 2.22 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.42 (1H, dd, J = 8.7, 4.8 Hz), 4.52 (1H, dd, J = 9.0, 4.5 Hz), 4.83 (1H, t, J = 9.0 Hz ), 6.64 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.15 (1H, s).

N- (3- (4-Isopropylphenyl) -4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, The title compound was synthesized using 3- (4-isopropylphenyl) -4,5,7-trimethyl-2,3-dihydro-1-benzofuran-6-amine obtained in Reference Example 316. Yield 58%. Melting point 214-215 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.16 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.04 (3H, s), 2.14 (3H, s), 2.31 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.40 (1H, dd, J = 8.7, 4.5 Hz), 4.52 (1H, dd, J = 9.0, 4.5 Hz), 4.81 (1H , t, J = 9.0 Hz), 6.60 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, The title compound was synthesized using 3- (4-isopropylphenyl) -4,5,6-trimethyl-2,3-dihydro-1-benzofuran-7-amine obtained in Reference Example 317. Yield 59%. Melting point 190-191 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.09 (3H, s), 2.16 (3H, s), 2.29 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.38 (1H, dd, J = 8.7, 5.1 Hz), 4.55 (1H, dd, J = 9.3, 4.5 Hz), 4.81 (1H , t, J = 9.3 Hz), 6.71 (1H, br s), 7.04 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz).

4- (Benzyloxy) -N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide In the same manner as in Example 1, Using 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine and 4-benzyloxybutyryl chloride obtained in Reference Example 30, the title compound was Synthesized. Yield 52%. Melting point 85-86 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.78 (3H, s), 1.98-2.21 (8H, m), 2.50 (2H, t, J = 6.9 Hz), 2.86 (1H, septet, J = 6.9 Hz), 3.58 (2H, t, J = 6.0 Hz), 4.37-4.56 (4H, m), 4.81 (1H, t, J = 9.0 Hz), 6.80 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz), 7.18-7.37 (5H, m).

N- (3- (4-Isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan-5-yl) -3,3-dimethylbutanamide
In the same manner as in Example 1, using the 3- (4-isopropylphenyl) -4-methyl-2,3-dihydronaphtho [1,2-b] furan-5-amine obtained in Reference Example 318, the title compound was used. Was synthesized. Yield 29%. Melting point 183-184 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.18 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 2.03 (3H, s), 2.37 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.64 (1H, dd, J = 8.7, 5.1 Hz), 4.72 (1H, dd, J = 8.4, 4.5 Hz), 5.05 (1H, t, J = 9.0 Hz), 6.86 (1H, br s), 7.06 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.37-7.52 (2H, m), 7.80 (1H, d, J = 8.1 Hz), 8.00 ( 1H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4-methyl-2,3,6,7,8,9-hexahydronaphtho [1,2-b] furan-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 1, 3- (4-isopropylphenyl) -4-methyl-2,3,6,7,8,9-hexahydronaphtho [1,2-b obtained in Reference Example 319] The title compound was synthesized using furan-5-amine. Yield 62%. Melting point 183-184 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.68-1.95 (7H, m), 2.24 (2H, s), 2.55-2.70 (4H , m), 2.86 (1H, septet, J = 6.9 Hz), 4.43 (1H, dd, J = 8.7, 5.1 Hz), 4.52 (1H, dd, J = 9.0, 5.1 Hz), 4.84 (1H, t, J = 9.0 Hz), 6.38 (1H, br s), 7.06 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4-methyl-3,6,7,8-tetrahydro-2H-indeno [4,5-b] furan-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, 3- (4-isopropylphenyl) -4-methyl-3,6,7,8-tetrahydro-2H-indeno [4,5-b] furan-5 obtained in Reference Example 320 was used. -The title compound was synthesized using an amine. Yield 59%. Melting point 201-202 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.04-2.28 (4H, m), 2.77-3.01 (5H , m), 4.41-4.57 (2H, m), 4.85 (1H, t, J = 8.1 Hz), 6.52 (1H, br s), 7.05 (2H, d, J = 8.1 Hz), 7.12 (2H, d , J = 8.1 Hz).

N-((3S) -3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 1. The title compound was synthesized using (S) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 326. Yield 84%. Melting point 147-148 [deg.] C. (hexane-ethyl acetate). [α] _D ²⁰ = −93 ° (c = 0.497, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.21 (3H, s), 2.23 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.40 (1H, dd, J = 8.4, 4.8 Hz), 4.49 (1H, dd, J = 9.0, 4.8 Hz), 4.82 (1H, t, J = 9.0 Hz ), 6.49 (1H, br s), 6.62 (1H, s), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

N- (3- (3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, The title compound was synthesized using 3- (3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 302. Yield 87%. Melting point 169-170 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.85 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 3.76 (3H, s ), 4.41 (1H, dd, J = 4.8, 9.0 Hz), 4.53 (1H, dd, J = 4.8, 9.0 Hz), 4.83 (1H, t, J = 8.7 Hz), 6.50 (1H, br s), 6.68-6.76 (3H, m), 7.19 (1H, t, J = 7.8 Hz).

N- (3- (3- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide 3- (3- (1,3-Dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1 obtained in Reference Example 301 in the same manner as in Example 1. -The title compound was obtained using benzofuran-5-amine. Yield 91%. Melting point 168-169 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.82 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 3.98-4.17 (4H , m), 4.32 (1H, dd, J = 5.0, 8.8 Hz), 4.58 (1H, dd, J = 5.0, 8.8 Hz), 4.84 (1H, t, J = 8.8 Hz), 5.75 (1H, s) , 6.49 (1H, br s), 7.08-7.12 (1H, m), 7.24-7.37 (3H, m).

N- (4-Isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1. The title compound was obtained using 3- (4-isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 303. Yield 97%. Melting point 195-196 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.18 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.16 (6H, s), 2.27 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.86 (3H, s), 4.33 (1H, dd, J = 3.3, 8.4 Hz), 4.82 (1H, t, J = 8.4 Hz), 4.87 (1H, dd , J = 3.3, 8.4 Hz), 6.54 (1H, br s), 6.66 (2H, s), 6.72 (1H, s).

3,3-Dimethyl-N- (4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in Reference Example 306 in the same manner as in Example 1. The title compound was synthesized using 4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine. Yield 50%. Melting point 146-147 ° C (ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.83 (3H, s), 2.15 (3H, s), 2.20 (3H, s), 2.25 (2H, s), 4.41 (1H, dd , J = 4.8, 9.0 Hz), 4.56 (1H, dd, J = 4.8, 9.0 Hz), 4.84 (1H, t, J = 9.0 Hz), 6.50 (1H, br s), 7.06-7.18 (2H, m ), 7.20-7.30 (3H, m).

3,3-Dimethyl-N- (4,6,7-trimethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) butanamide In the same manner as in Example 1, The title compound was synthesized using 4,6,7-trimethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine obtained in Example 307. Yield 80%. Melting point 176-177 ° C (ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.82 (3H, s), 2.13 (3H, s), 2.17 (3H, s), 2.23 (2H, s), 2.30 (3H, s ), 4.38 (1H, dd, J = 4.8, 9.0 Hz), 4.51 (1H, dd, J = 4.8, 9.0 Hz), 4.82 (1H, t, J = 9.0 Hz), 6.57 (1H, br s), 6.98 (2H, d, J = 8.1 Hz), 7.07 (2H, d, J = 8.1 Hz).

N- (3- (biphenyl-4-yl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1. The title compound was synthesized using 3- (biphenyl-4-yl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 309. Yield 71%. Melting point 218-219 ° C. (ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.88 (3H, s), 2.16 (3H, s), 2.19 (3H, s), 2.26 (2H, s), 4.45 (1H, dd , J = 4.5, 9.0 Hz), 4.60 (1H, dd, J = 4.5, 9.0 Hz), 4.87 (1H, t, J = 9.0 Hz), 6.52 (1H, br s), 7.20 (2H, d, J = 8.4 Hz), 7.32 (1H, t, J = 8.4 Hz), 7.42 (2H, d, J = 8.4 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J = 8.4 Hz).

3,3-Dimethyl-N- (4,6,7-trimethyl-3- (5-methylpyridin-2-yl) -2,3-dihydro-1-benzofuran-5-yl) butanamide Similar to Example 1 The title compound was synthesized using 4,6,7-trimethyl-3- (5-methylpyridin-2-yl) -2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 308. did. Yield 78%. Melting point 170-171 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.87 (3H, s), 2.05 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.26 (2H, s ), 4.55 (1H, dd, J = 4.5, 9.0 Hz), 4.74 (1H, dd, J = 4.5, 9.0 Hz), 4.88 (1H, t, J = 9.0 Hz), 6.54 (1H, br s), 6.91 (1H, d, J = 8.4 Hz), 7.38 (1H, dd, J = 1.8, 8.4 Hz), 8.36 (1H, d, J = 1.8 Hz).

3,3-Dimethyl-N- (3- (4-ethylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide In the same manner as in Example 1, The title compound was synthesized using 3- (4-ethylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Example 314. Yield 87%. Melting point 162-163 ° C. (THF-diisopropyl ether).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.20 (3H, t, J = 7.5 Hz), 1.84 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.60 (2H, q, J = 7.5 Hz), 4.40 (1H, dd, J = 4.8, 9.0 Hz), 4.53 (1H, dd, J = 4.8, 9.0 Hz), 4.82 (1H , t, J = 9.0 Hz), 6.50 (1H, br s), 7.04 (2H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz).

N- (3- (4-isobutylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Reference Example 144, Using 3- (4-isobutylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine obtained in Reference Example 312, 3- (4-isobutylphenyl) -4,6,7-trimethyl -2,3-Dihydro-1-benzofuran-5-amine was synthesized. Using this compound and tert-butylacetyl chloride, the title compound was synthesized in the same manner as in Example 1. Yield 34%. Melting point 153-154 ° C. (ethyl acetate-hexane)
¹ H-NMR (CDCl ₃ ) δ: 0.87 (6H, d, J = 6.9 Hz), 1.12 (9H, s), 1.72-1.86 (4H, m), 2.14 (3H, s), 2.17 (3H, s ), 2.25 (2H, s), 2.42 (2H, d, J = 7.2 Hz), 4.40 (1H, dd, J = 4.5, 9.0 Hz), 4.53 (1H, dd, J = 4.5, 9.0 Hz), 4.83 (1H, t, J = 9.0 Hz), 6.51 (1H, br s), 7.03 (4H, s).

N- (3- (4-cyclohexylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Reference Example 144, Using 3- (4-cyclohexylphenyl) -4,6,7-trimethyl-1-benzofuran-5-amine obtained in Reference Example 313, 3- (4-cyclohexylphenyl) -4,6,7-trimethyl -2,3-Dihydro-1-benzofuran-5-amine was obtained. Using this compound, the title compound was synthesized in the same manner as in Example 1. Yield 43%. Melting point 146-148 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.19-1.45 (4H, m), 1.70-1.95 (9H, m), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.45 (1H, br), 4.41 (1H, dd, J = 4.8, 9.0 Hz), 4.52 (1H, dd, J = 4.8, 9.0 Hz), 4.81 (1H, t, J = 9.0 Hz), 6.51 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

N- (3- (4- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide 3- (4- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1 obtained in Reference Example 310 in the same manner as in Example 1. -The title compound was synthesized using benzofuran-5-amine. Yield 96%. Melting point 193-194 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.81 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 3.99-4.06 (2H , m), 4.07-4.14 (2H, m), 4.36 (1H, dd, J = 4.5, 9.0 Hz), 4.57 (1H, dd, J = 4.5, 9.0 Hz), 4.83 (1H, t, J = 9.0 Hz), 5.76 (1H, s), 6.47 (1H, br s), 7.14 (2H, d, J = 8.1 Hz), 7.38 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7-vinyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Synthesized in Example 22. N- (7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide ( 1.23 g, 3.02 mmol) and p-toluenesulfonic acid monohydrate (20 mg) in toluene (20 mL) were heated to reflux at 80 ° C. for 1 hour in an argon atmosphere. The reaction solution was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 9) to obtain 1.09 g (yield 89%) of the title compound. Melting point 171-172 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.86 (3H, s), 2.246 (3H, s), 2.249 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.42-4.58 (2H, m), 4.80-4.92 (1H, m), 5.49 (1H, dd, J = 11.7, 2.1 Hz), 5.92 (1H, dd, J = 17.7, 2.1 Hz), 6.51 (1H, br s), 6.76 (1H, dd, J = 17.7, 11.7 Hz), 7.04 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

N- (7- (1,2-dihydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane N- (3- (4-isopropyl) synthesized in Example 83 in a mixed solution of amide AD-mixβ (4.62 g) in water (15 mL), tert-butanol (15 mL), and THF (15 mL). Phenyl) -4,6-dimethyl-7-vinyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (670 mg, 1.65 mmol) was added under ice-cooling, and 80 ° C. For 3 hours. Water and sodium sulfite were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1:20) to obtain 558 mg (yield 77%) of the title compound. Melting point 159-161 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.10-2.24 (5H, m), 2.86 (1H, septet , J = 6.9 Hz), 3.60-3.84 (2H, m), 4.40-4.57 (2H, m), 4.80-5.00 (2H, m), 6.70 (1H, br s), 7.01 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz), 2H not confirmed.

N- (7- (2-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide N- (7- (1,2-dihydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 84 , 3-Dimethylbutanamide (200 mg, 0.455 mmol) and palladium hydroxide carbon (20 mg) in ethanol (20 mL) were stirred at 60 ° C. for 3 hours in a hydrogen atmosphere. After removing the catalyst, the reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 7: 3) to obtain 40 mg (yield 21%) of the title compound. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.20 (3H, s), 2.25 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 2.94 (2H, t, J = 6.6 Hz), 3.80 (2H, t, J = 6.6 Hz), 4.40 (1H, dd, J = 8.4, 4.8 Hz), 4.52 (1H, dd, J = 9.0, 5.1 Hz), 4.81 (1H, t, J = 9.0 Hz), 6.53 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz), 1H not confirmed.

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7-propionyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 32. N- (7- (1-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-- obtained during the synthesis of Examples 30 and 31 The title compound was synthesized using a diastereo mixture of benzofuran-5-yl) -3,3-dimethylbutanamide. Yield 18%. Melting point 163-164 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.16 (3H, t, J = 7.4 Hz), 1.22 (6H, d, J = 7.0 Hz), 1.88 (3H, s), 2.17 ( 3H, s), 2.25 (2H, s), 2.78-3.01 (3H, m), 4.43-4.57 (2H, m), 4.87 (1H, t, J = 8.0 Hz), 6.48 (1H, br s), 7.03 (2H, d, J = 8.2 Hz), 7.14 (2H, d, J = 8.2 Hz).

N- (6-Bromo-3- (4-isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Reference Example 23. N- (3- (4-isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 64 was used. The title compound was synthesized. Yield 32%. Melting point 174-175 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.26 (2H, s), 2.31 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.44 (1H, dd, J = 8.7, 4.5 Hz), 4.52 (1H, dd, J = 9.0, 4.8 Hz), 4.93 (1H, t, J = 9.0 Hz ), 6.68 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4-methoxy-6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 36. N- (4-bromo-3- (4-isopropylphenyl) -6,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl obtained in Example 63 The title compound was synthesized using butanamide. Yield 21%. Melting point 161-162 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 2.13 (3H, s), 2.15 (3H, s), 2.24 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.44 (3H, s), 4.41 (1H, dd, J = 8.4, 4.8 Hz), 4.71 (1H, dd, J = 9.3, 4.8 Hz), 4.82 (1H , dd, J = 9.3, 8.4 Hz), 6.66 (1H, br s), 7.08 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -6-methoxy-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 36. N- (6-Bromo-3- (4-isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl obtained in Example 87 The title compound was synthesized using butanamide. Yield 37%. Melting point 162-163 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.83 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.69 (3H, s), 4.42 (1H, dd, J = 8.7, 4.8 Hz), 4.51 (1H, dd, J = 9.0, 5.1 Hz), 4.83 (1H , t, J = 8.7 Hz), 6.67 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

N- (7- (1-hydroxybutyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamidopropyl Magnesium chloride (2.0 M, THF solution, 10.0 mL, 20.0 mmol) was added to N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro obtained in Example 20. -1-Benzofuran-5-yl) -3,3-dimethylbutanamide (2.2 g, 5.40 mmol) was added at 0 ° C., and the reaction solution was stirred at the same temperature for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and 1N hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 627 mg (yield 26%) of the title compound as a low polar substance. Melting point 162-163 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 0.87-1.05 (3H, m), 1.11 (9H, s), 1.22 (6H, d, J = 7.0 Hz), 1.30-2.00 (7H, m), 2.15 (3H , s), 2.24 (2H, s), 2.86 (1H, septet, J = 7.0 Hz), 3.30 (1H, d, J = 10.2 Hz), 4.40-4.58 (2H, m), 4.78-4.92 (2H, m), 6.54 (1H, br s), 7.02 (2H, d, J = 8.2 Hz), 7.12 (2H, d, J = 8.2 Hz).

N- (7- (1-hydroxybutyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide The residue operated in the same manner as in Example 90 was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 547 mg (yield 22%) of the title compound as a highly polar substance. Melting point 150-151 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 0.88-1.04 (3H, m), 1.12 (9H, s), 1.22 (6H, d, J = 7.0 Hz), 1.30-2.00 (7H, m), 2.19 (3H , s), 2.25 (2H, s), 2.86 (1H, septet, J = 7.0 Hz), 3.28 (1H, d, J = 10.2 Hz), 4.40-4.55 (2H, m), 4.79-4.93 (2H, m), 6.47 (1H, br s), 7.02 (2H, d, J = 8.2 Hz), 7.14 (2H, d, J = 8.2 Hz).

N- (7-Butyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 23. N- (7- (1-hydroxybutyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1- The title compound was synthesized using a diastereo mixture of benzofuran-5-yl) -3,3-dimethylbutanamide. Yield 33%. Melting point 149-151 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 0.83-1.00 (3H, m), 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.34-1.58 (4H, m), 1.83 (3H , s), 2.16 (3H, s), 2.23 (2H, s), 2.62 (2H, t, J = 7.5 Hz), 2.85 (1H, septet, J = 6.9 Hz), 4.39 (1H, dd, J = 8.4, 4.5 Hz), 4.49 (1H, dd, J = 9.0, 4.5 Hz), 4.79 (1H, t, J = 9.0 Hz), 6.52 (1H, br s), 7.03 (2H, d, J = 8.1 Hz) ), 7.11 (2H, d, J = 8.1 Hz).

4-hydroxy-N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide 3- (4- To a solution of (isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine (300 mg, 1.02 mmol) in THF (20 mL) under an argon atmosphere, n-butyllithium ( 1.6 M, hexane solution, 1.25 mL, 2.04 mmol) was added dropwise at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. To the reaction solution, γ-butyrolactone (300 mg, 0.98 mmol) was added dropwise and stirred for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 1) to give 174 mg (yield 45%) of the title compound. Melting point 156-157 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.30 (6H, m), 1.80-2.20 (11H, m), 2.56 (2H, t, J = 6.8 Hz), 2.70 (1H, br s), 2.86 ( 1H, septet, J = 6.9 Hz), 3.55-3.78 (2H, m), 4.38-4.57 (2H, m), 4.78-4.90 (1H, m), 6.78 (1H, br s), 7.00-7.18 (4H , m).

N- (7- (hydroxy (phenyl) methyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide A THF (10 mL) solution of bromobenzene (770 mg, 4.91 mmol) was dropped into a mixture of magnesium (119 mg, 4.91 mmol) and a catalytic amount of iodine under an argon atmosphere, and the mixture was stirred at room temperature for 20 minutes. N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- obtained in Example 20 was added to the reaction solution. A solution of dimethylbutanamide (400 mg, 0.98 mmol) in THF (5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to ice and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to obtain 512 mg (yield 99%) of the title compound. Yield 99%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.15 (3H, s), 2.24 (2H, s), 2.78-2.91 (1H, m), 3.88-3.99 (1H, m), 4.37-4.55 (2H, m), 4.75-4.90 (1H, m), 6.03 (1H, d, J = 9.3 Hz), 6.58- 6.62 (1H, m), 6.98-7.45 (9H, m).

N- (7- (hydroxy (4-isopropylphenyl) methyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- Dimethylbutanamide The title compound was synthesized in the same manner as in Example 94 using 4-isopropyl-1-bromobenzene. Yield 70%. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.18-1.31 (12H, m), 1.89 (3H, s), 2.13 (3H, s), 2.23 (2H, s), 2.79-2.95 (2H, m), 3.89-4.07 (1H, m), 4.39-4.48 (2H, m), 4.77-4.91 (1H, m), 5.98 (1H, d, J = 8.4 Hz), 6.55 (1H, d , J = 6.6 Hz), 6.98-7.22 (6H, m), 7.29 (2H, d, J = 8.1 Hz).

N- (7-benzyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 94 N- (7- (hydroxy (phenyl) methyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide A solution of (512 mg, 1.05 mmol) and 10% -palladium carbon (50% water content, 50 mg) in acetic acid (20 mL) was stirred at 80 ° C. for 1.5 hours in a hydrogen atmosphere. After removing the catalyst, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 330 mg (yield 67%) of the title compound. Melting point 153-154 [deg.] C.
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.10 (3H, s), 2.23 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.04 (2H, s), 4.43 (1H, dd, J = 8.4, 4.2 Hz), 4.56 (1H, dd, J = 9.0, 4.8 Hz), 4.83 (1H , t, J = 9.0 Hz), 6.46 (1H, br s), 7.03-7.28 (9H, m).

N- (7- (4-Isopropylbenzyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 96, N- (7- (hydroxy (4-isopropylphenyl) methyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro- obtained in Example 95 was used. The title compound was synthesized using 1-benzofuran-5-yl) -3,3-dimethylbutanamide. Yield 64%. Melting point 157-158 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.22 (6H, d, J = 6.9 Hz), 1.87 (3H, s), 2.10 ( 3H, s), 2.22 (2H, s), 2.77-2.92 (2H, m), 3.99 (2H, s), 4.42 (1H, dd, J = 9.0, 4.8 Hz), 4.55 (1H, dd, J = 9.3, 4.8 Hz), 4.82 (1H, t, J = 9.0 Hz), 6.45 (1H, br s), 7.00-7.17 (8H, m).

5-((3,3-Dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid obtained in Example 20. N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (500 mg, 1.23 mmol ), Sodium dihydrogen phosphate (40 mg), hydrogen peroxide (0.125 mL) in acetonitrile (5 mL) -water (2 mL) in a mixture of sodium chlorite (190 mg, 1.69 mmol) in water (2 mL) solution was added at room temperature and heated at the same temperature for 2 hours. An aqueous sodium hydrogen sulfite solution was added, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 380 mg (yield 73%) of the title compound. Melting point 194-195 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, m), 2.28 (2H, s), 2.51 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.47-4.65 (2H, m), 5.01 (1H, t, J = 9.0 Hz), 6.59 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz), 1H not confirmed.

N- (7-cyano-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 35 N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (0.5 g, 1.09 mmol) ), A solution of copper cyanide (300 mg 3.27 mmol) in dimethyl sulfoxide (30 mL) was heated at 180 ° C. for 14 hours. Aqueous ammonia was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 3: 1) to obtain 360 mg (yield 82%) of the title compound. Melting point 135-136 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.25 (2H, s), 2.38 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.50-4.65 (2H, m), 5.01 (1H, t, J = 10.8 Hz), 6.58 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J = 8.1 Hz).

N-((3S) -7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples 38, N-((3S) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 71 , 3-Dimethylbutanamide was used to synthesize the title compound. Yield 46%. Melting point 177-178 [deg.] C. (hexane-ethyl acetate). [α] _D ²⁰ = −6.0 ° (c = 0.510, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.22 (3H, s), 2.25 (2H, s), 2.58 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.44-4.56 (2H, m), 4.89 (1H, t, J = 8.1 Hz), 6.54 (1H, br s), 7.03 ( 2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 35 N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (300 mg, 0.654 mmol ), Phenylboronic acid (88 mg, 0.720 mmol), palladium (0) tetrakistriphenylphosphine (27 mg, 0.023 mmol) in 2M aqueous sodium carbonate (10 mL) -1,2-dimethoxyethane (5 mL). The mixture was heated to reflux for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, the insoluble material was collected by filtration, the filtrate was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 170 mg (yield 57%) of the title compound. Melting point 178-182 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.06 (3H, s), 2.26 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.37 (1H, dd, J = 9.0, 4.8 Hz), 4.56 (1H, dd, J = 9.3, 5.1 Hz), 4.79 (1H, t, J = 9.0 Hz ), 6.59 (1H, br s), 7.09 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz), 7.30-7.50 (5H, m).

N- (3- (4-Isopropylphenyl) -7- (6-methoxypyridin-3-yl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- Dimethylbutanamide N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5 obtained in Example 35 in the same manner as in Example 101. The title compound was synthesized using -yl) -3,3-dimethylbutanamide and (6-methoxypyridin-3-yl) boronic acid. Yield 48%. Melting point 120-123 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.08 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.97 (3H, s), 4.38 (1H, dd, J = 8.7, 4.8 Hz), 4.56 (1H, dd, J = 9.3, 5.1 Hz), 4.79 (1H , t, J = 9.3 Hz), 6.52 (1H, br s), 6.81 (1H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.4 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.57 (1H, dd, J = 8.4, 2.4 Hz), 8.13 (1H, d, J = 2.4 Hz).

N- (3- (4-Isopropylphenyl) -7- (4-methoxyphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 101, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 35- The title compound was synthesized using 3,3-dimethylbutanamide and (4-methoxyphenyl) boronic acid. Yield 40%. Melting point 129-131 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.07 (3H, s), 2.26 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.84 (3H, s), 4.38 (1H, dd, J = 9.0, 4.8 Hz), 4.56 (1H, dd, J = 9.3, 4.8 Hz), 4.79 (1H , t, J = 9.0 Hz), 6.53 (1H, br s), 6.97 (2H, d, J = 8.7 Hz), 7.09 (2H, d, J = 8.4 Hz), 7.14 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.7 Hz).

N- (7- (6-Fluoropyridin-3-yl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- Dimethylbutanamide N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5 obtained in Example 35 in the same manner as in Example 101. The title compound was synthesized using -yl) -3,3-dimethylbutanamide and (6-fluoropyridin-3-yl) boronic acid. Yield 58%. Melting point 135-137 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.93 (3H, s), 2.07 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.38 (1H, dd, J = 8.7, 4.8 Hz), 4.58 (1H, dd, J = 9.0, 4.8 Hz), 4.81 (1H, t, J = 9.0 Hz ), 6.60 (1H, br s), 7.00 (1H, dd, J = 8.4, 3.0 Hz), 7.08 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J = 8.1 Hz), 7.79 ( 1H, dt, J = 8.4, 2.1 Hz), 8.19 (1H, s).

N- (3- (4-Isopropylphenyl) -7- (3-methoxyphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 101, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 35- The title compound was synthesized using 3,3-dimethylbutanamide and (3-methoxyphenyl) boronic acid. Yield 64%. Melting point 209-210 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.07 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.82 (3H, s), 4.38 (1H, dd, J = 8.7, 4.8 Hz), 4.56 (1H, dd, J = 9.0, 5.1 Hz), 4.80 (1H , t, J = 9.0 Hz), 6.52 (1H, br s), 6.86-6.94 (3H, m), 7.10 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz), 7.35 (1H, dd, J = 8.7, 7.8 Hz).

N- (3- (4-Isopropylphenyl) -4,7-dimethyl-6-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 101. N- (6-Bromo-3- (4-isopropylphenyl) -4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl obtained in Example 87 The title compound was synthesized using butanamide and phenylboronic acid. Yield 42%. Melting point 212-213 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 0.82 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.85-1.93 (8H, m), 2.88 (1H, septet, J = 6.9 Hz), 4.48 (1H, dd, J = 8.7, 4.8 Hz), 4.60 (1H, dd, J = 9.0, 5.1 Hz), 4.89 (1H, t, J = 9.0 Hz), 6.21 (1H, br s), 7.09- 7.43 (9H, m).

N- (7- (3- (acetylamino) phenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- obtained in Example 35 Dimethylbutanamide (321 mg, 0.7 mmol), (3- (acetylamino) phenyl) boronic acid (188 mg, 0.7 mmol), palladium (0) tetrakistriphenylphosphine (40.5 mg, 0.035 mmol), 2N sodium carbonate A solution of dimethoxyethane (2.1 mL) -ethanol (0.7 mL) in an aqueous solution (1.05 mL) was heated to 150 ° C. in a microwave reactor and reacted for 5 minutes. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 2: 1) to obtain 308 mg (yield 86%) of the title compound. Melting point 247-248 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.05 (3H, s), 2.15 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.36 (1H, dd, J = 4.9, 9.0 Hz), 4.54 (1H, dd, J = 4.9, 9.0 Hz), 4.77 (1H , t, J = 9.0 Hz), 6.54 (1H, s), 7.07-7.15 (5H, m), 7.26-7.39 (3H, m), 7.60 (1H, br).

N- (7- (3-fluorophenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 35- The title compound was obtained using 3,3-dimethylbutanamide and (3-fluorophenyl) boronic acid. Yield 67%. Melting point 182-183 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.06 (3H, s), 2.26 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.38 (1H, dd, J = 4.9, 9.0 Hz), 4.56 (1H, dd, J = 4.9, 9.0 Hz), 4.80 (1H, t, J = 9.0 Hz) ), 6.51 (1H, s), 6.99-7.17 (7H, m), 7.34-7.42 (1H, m).

N- (7- (3-nitrophenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 35- The title compound was obtained using 3,3-dimethylbutanamide and (3-nitrophenyl) boronic acid. Yield 59%. Melting point 209-210 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.94 (3H, s), 2.07 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.38 (1H, dd, J = 4.9, 9.0 Hz), 4.57 (1H, dd, J = 4.9, 9.0 Hz), 4.81 (1H, t, J = 9.0 Hz) ), 6.52 (1H, s), 6.63-6.73 (3H, m), 7.07 (2H, d, J = 8.2 Hz), 7.15 (2H, d, J = 8.2 Hz), 7.59 (1H, t, J = 7.7 Hz), 7.66-7.71 (1H, m), 8.17-8.23 (2H, m).

3- (5-((3,3-Dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) methyl benzoate In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) obtained in Example 35) The title compound was obtained using -3,3-dimethylbutanamide and (3-methoxycarbonyl) phenylboronic acid. Yield 55%. Melting point 206-208 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.93 (3H, s), 2.05 (3H, s), 2.26 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.91 (3H, s), 4.37 (1H, dd, J = 4.9, 9.0 Hz), 4.57 (1H, dd, J = 4.9, 9.0 Hz), 4.80 (1H , t, J = 9.0 Hz), 6.57 (1H, s), 7.08 (2H, d, J = 8.2 Hz), 7.13 (2H, d, J = 8.2 Hz), 7.47-7.56 (2H, m), 7.98 -8.03 (2H, m).

N- (7- (3-acetylphenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 35- The title compound was obtained using 3,3-dimethylbutanamide and (3-acetylphenyl) boronic acid. Yield 79%. Melting point 209-210 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.93 (3H, s), 2.05 (3H, s), 2.27 (2H, s), 2.62 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.37 (1H, dd, J = 4.9, 9.0 Hz), 4.57 (1H, dd, J = 4.9, 9.0 Hz), 4.80 (1H , t, J = 9.0 Hz), 6.53 (1H, s), 7.08 (2H, d, J = 8.2 Hz), 7.14 (2H, d, J = 8.2 Hz), 7.50-7.56 (2H, m), 7.91 -7.97 (2H, m).

Ethyl 3- (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) benzoate In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) obtained in Example 35) The title compound was obtained using -3,3-dimethylbutanamide and 3- (ethoxycarbonyl) phenylboronic acid. Yield 63%. Melting point 175-177 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.39 (3H, t, J = 7.1 Hz), 1.93 (3H, s), 2.04 ( 3H, s), 2.27 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.34-4.42 (3H, m), 4.57 (1H, dd, J = 4.7, 9.3 Hz), 4.79 (1H , dd, J = 8.8, 9.3 Hz), 6.52 (1H, s), 7.08 (2H, d, J = 8.4 Hz), 7.14 (2H, d, J = 8.4 Hz), 7.45-7.55 (2H, m) , 8.00-8.05 (2H, m).

N- (7- (4-methylphenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 35- The title compound was obtained using 3,3-dimethylbutanamide and (4-methylphenyl) boronic acid. Yield 68%. Melting point 194-195 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.06 (3H, s), 2.26 (2H, s), 2.38 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.36 (1H, dd, J = 4.9, 8.8 Hz), 4.55 (1H, dd, J = 4.9, 9.3 Hz), 4.81 (1H , dd, J = 8.8, 9.3 Hz), 6.50 (1H, s), 7.07 (2H, d, J = 8.3 Hz), 7.11 (2H, d, J = 8.3 Hz), 7.22 (4H, s).

N- (3- (4-Isopropylphenyl) -7- (pyridin-3-yl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) obtained in Example 35) The title compound was obtained using -3,3-dimethylbutanamide and pyridin-3-ylboronic acid. Yield 32%. Melting point 142-144 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.93 (3H, s), 2.08 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.39 (1H, dd, J = 5.0, 9.1 Hz), 4.58 (1H, dd, J = 5.0, 9.1 Hz), 4.81 (1H, t, J = 9.1 Hz) ), 6.56 (1H, s), 7.09 (2H, d, J = 8.2 Hz), 7.15 (2H, d, J = 8.2 Hz), 7.26-7.38 (1H, m), 7.67-7.72 (1H, m) , 8.56-8.61 (2H, m).

N- (3- (4-Isopropylphenyl) -7- (pyridin-4-yl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) obtained in Example 35) The title compound was obtained using -3,3-dimethylbutanamide and pyridin-4-ylboronic acid. Yield 72%. Melting point 150-152 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.93 (3H, s), 2.07 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.39 (1H, dd, J = 4.9, 8.8 Hz), 4.57 (1H, dd, J = 4.9, 9.3 Hz), 4.81 (1H, t, J = 9.0 Hz ), 6.53 (1H, s), 7.07 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 5.9 Hz), 8.65 (2H, d , J = 5.9 Hz).

(5-((3,3-Dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) boronic acid Example 35 N- (7-Bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (1.38 g , 3 mmol) in THF (20 mL) was cooled to −72 ° C., n-butyllithium (1.6 M THF solution, 5.63 mL, 9 mmol) was added, and the mixture was stirred for 30 minutes, and further triisopropyl boronate (2.42). mL, 10.5 mmol) was added. The reaction mixture was warmed to room temperature over 1 hour, treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol 9: 1) to obtain 613 mg (yield 48%) of the title compound. Melting point 151-153 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.26 (2H, s), 2.49 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.45-4.55 (2H, m), 4.87 (1H, t, J = 9.0 Hz), 5.88 (2H, s), 6.49 (1H, s), 7.01 (2H , d, J = 8.2 Hz), 7.11 (2H, d, J = 8.2 Hz).

N- (3- (4-Isopropylphenyl) -7- (pyridin-2-yl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 107, (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro obtained in Example 116 was obtained. The title compound was obtained using -1-benzofuran-7-yl) boronic acid and 2-bromopyridine. Yield 53%. Melting point 198-200 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.04 (3H, s), 2.26 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.37 (1H, dd, J = 4.9, 9.0 Hz), 4.57 (1H, dd, J = 4.9, 9.0 Hz), 4.83 (1H, t, J = 9.0 Hz) ), 6.75 (1H, s), 7.05-7.13 (4H, m), 7.22-7.26 (1H, m), 7.43 (1H, d, J = 7.7 Hz), 7.74 (1H, td, J = 7.7, 0.8 Hz), 8.69-8.73 (1H, m).

N- (3- (4-Isopropylphenyl) -7- (5-methylpyridin-2-yl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- Dimethylbutanamide In the same manner as in Example 107, (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2, obtained in Example 116 was obtained. The title compound was obtained using 3-dihydro-1-benzofuran-7-yl) boronic acid and 2-bromo-5-methylpyridine. Yield 67%. Melting point 228-229 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.01 (3H, s), 2.25 (2H, s), 2.37 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.36 (1H, dd, J = 4.9, 9.0 Hz), 4.57 (1H, dd, J = 4.9, 9.0 Hz), 4.81 (1H , t, J = 9.0 Hz), 6.90 (1H, s), 7.09 (2H, d, J = 8.3 Hz), 7.11 (2H, d, J = 8.3 Hz), 7.32 (1H, d, J = 8.0 Hz) ), 7.53-7.58 (1H, m), 8.54 (1H, br s).

N- (7- (6-Aminopyridin-2-yl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- Dimethylbutanamide In the same manner as in Example 107, (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2, obtained in Example 116 was obtained. The title compound was obtained using 3-dihydro-1-benzofuran-7-yl) boronic acid and 2-amino-6-bromopyridine. Yield 68%. Melting point 237-239 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.10 (3H, s), 2.25 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.36 (1H, dd, J = 4.9, 9.0 Hz), 4.54 (2H, brs), 4.56 (1H, dd, J = 4.9, 9.0 Hz), 4.83 (1H , t, J = 9.0 Hz), 6.45 (1H, d, J = 8.2 Hz), 6.47 (1H, s), 6.77 (1H, d, J = 7.4 Hz), 7.08 (2H, d, J = 8.6 Hz) ), 7.12 (2H, d, J = 8.6 Hz), 7.50 (1H, dd, J = 7.4, 8.2 Hz).

N- (7- (3-dimethylaminophenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 107, (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro obtained in Example 116 was obtained. The title compound was obtained using -1-benzofuran-7-yl) boronic acid and 3-bromo-N, N-dimethylaniline. Yield 77%. Melting point 197-199 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.06 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 2.95 (6H, s), 4.34-4.39 (1H, m), 4.53-4.58 (1H, m), 4.77 (1H, t, J = 9.1 Hz), 6.50 (1H, s), 6.63-6.77 (3H, m), 7.06-7.16 (4H, m), 7.27-7.33 (1H, m).

N- (7- (6- (acetylamino) pyridin-2-yl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 , 3-Dimethylbutanamide N- (7- (6-aminopyridin-2-yl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro- obtained in Example 119 Acetyl chloride (0.015 mL, 0.22 mmol) was added to a solution of 1-benzofuran-5-yl) -3,3-dimethylbutanamide (94.3 mg, 0.2 mmol) and triethylamine (0.042 mL, 0.3 mmol) in THF (1 mL). It added at 0 degreeC and stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 1: 1) to obtain 51 mg (yield 50%) of the title compound. Mp 205-208 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.59 (3H, s), 1.90 (3H, s), 2.07 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.33-4.39 (1H, m), 4.57 (1H, dd, J = 4.9, 9.3 Hz), 4.82 (1H, t, J = 9.1 Hz), 6.49 (1H, s), 7.03-7.18 (5H, m), 7.76 (1H, t, J = 7.9 Hz), 7.99 (1H, br), 8.14 (1H, d, J = 7.9 Hz) .

N- (7- (3-aminophenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide N- (7- (3-nitrophenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3, obtained in Example 109. To a solution of 3-dimethylbutanamide (2.50 g, 5 mmol) and ammonium formate (1.26 g, 20 mmol) in ethanol (50 mL) was added 10% -palladium carbon (50% water content, 0.25 g) and heated to 65 ° C. And stirred for 2 hours. The reaction solution was cooled to room temperature, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 2.15 g (yield 92%) of the title compound. Melting point 170-172 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.05 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.67 (2H, brs), 4.37 (1H, dd, J = 4.9, 9.0 Hz), 4.54 (1H, dd, J = 4.9, 9.0 Hz), 4.77 (1H , t, J = 9.0 Hz), 6.51 (1H, s), 6.63-6.73 (3H, m), 7.05-7.15 (4H, m), 7.19 (1H, dd, J = 5.0, 5.8 Hz).

N- (3- (4-Isopropylphenyl) -7- (3-propionylaminophenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 121, N- (7- (3-aminophenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran obtained in Example 122 was obtained. The title compound was obtained using -5-yl) -3,3-dimethylbutanamide and propionyl chloride. Yield 84%. Melting point 237-239 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.20-1.26 (9H, m), 1.91 (3H, s), 2.05 (3H, s), 2.26 (2H, s), 2.37 (2H , q, J = 7.4 Hz), 2.86 (1H, septet, J = 6.9 Hz), 4.35 (1H, dd, J = 4.9, 8.5 Hz), 4.54 (1H, dd, J = 4.9, 9.2 Hz), 4.77 (1H, t, J = 9.1 Hz), 6.50 (1H, s), 7.02-7.09 (3H, m), 7.13 (2H, d, J = 8.0 Hz), 7.24 (1H, br), 7.30-7.40 ( 2H, m), 7.63 (1H, br).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7- (pyrimidin-5-yl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 107, (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro obtained in Example 116 was obtained. The title compound was obtained using -1-benzofuran-7-yl) boronic acid and 5-bromopyrimidine. Yield 77%. Melting point 167-169 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.94 (3H, s), 2.12 (3H, s), 2.28 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.40 (1H, dd, J = 4.9, 9.0 Hz), 4.58 (1H, dd, J = 4.9, 9.0 Hz), 4.83 (1H, t, J = 9.0 Hz) ), 6.53 (1H, s), 7.07 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz), 8.76 (2H, s), 9.18 (1H, s).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7- (1,3-thiazol-2-yl) -2,3-dihydro-1-benzofuran-5-yl) -3,3 -Dimethylbutanamide (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2 obtained in Example 116 in the same manner as in Example 107. , 3-Dihydro-1-benzofuran-7-yl) boronic acid and 2-bromo-1,3-thiazole gave the title compound. Yield 64%. Melting point 164-166 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.25 (3H, s), 2.27 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.46 (1H, dd, J = 4.9, 9.0 Hz), 4.58 (1H, dd, J = 4.9, 9.0 Hz), 4.90 (1H, t, J = 9.0 Hz ), 6.72 (1H, s), 7.07 (2H, d, J = 8.4 Hz), 7.14 (2H, d, J = 8.4 Hz), 7.47 (1H, d, J = 3.2 Hz), 7.93 (1H, d , J = 3.2 Hz).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7- (3-thienyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples In the same manner as in 107, (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1 obtained in Example 116 was obtained. The title compound was obtained using -benzofuran-7-yl) boronic acid and 3-bromothiophene. Yield 49%. Melting point 172-174 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.14 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.40 (1H, dd, J = 4.9, 9.0 Hz), 4.55 (1H, dd, J = 4.9, 9.0 Hz), 4.82 (1H, t, J = 9.0 Hz ), 6.51 (1H, s), 7.05-7.17 (5H, m), 7.26-7.43 (2H, m).

N- (7- (1H-imidazol-4-yl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 107, (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3 obtained in Example 116 was obtained. The title compound was obtained using -dihydro-1-benzofuran-7-yl) boronic acid and 4-bromoimidazole. Yield 48%. Mp 277-279 [deg.] C (ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.28 (2H, s), 2.34 (3H, brs), 2.86 (1H, septet, J = 6.9 Hz), 4.40-4.58 (2H, m), 4.81-4.88 (1H, m), 6.50 (1H, s), 6.92 (1H, s), 7.06 (2H, d, J = 8.3Hz), 7.11 (2H, d, J = 8.3 Hz), 7.21 (1H, br s), 7.68 (1H, s).

N- (7- (3-furyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples In the same manner as in 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 35 , 3-Dimethylbutanamide and 3-furylboronic acid were used to give the title compound. Yield 51%. Melting point 183-185 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.21 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.41 (1H, dd, J = 8.5, 4.9 Hz), 4.55 (1H, dd, J = 9.6, 4.9 Hz), 4.83 (1H, dd, J = 8.5, 9.6 Hz), 6.50 (1H, s), 6.57 (1H, d, J = 1.9 Hz), 7.06 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.3 Hz), 7.48-7.50 (1H, m), 7.53-7.55 (1H, m).

N- (7- (1H-pyrrol-2-yl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5 obtained in Example 35 was used. Yl) -3,3-dimethylbutanamide and (1- (tert-butoxycarbonyl) -1H-pyrrol-2-yl) boronic acid were used to give the title compound. Yield 19%. Melting point 188-190 ° C. (ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.27 (2H, s), 2.39 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.45-4.50 (1H, m), 4.53-4.59 (1H, m), 4.87 (1H, t, J = 8.6 Hz), 6.30-6.34 (1H, m) , 6.42 (1H, br), 6.53 (1H, s), 6.87 (1H, br), 7.05 (2H, d, J = 8.0Hz), 7.11 (2H, d, J = 8.0 Hz), 9.32 (1H, br).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7- (2-thienyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples In the same manner as in 107, (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1 obtained in Example 116 was obtained. The title compound was synthesized using -benzofuran-7-yl) boronic acid and 2-bromothiophene. Yield 58%. Melting point 155-156 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.91 (3H, s), 2.16 (3H, s), 2.26 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.41 (1H, dd, J = 8.7, 5.1 Hz), 4.57 (1H, dd, J = 9.3, 5.1 Hz), 4.84 (1H, t, J = 10.8 Hz) ), 6.50 (1H, br s), 7.00-7.16 (6H, m), 7.38 (1H, dd, J = 5.1, 1.2 Hz).

N- (7- (5-acetyl-2-thienyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 107, (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3 obtained in Example 116 was obtained. The title compound was synthesized using -dihydro-1-benzofuran-7-yl) boronic acid and 2-acetyl-5-bromothiophene. Yield 65%. Melting point 157-158 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.19 (3H, s), 2.27 (2H, s), 2.57 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.43 (1H, dd, J = 8.1, 4.8 Hz), 4.58 (1H, dd, J = 9.9, 4.5 Hz), 4.85 (1H , t, J = 9.0 Hz), 6.54 (1H, br s), 7.05-7.21 (5H, m), 7.71 (1H, d, J = 3.9 Hz).

N- (7- (5-acetyl-3-thienyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 107, (5-((3,3-dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3 obtained in Example 116 was obtained. The title compound was synthesized using -dihydro-1-benzofuran-7-yl) boronic acid and 2-acetyl-4-bromothiophene. Yield 62%. Melting point 133-134 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.15 (3H, s), 2.27 (2H, s), 2.58 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.41 (1H, dd, J = 8.7, 4.8 Hz), 4.58 (1H, dd, J = 9.3, 5.1 Hz), 4.83 (1H , t, J = 9.0 Hz), 6.56 (1H, br s), 7.08 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J = 8.1 Hz), 7.58 (1H, d, J = 1.2 Hz), 7.74 (1H, d, J = 1.2 Hz).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7- (4-methyl-1,3-thiazol-2-yl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-Dimethylbutanamide (5-((3,3-Dimethylbutanoyl) amino) -3- (4-isopropylphenyl) -4,6 obtained in Example 116 in the same manner as in Example 107. The title compound was synthesized using -dimethyl-2,3-dihydro-1-benzofuran-7-yl) boronic acid and 2-bromo-4-methyl-1,3-thiazole. Yield 62%. Melting point 240-241 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.22 (3H, s), 2.26 (2H, s), 2.53 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.44 (1H, dd, J = 8.7, 5.4 Hz), 4.64 (1H, dd, J = 9.3, 5.7 Hz), 4.90 (1H , t, J = 9.0 Hz), 6.61 (1H, br s), 7.01 (1H, s), 7.07 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

(+)-N-((3R) -7-hydroxy-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide (+)-N-((3R) -3- (4-isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5 obtained in Example 52 Yl) -3,3-dimethylbutanamide (500 mg, 1.22 mmol) in methylene chloride (20 mL) with boron tribromide (1.0 M methylene chloride solution, 3.0 mL, 3.0 mmol) in an argon atmosphere at -78. It was dripped at ° C. The reaction mixture was warmed to room temperature, added to saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to synthesize 378 mg (yield 78%) of the title compound. Melting point 202-203 [deg.] C (ethyl acetate-hexane). [α] _D ²⁰ = + 79.0 ° (c = 0.49, chloroform).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.80 (3H, s), 2.14 (3H, s), 2.24 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.46 (1H, dd, J = 4.5, 8.7 Hz), 4.55 (1H, dd, J = 4.5, 8.7 Hz), 4.86 (1H, t, J = 8.7 Hz) ), 4.89 (1H, br s), 6.49 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

N- (7-hydroxy-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 134. N- (3- (4-Isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl obtained in Example 36 The title compound was synthesized using butanamide. Yield 78%. Melting point 181-182 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.80 (3H, s), 2.14 (3H, s), 2.25 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.46 (1H, dd, J = 4.5, 8.7 Hz), 4.55 (1H, dd, J = 4.5, 8.7 Hz), 4.84 (1H, t, J = 8.7 Hz) ), 4.95 (1H, br s), 6.51 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

N- (7-ethoxy-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 135 N- (7-hydroxy-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (300 mg, 0.76 mmol) ), Potassium carbonate (105 mg, 0.76 mmol), and diethyl sulfate (117 mg, 0.76 mmol) in acetone (15 mL) were heated to reflux for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to obtain 378 mg (yield 78%) of the title compound. Melting point 174-175 [deg.] C (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.37 (3H, t, J = 7.2 Hz), 1.82 (3H, s), 2.16 ( 3H, s), 2.24 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.07-4.20 (2H, m), 4.43-4.53 (2H, m), 4.85 (1H, t, J = 8.1 Hz), 6.47 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

Tert-butyl (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamate obtained in Reference Example 30 in the same manner as in Reference Example 59 The title compound was synthesized using 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 53%. Melting point 121-122 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.20-1.50 (9H, m), 1.87 (3H, s), 2.17 (6H, s), 2.86 (1H, septet , J = 6.9 Hz), 4.40 (1H, dd, J = 4.5, 8.7 Hz), 4.47-4.51 (1H, m), 4.80 (1H, t, J = 8.7 Hz), 5.71 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

(3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl 3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine (1.48 g, 5 mmol) and triethylamine (0.22 mL, 1.61 mmol) in THF (15 mL) To the solution, 2,2,2-trichloroethyl chloroformate (0.76 mL, 5.5 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 3: 1) to obtain 2.19 g (yield 93%) of the title compound. Melting point 137-140 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.10 (6H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.38- 4.45 (1H, m), 4.50-4.56 (1H, m), 4.75-4.86 (3H, m), 6.15 (1H, s), 7.03 (2H, d, J = 8.0 Hz), 7.11 (2H, d, J = 8.0 Hz).

(7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl As in Example 138 The title compound was synthesized using 7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 328. Yield 82%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.5 Hz), 1.22 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.22 (3H, s), 2.66 ( 2H, q, J = 7.5 Hz), 2.86 (1H, septet, J = 6.9 Hz), 4.42 (1H, dd, J = 5.1, 8.7 Hz), 4.53 (1H, dd, J = 4.8, 9.3 Hz), 4.75-4.90 (3H, m), 6.15 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

(3- (4-Isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl As in Example 138. Then, the title compound was synthesized using 3- (4-isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 327. Yield 68%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.86 (3H, s), 2.19 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.90 ( 3H, s), 4.45-4.58 (2H, m), 4.77-4.92 (3H, m), 6.15 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz).

(7- (3-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl 3- (5-Amino-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl) propane obtained in Reference Example 322 in the same manner as in Example 138 The title compound was synthesized using -1-ol. Yield 51%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.85-2.05 (5H, m), 2.21 (3H, s), 2.70-2.92 (3H, m), 4.27 (2H , t, J = 6.6 Hz), 4.40 (1H, dd, J = 5.1, 8.7 Hz), 4.52 (1H, dd, J = 5.1, 9.1 Hz), 4.77-4.92 (3H, m), 6.15 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 1H Not confirmed.

(3- (4-Isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl As in Example 138. The title compound was synthesized using 3- (4-isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 329. Yield 89%. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.95 (3H, s), 2.10 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.38 ( 1H, dd, J = 5.1, 8.7 Hz), 4.56 (1H, dd, J = 4.8, 9.3 Hz), 4.75-4.90 (3H, m), 6.20 (1H, br s), 7.08 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz), 7.24-7.50 (5H, m).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) pyrrolidine-1-carboxamide obtained in Example 138 (3- (4 -Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl (353 mg, 0.75 mmol) and pyrrolidine (0.076 mL, 0.9 mmol) in dimethyl sulfoxide (5 mL) was added diisopropylethylamine (0.13 mL, 0.75 mmol) at room temperature, heated to 50 ° C. and reacted for 16 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 1: 1) to obtain 130 mg (yield 44%) of the title compound. Melting point 186-188 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 1.87 (3H, s), 1.92-2.00 (4H, m), 2.17 (3H, s), 2.17 (3H, s ), 2.85 (1H, septet, J = 6.9 Hz), 3.43 (4H, br), 4.38-4.43 (1H, m), 4.48-4.53 (1H, m), 4.78-4.84 (1H, m), 5.43 ( 1H, s), 7.04 (2H, d, J = 8.2 Hz), 7.10 (2H, d, J = 8.2 Hz).

N, N-diethyl-N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) urea In the same manner as in Example 143, (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl and diethylamine obtained in Example 138 To give the title compound. Yield 68%. Melting point 79-81 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.18-1.23 (12H, m), 1.86 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.85 (1H, septet, J = 7.0 Hz ), 3.31-3.40 (4H, m), 4.38-4.43 (1H, m), 4.48-4.54 (1H, m), 4.80 (1H, t, J = 8.8 Hz), 5.54 (1H, s), 7.04 ( 2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

N- (2-hydroxyethyl) -N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) urea Same as Example 143 (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloro obtained in Example 138 The title compound was obtained using ethyl and 2-hydroxyethylamine. Yield 89%. Melting point 186-188 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.19 (3H, s), 2.20 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.23 (1H, br), 3.32 (2H, br), 3.64 (2H, br), 4.43-4.48 (1H, m), 4.50-4.56 (1H, m), 4.65 (1H, br) , 4.85 (1H, t, J = 8.8 Hz), 5.64 (1H, br), 7.03 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -N ′-(2-methoxyethyl) urea Same as Example 143 (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloro obtained in Example 138 The title compound was synthesized using ethyl and 2-methoxyethylamine. Yield 58%. Melting point 172-173 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.18 (6H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.05- 3.44 (7H, m), 4.40-4.63 (3H, m), 4.85 (1H, t, J = 9.0 Hz), 5.53 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.13 ( 2H, d, J = 8.1 Hz).

N- (2- (dimethylamino) ethyl) -N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) urea Examples 143, (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2, obtained in Example 138 The title compound was synthesized using 2-trichloroethyl and 2- (dimethylamino) ethylamine. Yield 54%. Melting point 133-134 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.10 (6H, br s), 2.19 (6H, s), 2.28 (2H, br s ), 2.87 (1H, septet, J = 6.9 Hz), 3.10-3.35 (2H, m), 4.44 (1H, dd, J = 8.7, 4.8 Hz), 4.53 (1H, dd, J = 9.0, 4.5 Hz) , 4.69 (1H, br s), 4.85 (1H, t, J = 9.0 Hz), 5.70 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

N- (7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -N ′-(2-hydroxyethyl) urea Example 143 In the same manner as described above, (7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2 obtained in Example 139 , 2-Trichloroethyl and 2-aminoethanol were used to synthesize the title compound. Yield 57%. Melting point 147-148 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.5 Hz), 1.22 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.23 (3H, s), 2.25- 2.75 (2H, m), 2.87 (1H, septet, J = 6.9 Hz), 3.17-3.40 (3H, m), 3.44-3.70 (2H, m), 4.40-4.58 (2H, m), 4.68 (1H, br s), 4.85 (1H, t, J = 8.4 Hz), 5.71 (1H, br s), 7.03 (2H, d, J = 7.8 Hz), 7.14 (2H, d, J = 7.8 Hz).

N- (2-hydroxyethyl) -N ′-(3- (4-isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) urea Example 143 (3- (4-Isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2 obtained in Example 140 , 2-Trichloroethyl and 2-aminoethanol were used to synthesize the title compound. Yield 59%. Melting point 127-129 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.86 (3H, s), 2.19 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.17- 3.40 (3H, m), 3.44-3.72 (2H, m), 3.91 (3H, s), 4.40-4.90 (4H, m), 5.83 (1H, br s), 7.03 (2H, d, J = 7.8 Hz ), 7.14 (2H, d, J = 7.8 Hz).

N- (2-hydroxyethyl) -N ′-(7- (3-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl ) Urea In the same manner as in Example 143, (7- (3-hydroxypropyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran obtained in Example 141 was used. -5-yl) carbamic acid The title compound was synthesized using 2,2,2-trichloroethyl and 2-aminoethanol. Yield 53%. Melting point 153-154 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.69-1.94 (5H, m), 2.07-2.40 (4H, m), 2.72-2.90 (3H, m), 3.00 -3.40 (3H, m), 3.42-3.75 (4H, m), 4.41-4.70 (3H, m), 4.85 (1H, t, J = 8.4 Hz), 5.63 (1H, br s), 7.00 (2H, d, J = 7.8 Hz), 7.13 (2H, d, J = 7.8 Hz).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -N′-propylurea In the same manner as in Example 143, (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl and 1-propyl obtained in 138 The title compound was synthesized using an amine. Yield 53%. Melting point 177-178 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 0.81 (3H, br s), 1.22 (6H, d, J = 6.9 Hz), 1.41 (2H, br s), 1.87 (3H, s), 2.19 (6H, s ), 2.86 (1H, septet, J = 6.9 Hz), 3.14 (2H, br s), 4.18 (1H, br s), 4.45 (1H, dd, J = 8.4, 4.8 Hz), 4.53 (1H, dd, J = 9.3, 4.8 Hz), 4.85 (1H, t, J = 9.0 Hz), 5.51 (1H, br s), 7.01 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 7.8 Hz ).

N- (2-hydroxyethyl) -N ′-(3- (4-isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) urea Example 143 (3- (4-Isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2 obtained in Example 142 , 2-Trichloroethyl and 2-aminoethanol were used to synthesize the title compound. Yield 59%. Melting point 152-155 ° C (hexane-ethyl acetate). ¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.71 (2H, br s), 1.88 (3H, s), 2.19 (6H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.15-3.40 (3H, m), 3.42-3.67 (2H, m), 4.35-4.58 (3H, m), 4.85 (1H, t, J = 8.7 Hz), 5.64 (1H, br s), 7.04 (2H, br s), 7.14 (2H, d, J = 7.8 Hz).

N- (3-hydroxypropyl) -N ′-(3- (4-isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) urea Example 143 (3- (4-Isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2 obtained in Example 142 , 2-Trichloroethyl and 3-amino-1-propanol were used to synthesize the title compound. Yield 65%. Melting point 145-146 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.40-1.60 (4H, m), 1.88 (3H, br s), 2.19 (6H, s), 2.87 (1H, septet, J = 6.9 Hz), 3.00-3.70 (5H, m), 4.36 (1H, br s), 4.45 (1H, dd, J = 8.4, 4.8 Hz), 4.52 (1H, dd, J = 8.7, 4.8 Hz), 4.85 (1H, t, J = 9.0 Hz), 5.50 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz).

N- (3-hydroxypropyl) -N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) urea Same as Example 143 (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloro obtained in Example 138 The title compound was synthesized using ethyl and 3-amino-1-propanol. Yield 33%. Melting point 185-186 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.97 (3H, s), 2.12 (3H, s), 2.88 (1H, septet, J = 6.9 Hz), 3.24- 3.78 (5H, m), 4.43 (1H, dd, J = 9.0, 4.8 Hz), 4.57 (1H, dd, J = 9.1, 4.5 Hz), 4.72-4.90 (2H, m), 5.66 (1H, br s ), 7.09 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.28-7.50 (5H, m).

N- (4-hydroxybutyl) -N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) urea Same as Example 143 (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloro obtained in Example 138 The title compound was synthesized using ethyl and 4-amino-1-butanol. Yield 28%. Melting point 145-146 ° C (ethanol-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.40-1.60 (4H, m), 1.88 (3H, s), 2.19 (6H, s), 2.87 (1H, septet , J = 6.9 Hz), 3.00-3.30 (2H, m), 3.40-3.71 (2H, m), 4.36 (1H, br s), 4.45 (1H, dd, J = 8.4, 4.8 Hz), 4.52 (1H , dd, J = 8.7, 4.8 Hz), 4.85 (1H, t, J = 9.0 Hz), 5.50 (1H, br s), 7.02 (2H, d, J = 7.8 Hz), 7.13 (2H, d, J = 7.8 Hz), 1H not confirmed.

N- (2-hydroxy-1,1-dimethylethyl) -N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) Urea (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2 obtained in Example 138 in the same manner as in Example 143 , 2,2-Trichloroethyl and 2-amino-2-methyl-1-propanol were used to synthesize the title compound. Yield 39%. Melting point 157-158 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.00-1.30 (12H, m), 1.86 (3H, s), 2.18 (3H, s), 2.20 (3H, s), 2.86 (1H, septet, J = 6.9 Hz ), 3.42-3.60 (2H, m), 4.07-4.30 (1H, m), 4.45 (1H, dd, J = 8.7, 4.8 Hz), 4.54 (1H, dd, J = 9.0, 5.1 Hz), 4.87 ( 1H, t, J = 9.0 Hz), 5.38-5.62 (2H, m), 6.94-7.05 (2H, m), 7.12 (2H, d, J = 8.1 Hz).

N- (2-hydroxy-1,1-dimethylethyl) -N ′-(3- (4-isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5 Yl) urea In the same manner as in Example 143, (3- (4-isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl obtained in Example 142 ) The title compound was synthesized using 2,2,2-trichloroethyl carbamic acid and 2-amino-2-methyl-1-propanol. Yield 49%. Melting point 181-182 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.00-1.37 (12H, m), 1.95 (3H, s), 2.11 (3H, s), 2.88 (1H, septet, J = 6.9 Hz), 3.42-3.60 (2H , m), 4.10-4.47 (2H, m), 4.59 (1H, dd, J = 9.3, 4.8 Hz), 4.85 (1H, t, J = 9.0 Hz), 5.34 (1H, br s), 5.61 (1H , br s), 7.06 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.26-7.50 (5H, m).

N- (3-hydroxy-2,2-dimethylpropyl) -N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) Urea (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2 obtained in Example 138 in the same manner as in Example 143 , 2,2-Trichloroethyl and 3-amino-2,2-methyl-1-propanol were used to synthesize the title compound. Yield 61%. Melting point 117-118 ° C. (ethanol-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.48-0.80 (6H, m), 1.19 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.20 (6H, s), 2.57-3.35 (5H , m), 4.22-4.67 (4H, m), 4.88 (1H, t, J = 9.0 Hz), 5.64 (1H, d, J = 20.7 Hz), 7.02 (2H, d, J = 6.6 Hz), 7.10 -7.18 (2H, m).

N- (3-hydroxy-2,2-dimethylpropyl) -N ′-(3- (4-isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5 Yl) urea In the same manner as in Example 143, (3- (4-isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl obtained in Example 142 ) The title compound was synthesized using 2,2,2-trichloroethyl carbamic acid and 3-amino-2,2-methyl-1-propanol. Yield 77%. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 0.48-0.85 (6H, m), 1.22 (6H, d, J = 6.9 Hz), 1.97 (3H, s), 2.11 (3H, s), 2.57-3.35 (5H , m), 4.22-4.67 (4H, m), 4.84 (1H, t, J = 9.0 Hz), 5.72 (1H, d, J = 21.6 Hz), 7.07 (2H, d, J = 8.1 Hz), 7.14 (2H, d, J = 8.1 Hz), 7.27-7.45 (5H, m).

N- (2-hydroxypropyl) -N ′-(3- (4-isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) urea Example 143 (3- (4-Isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2 obtained in Example 142 , 2-Trichloroethyl and 1-amino-2-propanol were used to synthesize the title compound. Yield 58%. Melting point 171-182 ° C. (ethanol-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (3H, br s), 1.23 (6H, d, J = 6.9 Hz), 1.97 (3H, s), 2.12 (3H, s), 2.60-3.50 (4H, m), 3.83 (1H, br s), 4.42 (1H, dd, J = 9.0, 4.5 Hz), 4.56 (1H, dd, J = 9.3, 4.8 Hz), 4.74 (1H, br s), 4.83 (1H , t, J = 9.0 Hz), 5.65 (1H, br s), 7.07 (2H, d, J = 6.6 Hz), 7.15 (2H, d, J = 6.6 Hz), 7.27-7.48 (5H, m).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, Reference Example The title compound was synthesized using 3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothiophen-5-amine obtained in 291. Yield 81%. Melting point 151-152 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.21 (3H, s), 2.24 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.14 (1H, dd, J = 11.4, 1.8 Hz), 3.92 (1H, dd, J = 11.4, 8.4 Hz), 4.64 (1H, d, J = 7.8 Hz ), 6.51 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.03 (1H, s), 7.09 (2H, d, J = 8.1 Hz).

N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide As in Reference Example 259. N- (3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide obtained in Example 161 was used. The title compound was synthesized. Yield 55%. Melting point 207-208 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.86 (3H, s), 2.24 (2H, s), 2.32 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.13 (1H, dd, J = 11.1, 2.1 Hz), 3.92 (1H, dd, J = 11.1, 8.7 Hz), 4.83 (1H, d, J = 8.1 Hz) ), 6.61 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide As in Example 20. N- (3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide obtained in Example 161 was used. The title compound was synthesized. Yield 65%. Melting point 134-140 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.99 (3H, s), 2.29 (2H, s), 2.55 (3H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.16 (1H, dd, J = 11.4, 1.8 Hz), 3.83 (1H, dd, J = 11.4, 9.0 Hz), 4.64 (1H, d, J = 9.0 Hz ), 6.64 (1H, br s), 7.00 (2H, d, J = 8.1 Hz), 7.09 (2H, d, J = 8.1 Hz), 10.5 (1H, s).

N- (7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide methylmagnesium bromide (1.0 M , THF solution, 10 mL, 10 mmol), N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien- 5-yl) -3,3-dimethylbutanamide (600 mg, 1.42 mmol) was added at 0 ° C., and then the reaction solution was stirred at room temperature for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Triethylsilane (1.0 mL) was added to a mixture of the obtained residue trifluoroacetic acid (3 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, the aqueous layer was made alkaline, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 345 mg (yield 57%) of the title compound. Melting point 172-173 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.18 (3H, t, J = 7.8 Hz), 1.21 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.20 ( 3H, s), 2.26 (2H, s), 2.66 (2H, q, J = 7.8 Hz), 2.85 (1H, septet, J = 6.9 Hz), 3.12 (1H, dd, J = 11.4, 1.8 Hz), 3.87 (1H, dd, J = 11.4, 8.7 Hz), 4.69 (1H, d, J = 8.7 Hz), 6.51 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7-propyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide As in Example 164. N- (7-formyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethyl obtained in Example 163 The title compound was synthesized using butanamide and ethylmagnesium bromide. Yield 22%. Melting point 159-160 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.5 Hz), 1.12 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.50-1.70 (2H, m), 1.89 (3H, s), 2.18 (3H, s), 2.26 (2H, s), 2.61 (2H, t, J = 6.9 Hz), 2.85 (1H, septet, J = 6.9 Hz), 3.11 (1H, d , J = 14.4 Hz), 3.86 (1H, dd, J = 14.4, 8.4 Hz), 4.69 (1H, dd, J = 8.4 Hz), 6.53 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide As in Example 38. N- (3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide obtained in Example 161 was used. The title compound was synthesized. Yield 69%. Melting point 218-219 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.94 (3H, s), 2.20 (3H, s), 2.27 (2H, s), 2.57 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.15 (1H, dd, J = 11.1, 1.8 Hz), 3.87 (1H, dd, J = 11.1, 8.4 Hz), 4.66 (1H , d, J = 8.4 Hz), 6.63 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

N- (7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-1-oxide-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide Examples N- (7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide (225) m-Chloroperbenzoic acid (124 mg, 0.716 mmol) was added to a methylene chloride (10 mL) mixture of mg, 0.512 mmol) and sodium bicarbonate (65 mg, 1.01 mmol) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. . An aqueous sodium hydrogen sulfite solution was added, and the organic layer was separated. The aqueous layer was extracted with methylene chloride, and the combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 3: 1) to obtain 50 mg (yield 22%) of the title compound. Melting point 195-196 ° C. (diethyl ether-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.18 (3H, t, J = 7.8 Hz), 1.21 (6H, d, J = 6.9 Hz), 1.72 (3H, s), 2.18 ( 3H, s), 2.26 (1H, d, J = 13.2 Hz), 2.32 (1H, d, J = 13.2 Hz), 2.87-2.98 (2H, m), 3.04-3.17 (1H, m), 3.26 (1H , dd, J = 14.4, 7.2 Hz), 3.55 (1H, dd, J = 13.8, 7.2 Hz), 5.10 (1H, d, J = 6.6 Hz), 6.90 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.82 (1H, br s).

N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-1-oxide-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide Examples N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide (960) m-Chloroperbenzoic acid (530 mg, 3.07 mmol) was added to a methylene chloride (20 mL) mixture of mg, 2.19 mmol) and sodium bicarbonate (276 mg, 3.29 mmol) at 0 ° C., and the mixture was stirred at room temperature for 2 hours. . An aqueous sodium hydrogen sulfite solution was added, and the organic layer was separated. The aqueous phase was extracted with methylene chloride, and the combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 123 mg (yield 12%) of the title compound as a low polar substance. Melting point 214-216 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.98 (3H, s), 2.20 (3H, s), 2.29 (2H, s), 2.71 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.15 (1H, dd, J = 14.4, 2.1 Hz), 3.70 (1H, dd, J = 14.4, 8.7 Hz), 4.72 (1H , d, J = 8.7 Hz), 6.81 (1H, br s), 7.12 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz).

N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-1-oxide-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide Examples The residue operated in the same manner as in 168 was purified by silica gel column chromatography (ethyl acetate) to obtain 274 mg (yield 28%) of the title compound as a highly polar substance. Melting point 214-215 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.84 (3H, s), 2.20 (3H, s), 2.30 (2H, s), 2.65 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.30-3.40 (1H, m), 3.56 (1H, dd, J = 13.2, 7.5 Hz), 5.07 (1H, d, J = 6.3 Hz), 6.90 (2H, d, J = 8.1 Hz), 7.13 (2H, d, J = 8.1 Hz), 7.56 (1H, br s).

N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-1,1-dioxide-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide N- (3- (4-Isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide (560 mg, obtained in Example 161) 1.41 mmol) and iron powder (5.2 mg, 0.094 mmol) in methylene chloride (10 mL) were mixed with bromine (225 mg, 1.41 mmol) at 0 ° C. and stirred at the same temperature for 1 hour. Water was poured into the reaction mixture and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. M-Chloroperbenzoic acid (161 mg, 1.01 mmol) was added to a methylene chloride (5 mL) mixture of the obtained residue and sodium hydrogen carbonate (150 mg, 1.79 mmol) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydrogen sulfite solution was added, and the organic layer was separated. The aqueous phase was extracted with methylene chloride, and the combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 3: 1) to obtain 393 mg (yield 55%) of the title compound. Melting point 211-213 [deg.] C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.86 (3H, s), 2.28 (2H, s), 2.36 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.47 (1H, dd, J = 13.8, 2.4 Hz), 3.95 (1H, dd, J = 13.8, 9.6 Hz), 4.65 (1H, d, J = 9.6 Hz) ), 7.00 (2H, d, J = 8.1 Hz), 7.07 (1H, br s), 7.12 (2H, d, J = 8.1 Hz).

N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-1,1-dioxide-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-1-oxide-2,3-dihydro-1-benzothien-5-yl) -3 synthesized in Examples 168 and 169 , 3-Dimethylbutanamide diastereomeric mixture (540 mg, 1.19 mmol) and sodium hydrogen carbonate (150 mg, 1.79 mmol) in methylene chloride (5 mL) at 0 ° C. with m-chloroperbenzoic acid (287 mg, 1.67 mmol) was added and stirred at room temperature for 2 hours. An aqueous sodium hydrogen sulfite solution was added, and the organic layer was separated. The aqueous layer was extracted with methylene chloride, and the combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 320 mg (yield 57%) of the title compound. Melting point 184-186 ° C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.07 (3H, s), 2.32 (2H, s), 2.68 (3H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.42 (1H, dd, J = 14.4, 2.4 Hz), 3.86 (1H, dd, J = 14.4, 9.3 Hz), 4.71 (1H , dd, J = 9.3, 2.4 Hz), 7.00-7.21 (5H, m).

N- (7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-1,1-dioxide-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide N- (7-ethyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl) -3,3-dimethylbutanamide synthesized in Example 164 M-chloroperbenzoic acid (283 mg, 1.65 mmol) was added to a mixture of methylene chloride (20 mL) of (225 mg, 0.512 mmol) and sodium bicarbonate (250 mg, 0.590 mmol) at 0 ° C., and 2 hours at room temperature. Stir. An aqueous sodium hydrogen sulfite solution was added, and the organic layer was separated. The aqueous layer was extracted with methylene chloride, and the combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 74 mg (yield 28%) of the title compound. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.29 (3H, t, J = 7.2 Hz), 1.86 (3H, s), 2.25 ( 3H, s), 2.27 (2H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.07 (2H, q, J = 7.8 Hz), 3.12 (1H, d, J = 13.5 Hz), 3.87 ( 1H, dd, J = 13.5, 9.6 Hz), 4.66 (1H, d, J = 8.7 Hz), 6.86 (1H, br s), 7.01 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz).

N- (3- (3-formylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide N- obtained in Example 73 (3- (3- (1,3-Dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (910 mg, 2.15 mmol), a mixture of pyridinium p-toluenesulfonic acid (25 mg) in acetone (20 mL) -water (1.5 mL) was heated to reflux for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound 784 mg (yield 96%). Melting point 178-179 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.83 (3H, s), 2.16 (3H, s), 2.21 (3H, s), 2.25 (2H, s), 4.41 (1H, dd , J = 4.5, 9.0 Hz), 4.64 (1H, dd, J = 4.5, 9.0 Hz), 4.87 (1H, t, J = 9.0 Hz), 6.52 (1H, br s), 7.39-7.48 (2H, m ), 7.66 (1H, s), 7.72-7.76 (1H, m), 9.97 (1H, s).

N- (3- (4-formylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 173, N- (3- (4- (1,3-dioxolan-2-yl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) obtained in Example 82 The title compound was synthesized using -3,3-dimethylbutanamide. Yield 95%. Melting point 195-196 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.83 (3H, s), 2.16 (3H, s), 2.19 (3H, s), 2.25 (2H, s), 6.51 (1H, br s), 7.31 (2H, d, J = 8.4 Hz), 7.80 (2H, d, J = 8.4 Hz), 9.97 (1H, s).

N- (3- (4- (1-hydroxyethyl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Example 22 In the same manner as described above, N- (3- (4-formylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- The title compound was synthesized using dimethylbutanamide and methylmagnesium bromide. Yield 93%. Melting point 144-145 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.47 (3H, d, J = 6.3 Hz), 1.78 (1H, br s), 1.83 (3H, s), 2.15 (3H, s) , 2.17 (3H, s), 2.24 (2H, s), 4.39 (1H, dd, J = 4.5, 9.0 Hz), 4.54 (1H, dd, J = 4.5, 9.0 Hz), 4.79-4.90 (2H, m ), 6.50 (1H, br s), 7.10 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz).

N- (3- (4-acetylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 32, N- (3- (4- (1-hydroxyethyl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- obtained in Example 175 The title compound was synthesized using dimethylbutanamide. Yield 65%. MP 181-182 ° C (THF-diisopropyl ether).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.82 (3H, s), 2.16 (3H, s), 2.19 (3H, s), 2.25 (2H, s), 2.57 (3H, s ), 4.40 (1H, dd, J = 4.5, 9.0 Hz), 4.61 (1H, dd, J = 4.5, 9.0 Hz), 4.86 (1H, t, J = 9.0 Hz), 6.51 (1H, br s), 7.23 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.4 Hz).

(2E) -3- (3- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) phenyl) acrylic Ethyl acid Sodium hydride (60% liquid paraffin dispersion, 79 mg, 1.98 mmol) in DMF (10 mL) was added ethyl diethylphosphonoacetate (444 mg, 1.98 mmol) dropwise at 0 ° C. under an argon atmosphere. Stir for 30 minutes. N- (3- (3-formylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane obtained in Example 173 was used as a reaction solution. A solution of amide (684 mg, 1.80 mmol) in DMF (5 mL) was added dropwise at 0 ° C. and stirred for 30 minutes. The reaction solution was warmed to room temperature, added to water, and extracted with ethyl acetate-THF. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (750 mg, yield 93%). Melting point 199-200 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.33 (3H, t, J = 7.5 Hz), 1.83 (3H, s), 2.16 (3H, s), 2.19 (3H, s), 2.25 (2H, s), 4.27 (2H, q, J = 7.5 Hz), 4.39 (1H, dd, J = 4.5, 9.0 Hz), 4.54 (1H, dd, J = 4.5, 9.0 Hz), 4.84 (1H , t, J = 9.0 Hz), 6.38 (1H, d, J = 15.3 Hz), 6.50 (1H, br s), 7.14 (1H, d, J = 7.5 Hz), 7.24-7.31 (2H, m), 7.37 (1H, d, J = 7.5 Hz), 7.61 (1H, d, J = 15.3 Hz).

(2E) -3- (4- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) phenyl) acrylic Ethyl acid In the same manner as in Example 177, N- (3- (4-formylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) obtained in Example 174 The title compound was synthesized using -3,3-dimethylbutanamide. Yield 81%. Melting point 176-177 ° C (ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.33 (3H, t, J = 6.9 Hz), 1.84 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 4.26 (2H, q, J = 6.9 Hz), 4.40 (1H, dd, J = 4.5, 9.0 Hz), 4.57 (1H, dd, J = 4.5, 9.0 Hz), 4.84 (1H , t, J = 9.0 Hz), 6.38 (1H, d, J = 13.8 Hz), 6.51 (1H, br s), 7.15 (2H, d, J = 8.1 Hz), 7.43 (2H, d, J = 8.1 Hz), 7.64 (1H, d, J = 13.8 Hz).

(2E) -3- (4- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) phenyl) buta Ethyl-2-enoate In the same manner as in Example 177, N- (3- (4-acetylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran- obtained in Example 176 The title compound was obtained using 5-yl) -3,3-dimethylbutanamide. Yield 75%. Melting point 179-180 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.31 (3H, t, J = 7.2 Hz), 1.84 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 2.54 (3H, s), 4.20 (2H, q, J = 7.2 Hz), 4.40 (1H, dd, J = 4.5, 9.0 Hz), 4.56 (1H, dd, J = 4.5, 9.0 Hz), 4.84 (1H, t, J = 9.0 Hz), 6.09 (1H, s), 6.49 (1H, s), 7.12 (2H, d, J = 8.4 Hz), 7.37 (2H, d, J = 8.4 Hz).

Ethyl 3- (3- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) phenyl) propanoate (2E) -3- (3- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl obtained in 177 ) Phenyl) ethyl acrylate (400 mg, 0.89 mmol) and 10% -palladium carbon (50% water content, 40 mg) in ethanol (3 mL) -ethyl acetate (5 mL) Stir for hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (326 mg, yield 81%). Melting point 136-138 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (3H, t, J = 7.2 Hz), 1.82 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 2.57 (2H, t, J = 7.8 Hz), 2.89 (2H, t, J = 7.8 Hz), 4.27 (2H, q, J = 7.5 Hz), 4.39 (1H, dd, J = 4.5, 9.0 Hz), 4.54 (1H, dd, J = 4.5, 9.0 Hz), 4.84 (1H, t, J = 9.0 Hz), 6.50 (1H, br s), 7.14 (1H, d, J = 7.5 Hz), 7.24-7.31 (1H, t, J = 7.5 Hz), 7.37 (1H, d, J = 7.5 Hz), 7.61 (1H, d, J = 15.3 Hz).

Ethyl 3- (4- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) phenyl) propanoate (2E) -3- (4- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro) obtained in Example 178 in the same manner as in 180. The title compound was synthesized using ethyl -1-benzofuran-3-yl) phenyl) acrylate. Yield 84%. Melting point 103-105 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (3H, t, J = 6.9 Hz), 1.82 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.58 (2H, t, J = 7.8 Hz), 2.90 (2H, t, J = 7.8 Hz), 4.11 (2H, q, J = 6.9 Hz), 4.38 (1H, dd, J = 4.8, 9.0 Hz), 4.51 (1H, dd, J = 4.8, 9.0 Hz), 4.81 (1H, t, J = 9.0 Hz), 6.49 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.09 (2H, d, J = 8.1 Hz).

Ethyl 3- (4- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) phenyl) butanoate In the same manner as in 180, (2E) -3- (4- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro obtained in Example 179 was used. The title compound was synthesized using ethyl -1-benzofuran-3-yl) phenyl) but-2-enoate. Yield 76%. Melting point 100-101 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.17 (3H, t, J = 7.2 Hz), 1.26 (3H, d, J = 6.6 Hz), 1.83 (3H, s), 2.15 ( 3H, s), 2.17 (3H, s), 2.25 (2H, s), 2.44-2.60 (2H, m), 3.18-3.30 (1H, m), 4.11 (2H, q, J = 7.2 Hz), 4.39 (1H, dd, J = 4.8, 9.0 Hz), 4.52 (1H, dd, J = 4.8, 9.0 Hz), 4.81 (1H, t, J = 9.0 Hz), 6.49 (1H, br s), 7.05 (2H , d, J = 8.4 Hz), 7.11 (2H, d, J = 8.4 Hz).

N- (3- (4-Acetyl-3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In Example 72 Obtained N- (3- (3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (1.0 g, 2.62 mmol) ) In methylene chloride (20 mL) was added aluminum chloride (769 mg, 5.77 mmol) at −50 ° C. under an argon atmosphere. After stirring for 10 minutes, acetyl chloride (0.62 mL, 8.65 mmol) was added dropwise at the same temperature, and the temperature was gradually raised to room temperature. The reaction mixture was added to ice and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 993 mg (yield 89%) of the title compound. Melting point 131-133 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.84 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.26 (2H, s), 2.58 (3H, s ), 3.84 (3H, s), 4.39 (1H, dd, J = 4.8, 9.0 Hz), 4.58 (1H, dd, J = 4.8, 9.0 Hz), 4.85 (1H, t, J = 9.0 Hz), 6.54 (1H, br s), 6.72 (1H, s), 6.76 (1H, d, J = 8.1 Hz), 7.65 (1H, d, J = 8.1 Hz).

N- (3- (4-Isopropenyl-3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide potassium tert- Methyltriphenylphosphonium iodide (2.94 g, 7.29 mmol) was added to a solution of butoxide (818 mg, 7.29 mmol) in toluene (45 mL), and the mixture was stirred at 120 ° C. for 1 hour under an argon atmosphere. N- (3- (4-acetyl-3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 183 was added to the reaction solution. 3-Dimethylbutanamide (2.32 g, 5.48 mmol) was added and stirred at 120 ° C. for 2 hours. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane 2: 3) to obtain 1.93 g (yield 84%) of the title compound. )Obtained. Melting point 186-187 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.87 (3H, s), 2.08 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.26 (2H, s ), 3.76 (3H, s), 4.42 (1H, dd, J = 4.8, 9.0 Hz), 4.54 (1H, dd, J = 4.8, 9.0 Hz), 4.83 (1H, t, J = 9.0 Hz), 5.03 (1H, s), 5.11 (1H, s), 6.51 (1H, br s), 6.64-6.67 (2H, m), 7.60 (1H, d, J = 7.5 Hz).

N- (3- (4-Isopropyl-3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In Example 184 N- (3- (4-Isopropenyl-3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide ( 1.93 g, 4.58 mmol) and 10% -palladium carbon (containing 50% water, 193 mg) in ethanol (10 mL) were stirred in a hydrogen atmosphere at room temperature for 2 hours. After filtering the catalyst, the filtrate was concentrated to obtain 1.80 g (yield 93%) of the title compound. Melting point 170-171 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.17 (6H, d, J = 6.9 Hz), 1.86 (3H, s), 2.04 (3H, s), 2.14 (3H, s), 2.25 (2H, s), 3.24 (1H, septet, J = 6.9 Hz), 3.75 (3H, s), 4.42 (1H, dd, J = 5.1, 9.0 Hz), 4.52 (1H, dd, J = 5.1, 9.0 Hz), 4.85 (1H, t, J = 9.0 Hz), 6.50 (1H, br s), 6.61 (1H, s), 6.66 (1H, d, J = 8.1 Hz) 7.60 (1H, d, J = 8.1 Hz).

N- (3- (3-Hydroxy-4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In Example 185 N- (3- (4-Isopropyl-3-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (500 To a methylene chloride (5 mL) solution of mg, 1.18 mmol), boron tribromide (1.0 M, methylene chloride solution, 2.36 mL, 2.36 mmol) was added dropwise at −70 ° C. in an argon atmosphere, and the temperature was gradually raised to room temperature. Warm up. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 465 mg (yield 96%) of the title compound. Mp 220-221 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.17 (6H, d, J = 6.9 Hz), 1.81 (3H, s), 2.09 (3H, s), 2.12 (3H, s), 2.24 (2H, s), 3.15 (1H, septet, J = 6.9 Hz), 4.30-4.45 (2H, m), 4.74 (1H, t, J = 9.0 Hz), 6.42 (1H, br s), 6.61 ( 1H, d, J = 8.1 Hz), 6.87 (1H, br s), 7.03 (1H, d, J = 8.1 Hz), 1H not confirmed.

N- (2-hydroxy-4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 186 N- (4-Isopropyl-2-methoxyphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 74 was obtained. Used to synthesize the title compound. Yield 98%. Melting point 265-266 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.18 (6H, d, J = 6.9 Hz), 1.90 (3H, s), 2.15 (3H, s), 2.16 (3H, s), 2.27 (2H, s), 2.78 (1H, septet, J = 6.9 Hz), 4.42 (1H, dd, J = 9.9, 13.8 Hz), 4.75-4.85 (2H, m), 5.26 (1H, br), 6.53 (1H, br s), 6.62 (1H, s), 6.64 (1H, d, J = 8.1 Hz), 6.76 (1H, d, J = 8.1 Hz).

(5- (5-((3,3-Dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) -2-isopropylphenoxy) ethyl acetate N- (3- (3-Hydroxy-4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane obtained in Example 186 A mixture of amide (500 mg, 1.22 mmol), ethyl bromoacetate (245 mg, 1.47 mmol), potassium carbonate (253 mg, 1.83 mmol), and potassium iodide (10 mg) in acetone (10 mL) under an argon atmosphere For 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (548 mg, yield 91%). Melting point 149-150 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.84 (3H, s), 2.14 ( 3H, s), 2.17 (3H, s), 2.25 (2H, s), 3.34 (1H, septet, J = 6.9 Hz), 4.21 (2H, q, J = 7.2 Hz), 4.38 (1H, dd, J = 4.8, 9.0 Hz), 4.49 (1H, dd, J = 4.8, 9.0 Hz), 4.55 (2H, s), 4.80 (1H, t, J = 9.0 Hz), 6.47 (1H, s), 6.50 (1H , br s), 6.72 (1H, d, J = 7.8 Hz), 7.10 (1H, d, J = 7.8 Hz).

N-((3- (4-Isopropyl) -3- (2-oxopropoxy) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- Dimethylbutanamide In the same manner as in Example 188, N- (3- (3-hydroxy-4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Example 186 The title compound was obtained using -5-yl) -3,3-dimethylbutanamide and chloroacetone. Yield 82%. Melting point 133-135 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.26 (2H, s), 2.28 (3H, s), 3.34 (1H, septet, J = 6.9 Hz), 4.39 (1H, dd, J = 4.5, 9.0 Hz), 4.44 (2H, s), 4.50 (1H , dd, J = 4.5, 9.0 Hz), 4.81 (1H, t, J = 8.4 Hz), 6.39 (1H, s), 6.52 (1H, s), 6.76 (1H, d, J = 7.8 Hz), 7.14 (1H, d, J = 7.8 Hz).

( 2- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) -5-isopropylphenoxy) ethyl acetate In the same manner as in Example 188, N- (2-hydroxy-4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 187 , 3-Dimethylbutanamide was used to obtain the title compound. Yield 90%. Melting point 183-184 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.19 (6H, d, J = 6.9 Hz), 1.29 (3H, t, J = 7.2 Hz), 1.90 (3H, s), 2.16 ( 6H, s), 2.27 (2H, s), 2.82 (1H, septet, J = 6.9 Hz), 4.26 (2H, q, J = 7.2 Hz), 4.38 (1H, dd, J = 3.9, 9.0 Hz), 4.68 (2H, s), 4.83 (1H, t, J = 9.0 Hz), 4.97 (1H, dd, J = 3.9, 9.0 Hz), 6.53 (1H, br s), 6.58 (1H, s), 6.69 ( 2H, s).

N- ( 3- (4-Isopropyl-3- (2-methoxyethoxy) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl))-3,3-dimethyl Butanamide N- (3- (3-hydroxy-4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3 obtained in Example 186 -Mixing acetonitrile (5 mL) of dimethylbutanamide (200 mg, 0.49 mmol), 2-bromoethyl methyl ether (0.069 mL, 0.49 mmol), potassium carbonate (135 mg, 0.98 mmol), potassium iodide (10 mg) The solution was heated under an argon atmosphere for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate-hexane 2: 3) to obtain 176 mg (yield 77%) of the title compound. Melting point 155-156 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.18 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.25 (2H, s), 3.28 (1H, septet, J = 6.9 Hz), 3.44 (3H, s), 3.70-3.77 (2H, m), 4.02-4.06 (2H, m), 4.41 (1H, dd, J = 4.8, 8.7 Hz), 4.51 (1H, dd, J = 4.8, 8.7 Hz), 4.82 (1H, t, J = 8.7 Hz), 6.49 (1H, br s), 6.60 (1H, s), 6.69 (1H, d, J = 7.8 Hz), 7.08 (1H, d, J = 7.8 Hz).

N-((4-Isopropyl-2- (2-methoxyethoxy) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl ) -3,3-dimethylbutanamide In the same manner as in Example 191, N- (2-hydroxy-4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 187 , 3-Dimethylbutanamide was used to synthesize the title compound. Yield 59%. Melting point 119-120 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.88 (3H, s), 2.15 (6H, s), 2.27 (2H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.45 (3H, s), 3.70-3.78 (2H, m), 4.14-4.18 (2H, m), 4.36 (1H, dd, J = 4.2, 8.7 Hz) , 4.83 (1H, t, J = 8.7 Hz), 4.91 (1H, dd, J = 4.2, 8.7 Hz), 6.55 (1H, br s), 6.65-6.75 (3H, m).

N- (3- (3- (2-hydroxyethoxy) -4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane Amide (5- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) -2 obtained in Example 188 -Lithium borohydride (43 mg, 2.00 mmol) was added to a solution of ethyl isopropylphenoxy) ethyl acetate (200 mg, 0.49 mmol) in THF (5 mL) under ice cooling. The reaction was warmed to room temperature and stirred for 60 hours. The reaction solution was added to ice, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (157 mg, yield 71%). Melting point 155-156 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.18 (6H, d, J = 6.9 Hz), 1.86 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.26 (2H, s), 3.25 (1H, septet, J = 6.9 Hz), 3.80-3.93 (2H, m), 4.00-4.04 (2H, m), 4.40 (1H, dd, J = 4.8, 9.0 Hz) , 4.50-4.58 (1H, m), 4.82 (1H, t, J = 9.0 Hz), 6.54 (1H, br s), 6.58 (1H, s), 6.73 (1H, d, J = 8.1 Hz), 7.10 (1H, d, J = 8.1 Hz) 1H not confirmed.

N- (3- (3- (3-hydroxypropyl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Example 193 3- (3- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3 obtained in Example 180 The title compound was synthesized using -yl) phenyl) ethyl propanoate. Yield 95%. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.79 (3H, s), 1.79-1.92 (2H, m), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H , s), 2.57-2.70 (2H, m), 3.53 (2H, br), 4.39 (1H, dd, J = 5.1, 9.0 Hz), 4.57 (1H, dd, J = 5.1, 9.0 Hz), 4.86 ( 1H, t, J = 9.0 Hz), 6.56 (1H, br s), 6.91 (1H, br s), 6.99-7.05 (2H, m), 7.23 (1H, t, J = 7.8 Hz), 1H not confirmed.

N- (3- (4- (3-hydroxypropyl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Example 193 In the same manner as described above, 3- (4- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran- obtained in Example 181 was used. The title compound was synthesized using ethyl 3-yl) phenyl) propanoate. Yield 77%. Melting point 119-120 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.80-1.90 (5H, m), 2.14 (3H, s), 2.17 (3H, s), 2.24 (2H, s), 2.65 (2H , t, J = 7.8 Hz), 3.64 (2H, t, J = 7.8 Hz), 4.39 (1H, dd, J = 4.8, 9.0 Hz), 4.52 (1H, dd, J = 4.8, 9.0 Hz), 4.82 (1H, t, J = 9.0 Hz), 6.56 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz), 1H not confirmed.

N- (3- (4- (3-hydroxy-1-methylpropyl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane Amide In the same manner as in Example 193, 3- (4- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro- obtained in Example 182 was used. The title compound was synthesized using ethyl 1-benzofuran-3-yl) phenyl) butanoate. Yield 85%. Melting point 145-147 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.24 (3H, d, J = 7.2 Hz), 1.76-1.90 (2H, m), 1.84 (3H, s), 2.15 (3H, s ), 2.18 (3H, s), 2.25 (2H, s), 2.80-2.90 (1H, m), 3.54 (2H, br), 4.41 (1H, dd, J = 4.8, 9.0 Hz), 4.52 (1H, dd, J = 4.8, 9.0 Hz), 4.82 (1H, t, J = 9.0 Hz), 6.49 (1H, br s), 7.05 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz). 1H unconfirmed.

N-((4-Isopropyl-2- (2-hydroxyethoxy) -4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl))-3,3 -Dimethylbutanamide In the same manner as in Example 193, 2- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro- obtained in Example 190 was used. The title compound was synthesized using 1-benzofuran-3-yl) -5-isopropylphenoxy) ethyl acetate. Yield 79%. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.87 (3H, s), 2.14 (3H, s), 2.18 (3H, s), 2.24 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.70-3.78 (2H, m), 3.93-4.00 (2H, m), 4.54 (1H, dd, J = 4.5, 8.1 Hz) , 4.66 (1H, dd, J = 4.5, 8.1 Hz), 4.80 (1H, t, J = 8.1 Hz), 6.49 (1H, br s), 6.66 (1H, s), 6.74 (1H, d, J = 7.8 Hz), 7.01 (1H, d, J = 7.8 Hz), 1H not confirmed.

3- (4- (5-((3,3-Dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) phenyl) butanoic acid Example 182 3- (4- (5-((3,3-dimethylbutanoyl) amino) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl) phenyl) butanoic acid obtained in Ethyl (150 mg, 0.32 mmol), 1N aqueous sodium hydroxide solution (2 mL) in THF (3 mL) -methanol (3 mL) were stirred at room temperature for 16 hours. The reaction solution was acidified with hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 107 mg (yield 74%) of the title compound. Melting point 209-210 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.28 (3H, d, J = 6.9 Hz), 1.81 (3H, s), 2.14 (3H, s), 2.17 (3H, s), 2.24 (2H, s), 2.48-2.62 (2H, m), 3.15-3.26 (1H, m), 4.38-4.42 (1H, m), 4.51 (1H, dd, J = 4.2, 8.7 Hz), 4.81 ( 1H, t, J = 8.7 Hz), 6.53 (1H, br s), 7.05 (2H, d, J = 7.8 Hz), 7.10 (2H, d, J = 7.8 Hz), 1H not confirmed.

N- (3- (4- (1-hydroxy-1-methylethyl) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane Amide In the same manner as in Example 22, N- (3- (4-acetylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 176 The title compound was synthesized using 3,3-dimethylbutanamide and methylmagnesium bromide. Yield 42%. Melting point 132-134 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.55 (6H, s), 1.73 (1H, br s), 1.84 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.25 (2H, s), 4.41 (1H, dd, J = 4.8, 9.0 Hz), 4.54 (1H, dd, J = 4.8, 9.0 Hz), 4.82 (1H, t, J = 9.0 Hz), 6.53 (1H, br s), 7.10 (2H, d, J = 8.1 Hz), 7.38 (2H, d, J = 8.1 Hz).

4,4,4-trifluoro-N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in Reference Example 30 3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine (200 mg, 0.68 mmol), 4,4,4-trifluorobutanoic acid (116 mg, 0.82 mmol), N-hydroxybenzotriazole (111 mg, 0.82 mmol), (3- (dimethylamino) propyl) ethylcarbodiimide hydrochloride (196 mg, 1.02 mmol), N, N-dimethylaminopyridine (25 mg) , 0.2 mmol) in DMF (5 mL) was stirred for 14 hours at room temperature. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate-hexane 3: 7) to obtain 194 mg (yield 68%) of the title compound. Melting point 206-207 ° C. (THF-diisopropyl ether).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.81 (3H, s), 1.96-2.35 (8H, m), 2.38-2.62 (2H, m), 2.86 (1H , septet, J = 6.9 Hz), 4.42 (1H, dd, J = 4.8, 9.0 Hz), 4.52 (1H, dd, J = 4.8, 9.0 Hz), 4.86 (1H, t, J = 9.0 Hz), 6.61 (1H, s), 7.00-7.05 (2H, m), 7.11-7.15 (2H, m).

N ^1- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -N ² , N ² -dimethylglycinamide Same as Example 200 Using 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine and N, N-dimethylglycine obtained in Reference Example 30, The compound was synthesized. Yield 40%. Melting point 95-96 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.84 (3H, s), 2.13 (3H, s), 2.18 (3H, s), 2.40 (6H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.11 (2H, s), 4.42 (1H, dd, J = 4.5, 9.0 Hz), 4.53 (1H, dd, J = 4.5, 9.0 Hz), 4.83 (1H , t, J = 9.0 Hz), 7.05 (2H, d, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz), 8.45 (1H, br s).

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -2,2-dimethylpropanamide In the same manner as in Example 1, The title compound was synthesized using 3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 30 and pivaloyl chloride. Yield 76%. Melting point 177-178 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 1.31 (9H, s), 1.80 (3H, s), 2. 09 (3H, s), 2.17 (3H, s ), 2.85 (1H, septet, J = 6.9 Hz), 4.38-4.43 (1H, m), 4.48-4.54 (1H, m), 4.81 (1H, t, J = 8.8 Hz), 6.75 (1H, br) , 7. 03 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide obtained in Example 58 in a manner analogous to Example 38. The title compound was obtained using N- (3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) formamide and acetyl chloride. Yield 48%. Melting point 177-179 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, m), 1.88 and 1.94 (3H), 2.25 and 2.28 (3H), 2.59 and 2.61 (3H), 2.81-2.85 (1H, m), 4.43-4.58 (2H, m), 4.88-4.98 (1H, m), 6.63 and 6.66 (1H), 7.01-7.05 (2H, m), 7.13-7.18 (2H, m), 7.92 and 8.39 (1H).

N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -N ′-(tert-butyl) urea in Reference Example 344 The obtained 7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine (711 mg, 2.2 mmol) was converted to N, N-dimethylacetamide ( After dissolution in 10 mL), tert-butyl isocyanate (0.30 mL, 2.64 mmol) was added at room temperature and heated to 60 ° C. After heating for 16 hours, tert-butyl isocyanate (0.30 mL, 2.64 mmol) was further added, and the mixture was stirred at 60 ° C. for 24 hours. The reaction solution was cooled to room temperature, poured into water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 1: 1) to obtain 70 mg (yield 12%) of the title compound. Melting point 207-208 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.18 (15H, m), 1.92 (3H, s), 2.29 (3H, s), 2.61 (3H, s), 2.88 (1H, septet, J = 7.0 Hz ), 3.98 (1H, br), 4.50-4.59 (2H, m), 4.90-4.98 (1H, m), 5.28 (1H, br), 7.00 (2H, d, J = 8.2 Hz), 7.15 (2H, d, J = 8.2 Hz)

N- (Cyclohexyl) -N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) urea As in Example 143, (3- (4-Isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl and cyclohexyl obtained in Example 138 The title compound was obtained using an amine. Yield 92%. Melting point 210-211 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.78-1.17 (3H, m), 1.21 (6H, d, J = 6.9 Hz), 1.21-1.38 (2H, m), 1.50-1.67 (3H, m), 1.78 -1.88 (4H, m), 2.14-2.20 (7H, m), 2.86 (1H, septet, J = 6.9 Hz), 3.61 (1H, br), 3.98 (1H, br), 4.42-4.47 (1H, m ), 4.51-4.57 (1H, m), 4.86 (1H, t, J = 9.0 Hz), 5.42 (1H, s), 6.99 (2H, d, J = 8.2 Hz), 7.12 (2H, d, J = 8.2 Hz).

(7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2,2-trichloroethyl As in Example 138. 7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 344 and 2,2,2-trichlorochloroformate The title compound was obtained using ethyl. Yield 91%. Melting point 186-189 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.93 (3H, s), 2.28 (3H, s), 2.60 (3H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.47-4.59 (2H, m), 4.75-4.96 (3H, m), 6.16 (1H, s), 7.03 (2H, d, J = 8.0 Hz), 7.15 (2H, d, J = 8.0 Hz)

N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -N ′-(3-hydroxypropyl) urea Example 143 In the same manner as described above, (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2 obtained in Example 206 , 2-Trichloroethyl and 3-hydroxypropylamine were used to give the title compound. Yield 59%.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.57 (2H, br), 1.93 (3H, s), 2.28 (3H, s), 2.61 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.33 (2H, br), 3.58 (2H, br), 4.50-4.59 (3H, m), 4.92 (1H, t, J = 10.3 Hz), 5.52 (1H , br), 7.02 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J = 8.1 Hz)

N- (tert-butyl) -N ′-(3- (4-isopropylphenyl) -7- (1-hydroxyethyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) Urea N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -N ′-(tert To a solution of (butyl) urea (718 mg, 1.7 mmol) in methanol (10 mL), sodium borohydride (64.3 mg, 1.7 mmol) was added at 0 ° C. and stirred for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 1: 1) to obtain 115 mg (yield 16%) of the highly polar title compound among the two isomers. Mp 212-214 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.20-1.27 (15H, m), 1.52-1.58 (3H, m), 1.89 (3H, s), 2.23 (3H, s), 2.87 (1H, septet, J = 7.0 Hz), 3.57 (1H, br), 4.03 (1H, br), 4.47-4.57 (2H, m), 4.88-4.97 (1H, m), 5.01-5.08 (1H, m), 5.26 (1H, br ), 6.98 (2H, d, J = 8.2 Hz), 7.13 (2H, d, J = 8.2 Hz)

N- (tert-butyl) -N ′-(3- (4-isopropylphenyl) -7-ethyl-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) urea Example 23 Similarly, N- (tert-butyl) -N ′-(3- (4-isopropylphenyl) -7- (1-hydroxyethyl) -4,6-dimethyl-2,3- The title compound was obtained using dihydro-1-benzofuran-5-yl) urea. Yield 53%. Melting point 207-209 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12-1.30 (18H, m), 1.87 (3H, s), 2.22 (3H, s), 2.61-2.72 (2H, m), 2.86 (1H, septet, J = 6.9 Hz), 4.00 (1H, br), 4.42-4.46 (1H, m), 4.50-4.56 (1H, m), 4.86 (1H, t, J = 9.0 Hz), 5.28 (1H, br), 6.98 ( 2H, d, J = 8.1 Hz), 7.11 (2H, d, J = 8.1 Hz).

N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -N ′-( 2 -hydroxyethyl) urea Example 143 In the same manner as described above, (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid 2,2 obtained in Example 206 , 2-Trichloroethyl and 2-hydroxyethylamine were used to give the title compound. Yield 66%.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6.9 Hz), 1.94 (3H, s), 2.29 (3H, s), 2.60 (3H, s), 2.80-2.97 (2H, m ), 3.32 (2H, br), 3.63 (2H, br), 4.49-4.57 (2H, m), 4.63 (1H, br), 4.92 (1H, t, J = 10.1 Hz), 5.63 (1H, br) , 7.01 (2H, d, J = 8.1 Hz), 7.15 (2H, d, J = 8.1 Hz).

N- (3- (4-Isopropylphenyl) -4,6-dimethyl-7- (3- (1-pyrrolidinyl) phenyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3- Dimethylbutanamide In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5 obtained in Example 35 was used. The title compound was obtained using -yl) -3,3-dimethylbutanamide and (3- (1-pyrrolidinyl) phenyl) boronic acid. Yield 17%. Melting point 206-207 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.24 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 1.95-2.04 (4H, m), 2.10 (3H, s ), 2.26 (2H, d, J = 1.4 Hz), 2.87 (1H, septet, J = 6.9 Hz), 3.23-3.33 (4H, m), 4.36 (1H, dd, J = 5.2, 8.7 Hz), 4.57 (1H, dd, J = 5.2, 9.2 Hz), 4.79 (1H, dd, J = 8.7, 9.2 Hz), 6.48-6.65 (4H, m), 7.11 (2H, d, J = 8.7 Hz), 7.15 ( 2H, d, J = 8.7 Hz), 7.27 (1H, t, J = 7.7 Hz).

N- (7- (4- (dimethylamino) phenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5 obtained in Example 35 was used. Yl) -3,3-dimethylbutanamide and (4- (dimethylamino) phenyl) boronic acid were used to give the title compound. Yield 17%. Melting point 180-181 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.23 (6H, d, J = 7.1 Hz), 1.92 (3H, s), 2.11 (3H, s), 2.27 (2H, d, J = 1.4 Hz), 2.87 (1H, septet, J = 7.0 Hz), 2.98 (6H, s), 4.38 (1H, dd, J = 4.9, 8.5 Hz), 4.55 (1H, dd, J = 4.9, 9.4 Hz) ), 4.79 (1H, dd, J = 8.5, 9.4 Hz), 6.50 (1H, s), 6.80 (2H, d, J = 7.7 Hz), 7.10 (2H, d, J = 8.6 Hz), 7.14 (2H , d, J = 8.6 Hz), 7.21 (2H, d, J = 7.7 Hz).

N- (7- (6- (dimethylamino) pyridin-3-yl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 , 3-Dimethylbutanamide In the same manner as in Example 107, N- (7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1- The title compound was obtained using benzofuran-5-yl) -3,3-dimethylbutanamide and (6- (dimethylamino) pyridin-3-yl) boronic acid. Yield 26%. Melting point 217-220 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.92 (3H, s), 2.12 (3H, s), 2.26 (2H, d, J = 1.4 Hz), 2.86 (1H, septet, J = 6.9 Hz), 3.12 (6H, s), 4.38 (1H, dd, J = 4.9, 8.8 Hz), 4.56 (1H, dd, J = 4.9, 9.4 Hz ), 4.79 (1H, dd, J = 8.8, 9.4 Hz), 6.53 (1H, s), 6.59 (1H, dd, J = 0.8, 8.8 Hz), 7.09 (2H, d, J = 8.4 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.47 (1H, dd, J = 2.3, 8.8 Hz), 8.15 (1H, dd, J = 0.8, 2.3 Hz).

N- (7- (4-Isopropylbenzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, The title compound was synthesized using 7- (4-isopropylbenzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 292. Yield 66%. Melting point 185-186 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.19 (6H, d, J = 6.9 Hz), 1.27 (3H, d, J = 6.9 Hz), 2.07 (3H, s), 2.27 ( 2H, s), 2.30 (3H, s), 2.80-2.90 (1H, septet, J = 6.9 Hz), 3.40-3.55 (1H, m), 3.93 (2H, m), 4.20 (1H, dd, J = 3.3, 8.7 Hz), 4.55 (1H, t, J = 8.7 Hz), 6.51 (1H, br s), 7.07 (4H, s).

N- (3-Ethyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 1. The title compound was synthesized using 3-ethyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 293. Yield 53%. Melting point 156-157 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.5 Hz), 1.13 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.50-1.61 (2H, m), 2.07 (3H, s), 2.16 (3H, s), 2.27 (2H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.24-3.33 (1H, m), 3.92 (2H, s), 4.37 (1H, dd, J = 3.0, 9.0 Hz), 4.48 (1H, t, J = 9.0 Hz), 6.50 (1H, br s), 7.06 (4H, s).

N- (7- (4-Isopropylbenzyl) -4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 1. The title compound was synthesized using 7- (4-isopropylbenzyl) -4,6-dimethyl-3-propyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 294. Yield 57%. Melting point 144-145 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.2 Hz), 1.13 (9H, s), 1.19 (6H, d, J = 6.9 Hz), 1.30-1.43 (2H, m ), 1.50-1.63 (2H, m), 2.06 (3H, s), 2.16 (3H, s), 2.26 (2H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.30-3.41 (1H, m), 3.92 (2H, s), 4.35 (1H, dd, J = 3.3, 9.0 Hz), 4.46 (1H, t, J = 8.7 Hz), 6.48 (1H, br s), 7.05 (4H, s) .

N- (3-Isopropyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 1. The title compound was synthesized using 3-isopropyl-7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 295. Yield 88%. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 0.73 (3H, d, J = 6.9 Hz), 0.99 (3H, d, J = 6.9 Hz), 1.19 (6H, d, J = 6.9 Hz), 2.06 (3H, s), 2.16 (3H, s), 2.26 (2H, s), 2.82 (1H, septet, J = 6.9 Hz), 3.31-3.36 (1H, m), 3.85 (1H, d, J = 15.6 Hz), 3.96 (1H, d, J = 15.6 Hz), 4.35 (1H, t, J = 9.0 Hz), 4.49 (1H, dd, J = 2.7, 9.0 Hz), 6.48 (1H, br s), 7.04 (4H, s).

N- (7- (4-Isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide In the same manner as in Example 1, 7- ( The title compound was synthesized using 4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine and n-butanoyl chloride. Yield 81%. Melting point 168-169 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.5 Hz), 1.20 (6H, d, J = 6.9 Hz), 1.72-1.89 (2H, m), 2.06 (3H, s), 2.10 (3H, s), 2.36 (2H, t, J = 7.5 Hz), 2.84 (1H, septet, J = 6.9 Hz), 3.15 (2H, t, J = 8.7 Hz), 3.92 (2H, s), 4.55 (2H, t, J = 8.7 Hz), 6.55 (1H, br s), 7.06 (4H, s).

N- (7- (4-Isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) propanamide 7- obtained in Reference Example 298 in the same manner as in Example 1. The title compound was synthesized using (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine and n-propanoyl chloride. Yield 78%. Melting point 177-178 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 1.29 (3H, t, J = 7.5 Hz), 2.06 (3H, s), 2.10 (3H, s), 2.41 ( 2H, q, J = 7.5 Hz), 2.78-2.88 (1H, septet, J = 6.9 Hz), 3.15 (2H, t, J = 8.7 Hz), 3.92 (2H, s), 4.56 (2H, t, J = 8.7 Hz), 6.56 (1H, br s), 6.99-7.10 (4H, m).

N- (7- (1- (4-Isopropylphenyl) vinyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) pentanamide In the same manner as in Example 1, Reference Example 298 The title compound was synthesized using 7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine and n-pentanoyl chloride obtained in 1 above. Yield 82%. Melting point 172-173 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, t, J = 7.5 Hz), 1.20 (6H, d, J = 6.9 Hz), 1.33-1.53 (2H, m), 1.69-1.79 (2H, m ), 2.06 (3H, s), 2.10 (3H, s), 2.39 (2H, t, J = 7.5 Hz), 2.78-2.88 (1H, septet, J = 6.9 Hz), 3.18 (2H, t, J = 8.4 Hz), 3.92 (2H, s), 4.56 (2H, t, J = 8.4 Hz), 6.54 (1H, br s), 7.01-7.13 (4H, m).

Tert-Butyl (4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamate 4,6-dimethyl-2,3- obtained in Reference Example 297 in the same manner as Reference Example 59 The title compound was synthesized using dihydro-1-benzofuran-5-amine. Yield 96%. Melting point 121-122 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, br), 2.14 (3H, s), 2.20 (3H, s), 3.09 (2H, t, J = 8.7 Hz), 4.54 (2H, t, J = 8.7 Hz), 5.73 (1H, br s), 6.50 (1H, s).

Tert-Butyl (7-bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamate The title compound was synthesized using tert-butyl -2,3-dihydro-1-benzofuran-5-yl) carbamate. Yield 93%. Melting point 176-177 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, br), 2.13 (3H, s), 2.32 (3H, s), 3.23 (2H, t, J = 8.4 Hz), 4.66 (2H, t, J = 8.4 Hz), 5.83 (1H, br s).

(7- (1-hydroxy-1- (4-isopropylphenyl) ethyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl Obtained in Example 222 (7-Bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl (500 mg, 1.46 mmol) and cerium chloride (360 mg, 3.21 mmol) in THF ( 8 mL) n-butyllithium (1.6 M hexane solution, 2.0 mL, 3.21 mmol) was added dropwise to the mixture at −78 ° C. under an argon atmosphere. After stirring at the same temperature for 30 minutes, a solution of 4-isopropylacetophenone (261 mg, 1.61 mmol) in THF (4 mL) was added dropwise to the reaction solution, stirred for 30 minutes, and then warmed to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 2: 3) to obtain 118 mg (yield 19%) of the title compound. Melting point 185-186 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 6.9 Hz), 1.46 (9H, br), 1.56 (3H, br s), 1.97 (3H, s), 2.15 (3H, s) , 2.87 (1H, septet, J = 6.9 Hz), 3.12 (2H, t, J = 8.7 Hz), 4.58 (2H, t, J = 8.7 Hz), 4.81 (1H, br s), 5.66 (1H, br s), 7.11 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz).

N- (7- (1- (4-Isopropylphenyl) ethyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide (7- (1- Hydroxy-1- (4-isopropylphenyl) ethyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl (120 mg, 0.28 mmol) in trifluoroacetic acid ( 1.5 mL) Triethylsilane (66 mg, 0.56 mmol) was added dropwise to the mixture and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and N- (7- (1- (4-isopropyl). Phenyl) ethyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) amine was obtained. To a THF (3 mL) solution of this compound and triethylamine (0.047 mL, 0.34 mmol), n-butanoyl chloride (0.034 mL, 0.34 mmol) was added dropwise under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 62 mg (yield 58%) of the title compound. Melting point 152-153 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.5 Hz), 1.21 (6H, d, J = 6.9 Hz), 1.66 (3H, d, J = 7.5 Hz), 1.71-1.89 ( 2H, m), 2.04 (3H, s), 2.09 (3H, s), 2.36 (2H, t, J = 7.5 Hz), 2.84 (1H, septet, J = 6.9 Hz), 3.09 (2H, t, J = 8.7 Hz), 4.43-4.60 (3H, m), 6.52 (1H, br s), 7.07 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz).

N- (7- (1- (4-Isopropylphenyl) ethyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 224 (7- (1-hydroxy-1- (4-isopropylphenyl) ethyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid obtained in Example 223 The title compound was synthesized using tert-butyl and tert-butylacetyl chloride. Yield 61%. Melting point 189-190 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.66 (3H, d, J = 7.2 Hz), 2.05 (3H, s), 2.11 ( 3H, s), 2.26 (2H, s), 2.84 (1H, septet, J = 6.9 Hz), 3.09 (2H, t, J = 8.7 Hz), 4.40-4.55 (3H, m), 6.47 (1H, br s), 7.07 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz).

N- (7- (1- (4-Isopropylphenyl) vinyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Same as Example 1 The title compound was obtained using (7- (1- (4-isopropylphenyl) vinyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) amine obtained in Reference Example 334. Was synthesized. Yield 51%. Melting point 188-189 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.99 (3H, s), 2.18 (3H, s), 2.28 (2H, s), 2.86 (1H, septet, J = 6.9 Hz), 3.15 (2H, t, J = 8.7 Hz), 4.51 (2H, t, J = 8.7 Hz), 5.14 (1H, s), 5.92 (1H, s), 6.53 (1H, br s), 7.10 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.1 Hz).

N- (tert-butyl) -N ′-(7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) urea In the same manner as in Example 47, The title compound was synthesized using 7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine and tert-butylamine obtained in Reference Example 298. Yield 83%. Melting point 197-198 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 1.24 (9H, s), 2.11 (3H, s), 2.16 (3H, s), 2.78-2.88 (1H, septet , J = 6.9 Hz), 3.17 (2H, t, J = 8.4 Hz), 3.94 (2H, s), 4.04 (1H, br s), 4.60 (2H, t, J = 8.4 Hz), 5.30 (1H, br s), 7.02 (2H, d, J = 8.1 Hz), 7.07 (2H, d, J = 8.1 Hz).

N- (2-hydroxyethyl) -N ′-(7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) urea In the same manner as in Example 47 The title compound was synthesized using 7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine and 2-hydroxyethylamine obtained in Reference Example 298. Yield 80%. Melting point 176-177 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.9 Hz), 2.14 (3H, s), 2.17 (3H, s), 2.78-2.88 (1H, septet, J = 6.9 Hz), 3.06 (1H, t, J = 4.5 Hz), 3.16 (2H, t, J = 8.4 Hz), 3.28-3.34 (2H, m), 3.60-3.66 (2H, m), 3.94 (2H, br s), 4.60 (2H, t, J = 8.4 Hz), 4.65 (1H, br s), 5.64 (1H, s), 7.07 (4H, s).

N- (7- (4-Isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide N-benzyl- obtained in Reference Example 338 N- (3-bromo-4-chloroethoxy-5- (4-isopropylbenzyl) -2,6-dimethylphenyl) -3,3-dimethylbutanamide (486 mg, 0.81 mmol) in THF (8 mL) N-Butyllithium (1.6 M hexane solution, 0.56 mL, 0.89 mmol) was added dropwise at −50 ° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. The reaction mixture was warmed to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4), and N-benzyl-N- (7- (4-isopropylbenzyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran. 186 mg (yield 47%) of -5-yl) -3,3-dimethylbutanamide was obtained. A mixed solution of this compound (186 mg, 0.38 mmol), 10% -palladium carbon (containing 50% water, 19 mg) in acetic acid (2 mL) was stirred at 85 ° C. for 14 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 60 mg (yield 40%) of the title compound. Melting point 201-202 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 2.08 (3H, s), 2.13 (3H, s), 2.27 (2H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.15 (2H, t, J = 5.7 Hz), 3.92 (2H, s), 4.56 (2H, t, J = 5.7 Hz), 6.51 (1H, br s) , 7.07 (4H, s).

N- (3-Hydroxymethyl-7- (4-isopropylbenzyl) -4,6-dimethylphenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In Reference Example 340 The obtained N- (4- (allyloxy) -3-bromo-5- (4-isopropylbenzyl) -2,6-dimethylphenyl) -3,3-dimethylbutanamide (674 mg, 1.39 mmol) in methylene chloride ( To the solution, m-chloroperbenzoic acid (239 mg, 1.39 mmol) was added to the solution under ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined organic layers were washed with 10% aqueous sodium sulfite solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and N- (3-bromo-5- (4-isopropylbenzyl) -2,6-dimethylphenyl- 4- (oxiran-2-ylmethoxy) -3,3-dimethylbutanamide was obtained, and a solution of this compound in THF (5 mL) was added with n-butyllithium (1.6 M hexane solution, 0.83) at −78 ° C. in an argon atmosphere. mL, 1.33 mmol) was added dropwise, and the reaction was stirred for 30 minutes.The reaction was warmed to room temperature, added to water, and extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to obtain 162 mg (yield 28%) of the title compound, mp 136-137 ° C. ( THF-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.07 (9H, s), 1.19 (6H, d, J = 6.9 Hz), 2.07 (3H, s), 2.17 (3H, s), 2.26 (2H, s), 2.82 (1H, septet, J = 6.9 Hz), 3.50-3.76 (3H, m), 3.92 (2H, s), 4.48 (1H, t, J = 9.0 Hz), 4.61 (1H, dd, J = 2.4, 9.0 Hz), 6.52 (1H, br s), 7.05 (4H, s), 1H not confirmed.

N- (4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide 4 obtained in Reference Example 358 in the same manner as in Example 1. , 6-Dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine was used to synthesize the title compound. Yield 97%. Melting point 158-159 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.85 (3H, s), 2.22 (3H, s), 2.24 (2H, s), 4.41 (1H, dd, J = 8.7, 4.8 Hz ), 4.53 (1H, dd, J = 9.3, 4.8 Hz), 4.85 (1H, t, J = 9.3 Hz), 6.45 (1H, br s), 6.63 (1H, s), 7.09-7.30 (5H, m ).

N- (7-formyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 20, Example 231 The title compound was synthesized using N- (4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in 1. Yield 74%. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.91 (3H, s), 2.27 (2H, s), 2.53 (3H, s), 4.53-4.62 (2H, m), 5.00 (1H , dd, J = 10.2 Hz), 6.45 (1H, br s), 7.13 (2H, d, J = 7.8 Hz), 7.20-7.35 (3H, m), 10.5 (1H, s).

N- (7- (4-Isopropylbenzyl) -4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide 4-isopropyl-1- A solution of bromobenzene (978 mg, 4.91 mmol) in THF (10 mL) was added dropwise to a mixture of magnesium (119 mg, 4.91 mmol) and a catalytic amount of iodine under an argon atmosphere, and the mixture was stirred at room temperature for 20 minutes. N- (7-formyl-4,6-dimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (200) obtained in Example 232 was added to the reaction solution. mg, 0.547 mmol) in THF (5 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to ice and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2), and N- (7- (hydroxy (4-isopropylphenyl) methyl) -4,6-dimethyl-3-phenyl-2, 3-Dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide was obtained. Triethylsilane (0.161 mL, 1.01 mmol) was added to a mixture of trifluoroacetic acid (5 mL) of this compound under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, the aqueous layer was made alkaline, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) and crystallized from hexane to obtain 70 mg of the title compound (yield 28%). Melting point 137-141 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.85 (3H, s), 2.11 (3H, s), 2.23 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.00 (2H, s), 4.42 (1H, dd, J = 8.7, 4.8 Hz), 4.58 (1H, dd, J = 13.8, 4.8 Hz), 4.85 (1H , d, J = 6.6 Hz), 6.45 (1H, br s), 7.05-7.35 (9H, m).

N- (3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide 3,3 obtained in Reference Example 63 -Dimethyl-N- (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide (1.0 g, 3.15 mmol) in methanol (100 mL) To the solution, sodium borohydride (238 mg, 6.30 mmol) was added at room temperature and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate to obtain 950 mg (yield 94%) of the title compound. Mp 204-206 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.29 (3H, s), 1.49 (3H, s), 2.09 (3H, s), 2.11 (3H, s), 2.23 (3H, s ), 2.30 (2H, s), 4.70 (1H, d, J = 9.2 Hz), 6.61 (1H, br s), 1H Not confirmed.

N- (3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Like Example 234, Reference Example 65 The title compound was synthesized using 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in 1 above. . Yield 92%. Melting point 184-185 [deg.] C. (THF-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.32 (3H, s), 1.48 (3H, s), 1.81 (1H, brs), 2.13 (6H, s), 2.25 (2H, s ), 4.73 (1H, brs), 6.79 (1H, brs), 7.34 (1H, s).

(7-Bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl In the same manner as in Example 234, in Reference Example 66 The title compound was synthesized using the obtained tert-butyl (7-bromo-2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamate. Yield 98%. Melting point 187-188 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl3) δ: 1.28-1.71 (15H, m), 1.70 (1H, brs), 2.26 (3H, s), 2.34 (3H, s), 4.80 (1H, d, J = 9.0 Hz) , 5.84 (1H, brs).

(2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl N-benzyl-2,2,4,6-tetra obtained in Reference Example 98 Methyl-2,3-dihydro-1-benzofuran-5-amine (4.1 g, 14.6 mmol), 10% -palladium carbon (50% water content, 400 mg) ammonium formate (1.84 g, 29.2 mmol) in methanol (70 mL The mixture was heated to reflux for 2 hours. The catalyst was removed by filtration, and the filtrate was distilled off under reduced pressure. Water and ethyl acetate were added to the residue, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized from ethyl acetate-hexane to obtain 2.60 g of 2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-ylamine. Obtained. A solution of this compound (2.60 g, 13.5 mmol) and ditert-butyl dicarbonate (6.20 mL, 27.0 mmol) in THF (50 mL) was heated to reflux for 16 hours. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 2.57 g (yield 60%) of the title compound. Melting point 121-123 [deg.] C.
¹ H-NMR (CDCl ₃ ) δ: 1.45 (6H, s), 1.50 (9H, s), 2.11 (3H, s), 2.19 (3H, s), 2.90 (2H, s), 5.72 (1H, br s), 6.44 (1H, s).

Tert-Butyl (7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) carbamate obtained in Example 237 in the same manner as in Reference Example 18 ( The title compound was synthesized using 2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid. Yield 54%. Melting point 115-117 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.38-1.59 (15H, m), 2.08 (3H, s), 2.31 (3H, s), 3.01 (2H, s), 5.81 (1H, br s).

N- (3-hydroxy-2,2,6,7-tetramethyl-3- (3-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Reference 3,3-Dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide (303 mg, 1 mmol) obtained in Example 65 ) In THF (10 mL), 3-tolylmagnesium bromide (1.0 M, 10 mL, 10 mmol) in THF was added dropwise at 0 ° C. under an argon atmosphere, and the mixture was warmed to room temperature. After stirring for 1 hour, the reaction solution was added to ice and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain 265 mg (yield 67%) of the title compound. Mp 113-114 ° C.

¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, s), 1.10 (9H, s), 1.59 (3H, s), 2.18-2.22 (8H, m), 2.36 (3H, s), 2.40 (1H , brs), 6.80 (1H, brs), 7.10-7.20 (2H, m), 7.22-7.26 (2H, m), 7.35 (1H, s).

N- (3-hydroxy-2,2,6,7-tetramethyl-3- (2-phenylethyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide 2 -A solution of chloroethylbenzene (648 mg, 4.6 mmol) in THF (5 mL) was added dropwise to a mixture of magnesium (112 mg, 4.6 mmol) and a catalytic amount of iodine under an argon atmosphere and stirred for 30 minutes. To the reaction solution, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide (300) obtained in Reference Example 65 was added. mg, 0.98 mmol) in THF (3 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to ice and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 2: 3) and recrystallized from ethyl acetate-hexane to obtain 201 mg (yield 51%) of the title compound. Melting point 99-100 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.37 (3H, s), 1.54 (3H, s), 1.99-2.30 (11H, m), 2.80 (1H, dt, J = 12.9, 4.8 Hz), 2.97 (1H, dt, J = 12.9, 4.8 Hz), 6.77 (1H, brs), 7.15-7.31 (6H, m).

N- (3-hydroxy-2,2,6,7-tetramethyl-3- (2- (trifluoromethoxy) phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide 1-bromo-2- (trifluoromethoxy) benzene (827 mg, 3.43 mmol) in THF (8 mL) under argon atmosphere, n-butyllithium (1.59 M hexane solution, 1.85 mL, 2.94 mmol) Was added dropwise at −78 ° C. and stirred for 30 minutes, and 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3- A solution of dihydro-1-benzofuran-5-yl) butanamide (300 mg, 0.98 mmol) in THF (3 mL) was added dropwise at −78 ° C. and stirred for 30 minutes, the reaction was warmed to room temperature and stirred for 1 hour. After adding water, extract with ethyl acetate and remove the organic layer. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane 2: 3), and re-purified from ethyl acetate-hexane. Crystallization gave 267 mg (59% yield) of the title compound, mp 160-161 ° C.
¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, s), 1.11 (9H, s), 1.62 (3H, s), 2.18 (6H, s), 2.22 (2H, s), 3.00 (1H, brs ), 6.79 (1H, brs), 7.15-7.36 (5H, m).

N- (3-hydroxy-2,2,6,7-tetramethyl-3- (2-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 239, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) obtained in Reference Example 65 The title compound was synthesized using butanamide and 2-tolylmagnesium bromide. Yield 43%. Melting point 111-112 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.10 (9H, s), 1.68 (3H, s), 2.17-2.26 (9H, m), 2.64 (3H, s), 6.82 (1H , brs), 6.90-7.26 (5H, m).

N- (3-hydroxy-2,2,6,7-tetramethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 241 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in Reference Example 65 and phenyllithium Used to synthesize the title compound. Yield 58%. Melting point 109-111 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, s), 1.10 (9H, s), 1.62 (3H, s), 2.18-2.22 (8H, m), 2.37 (1H, brs), 6.79 (1H , brs), 7.12 (1H, s), 7.27-7.38 (3H, m), 7.47-7.50 (2H, m).

N- (3-hydroxy-2,2,6,7-tetramethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide
Similar to Example 240, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl obtained in Reference Example 65 ) The title compound was synthesized using butanamide and 2-bromonaphthalene. Yield 65%. Melting point 142-144 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.89 (3H, s), 1.09 (9H, s), 1.65 (3H, s), 2.20-2.24 (8H, m), 2.46 (1H, brs), 6.82 (1H , brs), 7.16 (1H, s), 7.46-7.51 (2H, m), 7.60 (1H, d, J = 8.8 Hz), 7.80-7.86 (3H, m), 7.99 (1H, s).

N- (3-hydroxy-3- (3-isopropylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Analogously to Example 240, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) obtained in Reference Example 65 The title compound was synthesized using butanamide and 1-bromo-3-isopropylbenzene. Yield 76%. Melting point 136-137 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, s), 1.10 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.60 (3H, s), 2.14-2.22 (9H, m ), 2.90 (1H, septet, J = 6.9 Hz), 6.77 (1H, brs), 7.14-7.18 (2H, m), 7.23-7.28 (2H, m), 7.39 (1H, s).

N- (3-hydroxy-3- (2-methoxyphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 239, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) obtained in Reference Example 65 The title compound was synthesized using butanamide and 2-methoxyphenylmagnesium bromide. Yield 58%. Melting point 168-169 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, s), 1.10 (9H, s), 1.66 (3H, s), 2.15-2.21 (8H, m), 3.94 (3H, s), 5.17 (1H , brs), 6.82 (1H, brs), 6.89-6.97 (2H, m), 7.09 (1H, s), 7.12 (1H, d, J = 8.1 Hz), 7.28 (1H, d, J = 8.1 Hz) .

N- (3-hydroxy-3- (4-isopropylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Analogously to Example 240, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) obtained in Reference Example 65 The title compound was synthesized using butanamide and 1-bromo-4-isopropylbenzene. Yield 42%. Melting point 119-121 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, s), 1.11 (9H, s), 1.26 (6H, d, J = 6.9 Hz), 1.60 (3H, s), 2.18-2.22 (8H, m ), 2.29 (1H, s), 2.86 (1H, septet, J = 6.9 Hz), 6.80 (1H, br s), 7.15 (1H, s), 7.21 (2H, d, J = 8.0 Hz), 7.41 ( 2H, d, J = 8.0 Hz).

N- (3-hydroxy-2,2,6,7-tetramethyl-3- (2-thienyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples 2,3-Dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in Reference Example 65 And 2-bromothiophene were used to give the title compound as an oil. Yield 86%.
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.12 (9H, s), 1.64 (3H, s), 2.18 (3H, s), 2.19 (3H, s), 2.23 (2H, s ), 2.63 (1H, brs), 6.81 (1H, brs), 6.94-7.01 (2H, m), 7.29-7.32 (2H, m).

N- (3-Benzyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Reference Example 239 3,3-Dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in Reference Example 65 and benzylmagnesium chloride Was used to synthesize the title compound. Yield 88%. Melting point 212-213 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.08 (9H, s), 1.31 (3H, s), 1.43 (3H, s), 1.75 (1H, s), 2.09-2.17 (8H, m), 3.02 (1H , d, J = 13.6 Hz), 3.16 (1H, d, J = 13.6 Hz), 6.56 (1H, s), 6.66 (1H, brs), 7.20-7.38 (5H, m).

N- (3-hydroxy-3- (4-isopropylbenzyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Analogously to Example 240, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) obtained in Reference Example 65 The title compound was synthesized using butanamide and 4-isopropylbenzyl chloride. Yield 94%. Melting point 177-178 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.25 (6H, d, J = 6.9 Hz), 1.33 (3H, s), 1.43 (3H, s), 2.04 (1H, s), 2.11 (3H, s), 2.14 (3H, s), 2.19 (2H, m), 2.90 (1H, septet, J = 6.9 Hz), 3.00 (1H, d, J = 13.6 Hz), 3.13 (1H, d , J = 13.6 Hz), 6.66 (2H, brs), 7.15 (2H, d, J = 8.0 Hz), 7.24 (2H, d, J = 8.0 Hz).

N- (3-butyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide
In the same manner as in Example 241, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl obtained in Reference Example 65 ) The title compound was synthesized using butanamide and n-butyllithium. Yield 78%. Melting point 161-162 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.2 Hz), 1.13 (9H, s), 1.30-1.43 (6H, m), 1.49 (3H, s), 1.60-1.79 (3H , m), 1.90-1.99 (1H, m), 2.13 (6H, s), 2.24 (2H, s), 6.77 (1H, brs), 7.23 (1H, s).

N- (3- (2-furyl) -3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples Similar to 241, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in Reference Example 65 The title compound was synthesized using and furan. Yield 88%. Melting point 108-110 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, s), 1.13 (9H, s), 1.59 (3H, s), 2.17 (3H, s), 2.18 (3H, s), 2.24 (2H, s ), 2.59 (1H, brs), 6.35-6.37 (2H, m), 6.79 (1H, brs), 7.37 (1H, s), 7.43 (1H, s).

N- (3- (2,4-dimethoxyphenyl) -3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane Amide In the same manner as in Example 240, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-obtained in Reference Example 65 was used. Yl) The title compound was synthesized using butanamide and 1-bromo-2,4-dimethoxybenzene. Yield 62%. Melting point 150-151 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, s), 1.10 (9H, s), 1.65 (3H, s), 2.12-2.20 (8H, m), 3.79 (3H, s), 3.91 (3H , s), 5.03 (1H, brs), 6.43 (1H, dd, J = 8.4, 2.4 Hz), 6.52 (1H, d, J = 2.4 Hz), 6.92 (1H, brs), 7.05-7.08 (2H, m).

N- (3- (4-Bromophenyl) -3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 241, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) obtained in Reference Example 65 The title compound was synthesized using butanamide and 1,4-dibromobenzene. Yield 93%. Melting point 118-119 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, s), 1.10 (9H, s), 1.56 (3H, s), 2.17-2.22 (8H, m), 2.44 (1H, brs), 6.80 (1H , brs), 7.10 (1H, s), 7.36 (2H, d, J = 8.4 Hz), 7.48 (2H, d, J = 8.4 Hz).

N- (3-hydroxy-3- (4-methoxyphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Analogously to Example 240, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) obtained in Reference Example 65 The title compound was synthesized using butanamide and 1-bromo-4-methoxybenzene. Yield 72%. Melting point 110-111 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.84 (3H, s), 1.11 (9H, s), 1.58 (3H, s), 2.18-2.24 (9H, m), 3.81 (3H, s), 6.78 (1H , brs), 6.88 (2H, d, J = 9.0 Hz), 7.12 (1H, s), 7.40 (2H, d, J = 9.0 Hz).

N- (3-cyclohexyl-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 239 3,3-dimethyl-N- (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in Reference Example 63 and cyclohexyl The title compound was synthesized using magnesium bromide. Yield 66%. Melting point 170-171 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.60-2.10 (30H, m), 2.12 (3H, s), 2.20-2.40 (5H, m), 6.55 (1H, br s).

N- (3-hydroxy-2,2,4,6,7-pentamethyl-3- (2-pyridyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Analogously to Example 241, 3,3-dimethyl-N- (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl obtained in Reference Example 63 ) The title compound was synthesized using butanamide and 2-bromopyridine. Yield 45%. Mp 205-207 ° C.
¹ H-NMR (CDCl ₃ ) δ: 0.89 (3H, s), 1.12 (9H, s), 1.53 (3H, s), 1.64 (3H, s), 2.13 (3H, s), 2.14 (3H, s ), 2.25 (2H, s), 6.01 (1H, br s), 6.85 (1H, br s), 7.06 (1H, d, J = 6.0 Hz), 7.18-7.24 (1H, m), 7.60 (1H, dt, J = 7.8, 1.8 Hz), 8.56 (1H, dd, J = 7.8, 4.8 Hz).

N- (3-hydroxy-3- (4-methoxyphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Analogously to Example 241, 3,3-dimethyl-N- (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl obtained in Reference Example 63 ) The title compound was synthesized using butanamide and 4-bromoanisole. Yield 47%. Melting point 98-99 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, s), 1.13 (9H, s), 1.51 (3H, s), 1.85 (3H, s), 2.15 (3H, s), 2.16 (3H, s ), 2.27 (2H, s), 3.79 (3H, s), 6.59 (1H, br), 6.83 (3H, br), 7.38 (1H, br).

N- (3-hydroxy-3- (3-methoxyphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 241, 3,3-dimethyl-N- (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran - 5-yl obtained in Reference Example 63 ) The title compound was synthesized using butanamide and 3-bromoanisole. Yield 46%. Melting point 154-155 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.89 (3H, s), 1.13 (9H, s), 1.52 (3H, s), 1.87 (3H, s), 2.16 (3H, s), 2.17 (3H, s ), 2.27 (2H, s), 3.80 (3H, brs), 6.45 (1H, br), 6.53 (1H, s), 6.75-6.84 (1H, m), 7.20 (2H, br).

N- (3-hydroxy-3- (4-isopropylphenyl) -2,2,4,5,6-pentamethyl-2,3-dihydro-1-benzofuran-7-yl) -3,3-dimethylbutanamide In the same manner as in Example 240, 3,3-dimethyl-N- (2,2,4,5,6-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-7- obtained in Reference Example 64 was used. Yl) The title compound was synthesized using butanamide and 1-bromo-4-isopropylbenzene. Yield 71%. Melting point 178-179 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.82 (3H, s), 1.14 (9H, s), 1.24 (6H, d, J = 6.9 Hz), 1.49 (3H, s), 1.91 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 2.29 (2H, s), 2.35 (1H, s), 2.89 (1H, septet, J = 6.9 Hz), 6.40-7.80 (5H, m).

(3-Hydroxy-2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl Similar to Example 241 (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamate tert-butyl and 1-bromo-4 obtained in Reference Example 62 -The title compound was synthesized using methylbenzene. Yield 64%. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, s), 1.20-1.60 (9H, m), 1.50 (3H, s), 1.88 (3H, s), 2.15 (3H, s), 2.19 (3H , s), 2.34 (3H, s), 5.77 (1H, br s), 6.40-8.20 (4H, m), 1H unconfirmed.

(3-Hydroxy-3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl Similar to Example 241 And (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamate tert-butyl and 1-iodo-4 obtained in Reference Example 62. -The title compound was synthesized using isopropylbenzene. Yield 34%. Melting point 155-157 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, s), 1.24 (6H, d, J = 7.0 Hz), 1.20-1.64 (9H, m), 1.52 (3H, s), 1.89 (3H, s ), 2.08 (1H, s), 2.16 (3H, s), 2.20 (3H, s), 2.74-3.06 (1H, m), 5.75 (1H, br s), 6.40-8.20 (4H, m).

(3-Hydroxy-2,2,4,6,7-pentamethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl As in Example 241 Using tert-butyl (2,2,4,6,7-pentamethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) carbamate obtained in Reference Example 62 and 2-bromonaphthalene The title compound was synthesized. Yield 50%. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 0.90 (3H, br s), 1.20-1.70 (9H, m), 1.57 (3H, s), 1.86 (3H, br s), 2.19 (3H, s), 2.22 (3H, s), 2.29 (1H, s), 5.77 (1H, br s), 6.60-8.60 (7H, m).

N- (3- (3-formylphenyl) -3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide 2 N-Butyllithium (1.59 M hexane solution, 6.4 mL, 10.2 mmol) was added to a THF (20 mL) solution of-(3-bromophenyl) -1,3-dioxolane (1.65 mL, 10.9 mmol) under an argon atmosphere. The solution was added dropwise at −78 ° C. and stirred for 30 minutes. To the reaction solution, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide (1.0) obtained in Reference Example 65 was added. g, 3.30 mmol) in THF (10 mL) was added dropwise at −78 ° C. and stirred for 30 minutes. The reaction solution was warmed to room temperature and stirred for 1 hour, and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. . The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 2: 3) to give N- (3- (3- (1,3-dioxolan-2-yl) phenyl) -3-hydroxy-2, 2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide was obtained as an amorphous powder in 1.38 g (yield 92%). Obtained N- (3- (3- (1,3-dioxolan-2-yl) phenyl) -3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran- Pyridinium p-toluenesulfonate (5 mg, 0.03 mmol) was added to a mixed solution of 5-yl) -3,3-dimethylbutanamide (300 mg, 0.66 mmol) in acetone (4 mL) -water (0.3 mL). Stir for 30 minutes. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from THF-diisopropyl ether to obtain 194 mg (yield 72%) of the title compound. Melting point 189-190 ° C.
¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, s), 1.09 (9H, s), 1.59 (3H, s), 2.18-2.22 (8H, m), 2.66 (1H, s), 6.86 (1H , br s), 7.11 (1H, s), 7.52 (1H, t, J = 7.5 Hz), 7.76 (1H, d, J = 7.5 Hz), 7.84 (1H, d, J = 7.5 Hz), 7.99 ( 1H, s), 10.01 (1H, s).

N- (3-hydroxy-3- (3- (hydroxymethyl) phenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 21, N- (3- (3-formylphenyl) -3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1- obtained in Example 264 The title compound was obtained using benzofuran-5-yl) -3,3-dimethylbutanamide. Yield 86%. Melting point 169-171 [deg.] C. (THF-diisopropyl ether).
¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, s), 1.09 (9H, s), 1.60 (3H, s), 1.65 (1H, brs), 2.17-2.20 (8H, m), 2.41 (1H , br s), 4.60 (2H, s), 6.85 (1H, br s), 7.10 (1H, s), 7.25-7.42 (3H, m), 7.49 (1H, s).

N- (3-hydroxy-3- (3- (1-hydroxyethyl) phenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3 -Dimethylbutanamide In the same manner as in Example 22, N- (3- (3-formylphenyl) -3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro- obtained in Reference Example 264 The title compound was synthesized using 1-benzofuran-5-yl) -3,3-dimethylbutanamide and methylmagnesium bromide. Yield 43%. Melting point 206-207 ° C. (THF-diisopropyl ether).
¹ H-NMR (CDCl ₃ ) δ: 0.85 (3H, s), 1.09 (9H, s), 1.46-1.49 (3H, m), 1.60 (3H, s), 2.17-2.21 (9H, m), 2.27 (1H, brs), 4.88 (1H, br s), 6.80 (1H, s), 7.14 (1H, s), 7.30-7.45 (3H, m), 7.52 (1H, s).

N- (3-hydroxy-2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similarly to Reference Example 63, 5-amino-2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-3- 3 obtained in Reference Example 80 The title compound was synthesized using all. Yield 59%. Melting point 146-148 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, s), 1.12 (9H, s), 1.51 (3H, s), 1.71 (1H, s), 1.85 (3H, s), 2.16 (6H, s ), 2.27 (2H, s), 2.33 (3H, s), 6.60 (1H, br s), 6.82-7.80 (4H, m).

N- (3-hydroxy-2,2,4,6,7-pentamethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Reference In the same manner as in Example 63, the 5-amino-2,2,4,6,7-pentamethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 81 was used. Used to synthesize the title compound. Yield 82%. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 0.90 (3H, br. S), 1.11 (9H, s), 1.58 (3H, s), 1.83 (3H, br. S), 2.19 (6H, s), 2.26 (2H, s), 2.38 (1H, br. S), 6.40-8.60 (7H, m), 6.60 (1H, br s).

N- (3-hydroxy-2,2,4,6,7-pentamethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-5-yl) -3-methylbutanamide Reference Example 63 Like 5-amino-2,2,4,6,7-pentamethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 81 and 3- The title compound was synthesized using methylbutyryl chloride. Yield 32%. Melting point 108-110 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.80-1.10 (9H, m), 1.50-1.95 (7H, m), 2.05-2.80 (9H, m), 6.65 (1H, br s), 7.00-8.32 (7H , m).

N- (tert-butyl) -N ′-(3-hydroxy-2,2,4,6,7-pentamethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-5-yl) Urea As in Example 14, 5-amino-2,2,4,6,7-pentamethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-3- obtained in Reference Example 81 The title compound was synthesized using all. Yield 74%. Mp 212-214 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, br s), 1.27 (9H, s), 1.60 (3H, s), 1.88 (3H, br s), 2.21 (3H, s), 2.23 (3H , s), 2.44 (1H, br s), 4.12 (1H, br s), 5.33 (1H, br. s), 6.60-8.60 (7H, m).

3,3-Dimethyl-N- (2,2,6,7-tetramethyl-3- (2-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in Example 242 N- (3-hydroxy-2,2,6,7-tetramethyl-3- (2-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide ( To a solution of 120 mg, 0.3 mmol) in trifluoroacetic acid (2 mL) was added triethylsilane (71 mg, 0.6 mmol) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) and recrystallized from ethyl acetate-hexane to give 93 mg (yield 79%) of the title compound. Melting point 161-162 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.09 (9H, s), 1.56 (3H, s), 2.15-2.19 (8H, m), 2.39 (3H, s), 4.57 (1H , s), 6.60-6.75 (2H, m), 6.91 (1H, s), 7.00-7.18 (3H, m).

3,3-Dimethyl-N- (2,2,6,7-tetramethyl-3- (3-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) butanamide As in Example 271 N- (3-hydroxy-2,2,6,7-tetramethyl-3- (3-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 239 , 3-Dimethylbutanamide was used to synthesize the title compound. Yield 87%. Melting point 156-157 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, s), 1.09 (9H, s), 1.55 (3H, s), 2.15-2.19 (8H, m), 2.31 (3H, s), 4.27 (1H , s), 6.70 (1H, br s), 6.85-6.92 (3H, m), 7.04 (1H, d, J = 8.4 Hz), 7.16 (1H, t, J = 8.4 Hz).

N- (3- (3-Isopropylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 271 N- (3-hydroxy-3- (3-isopropylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 245 The title compound was synthesized using 3,3-dimethylbutanamide. Yield 65%. Melting point 162-163 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, s), 1.09 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.57 (3H, s), 2.15-2.20 (8H, m ), 2.86 (1H, septet, J = 6.9 Hz), 4.32 (1H, s), 6.72 (1H, br s), 6.90-7.09 (3H, m), 7.08-7.25 (2H, m).

N- (2,2,6,7-tetramethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 271, Example 243 Using N- (3-hydroxy-2,2,6,7-tetramethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in The title compound was synthesized. Yield 82%. Melting point 182-183 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.09 (9H, s), 1.57 (3H, s), 2.15-2.20 (8H, m), 4.32 (1H, s), 6.72 (1H , br s), 6.95 (1H, s), 7.06-7.11 (2H, m), 7.23-7.31 (3H, m).

N- (2,2,6,7-tetramethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 271 N- (3-hydroxy-2,2,6,7-tetramethyl-3- (2-naphthyl) -2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 244 The title compound was obtained as an oil using 3-dimethylbutanamide. Yield 84%.
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.06 (9H, s), 1.60 (3H, s), 2.16-2.22 (8H, m), 4.47 (1H, s), 6.77 (1H , brs), 6.93 (1H, s), 7.18 (1H, dd, J = 8.6, 1.6 Hz), 7.42-7.49 (2H, m), 7.58 (1H, br s), 7.73-7.82 (3H, m) .

N- (3- (2-methoxyphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 271 N- (3-hydroxy-3- (2-methoxyphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 246 The title compound was synthesized using 3,3-dimethylbutanamide. Yield 82%. Melting point 169-170 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, s), 1.10 (9H, s), 1.57 (3H, s), 2.15-2.19 (8H, m), 3.85 (3H, s), 4.82 (1H , s), 6.72 (1H, br s), 6.75-6.91 (4H, m), 7.15-7.26 (1H, m).

N- (3-Benzyl-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 271, Example 249 Using N- (3-benzyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in The title compound was synthesized. Yield 56%. Melting point 186-187 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.08 (9H, s), 1.33 (3H, s), 1.37 (3H, s), 2.09 (3H, s), 2.12 (3H, s), 2.17 (2H, s ), 2.89 (2H, d, J = 7.8 Hz), 3.42 (1H, t, J = 7.8 Hz), 6.49 (1H, s), 6.62 (1H, br s), 7.17-7.33 (5H, m).

N- (3- (4-Isopropylbenzyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 271 N- (3-hydroxy-3- (4-isopropylbenzyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 250 The title compound was synthesized using 3,3-dimethylbutanamide. Yield 63%. Melting point 130-132 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.10 (9H, s), 1.25 (6H, d, J = 6.9 Hz), 1.33 (3H, s), 1.43 (3H, s), 2.04 (1H, s), 2.11 (3H, s), 2.14 (3H, s), 2.19 (2H, m), 2.86 (1H, septet, J = 6.9 Hz), 3.00 (1H, d, J = 13.6 Hz), 3.13 (1H, d , J = 13.6 Hz), 6.66 (2H, br s), 7.15 (2H, d, J = 8.0 Hz), 7.24 (2H, d, J = 8.0 Hz).

N- (2,2,6,7-tetramethyl-3- (2-thienyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 271 N- (3-hydroxy-2,2,6,7-tetramethyl-3- (2-thienyl) -2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 248, The title compound was synthesized using 3-dimethylbutanamide. Yield 65%. Melting point 137-138 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.05 (3H, s), 1.10 (9H, s), 1.58 (3H, s), 2.15-2.21 (8H, m), 4.61 (1H, s), 6.77 (1H , br s), 6.85 (1H, d, J = 3.4 Hz), 6.97 (1H, dd, J = 4.8, 3.4 Hz), 7.10 (1H, s), 7.19 (1H, d, J = 4.8 Hz).

N- (2,2,6,7-tetramethyl-3- (2- (trifluoromethoxy) phenyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 271, N- (3-hydroxy-2,2,6,7-tetramethyl-3- (2- (trifluoromethoxy) phenyl-2,3-dihydro-1-) obtained in Example 241 was used. The title compound was synthesized using benzofuran-5-yl) -3,3-dimethylbutanamide Yield 47%, mp 155-156 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, s), 1.11 (9H, s), 1.62 (3H, s), 2.18 (6H, s), 2.22 (2H, s), 3.00 (1H, br s), 6.79 (1H, br s), 7.15-7.36 (5H, m).

N- (3-Butyl-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 271, Example 251 Using N- (3-butyl-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in The title compound was synthesized. Yield 77%. Melting point 129-130 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.2 Hz), 1.13 (9H, s), 1.30-1.43 (6H, m), 1.49 (3H, s), 1.60-1.79 (3H , m), 1.90-1.99 (1H, m), 2.13 (6H, s), 2.24 (2H, s), 6.77 (1H, br s), 7.23 (1H, s).

N- (3- (2-furyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 271 N- (3- (2-furyl) -3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 252, The title compound was synthesized using 3-dimethylbutanamide. Yield 67%. Melting point 126-127 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, s), 1.12 (9H, s), 1.59 (3H, s), 2.12-2.22 (8H, m), 4.44 (1H, s), 6.10 (1H , d, J = 3.2 Hz), 6.30-6.33 (1H, m), 6.74 (1H, br s), 7.10 (1H, s), 7.35-7.36 (1H, m).

N- (2,2,6,7-tetramethyl-3- (2-phenylethyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 271 N- (3-hydroxy-2,2,6,7-tetramethyl-3- (2-phenylethyl) -2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 240 The title compound was synthesized using 3,3-dimethylbutanamide. Yield 92%. Melting point 158-159 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.37 (3H, s), 1.45 (3H, s), 1.86-1.96 (2H, m), 2.12 (6H, s), 2.33 (2H , s), 2.65-2.83 (2H, m), 3.03 (1H, t, J = 7.8 Hz), 6.73 (1H, br s), 7.17-7.31 (6H, m).

N- (3- (4-Bromophenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 271 N- (3- (4-bromophenyl) -3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 254 The title compound was synthesized using 3,3-dimethylbutanamide. Yield 88%. Melting point 171-172 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.10 (9H, s), 1.54 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.20 (2H, s ), 4.28 (1H, s), 6.72 (1H, br s), 6.94-6.98 (3H, m), 7.41 (2H, d, J = 8.4 Hz).

N- (3- (4-methoxyphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 271 N- (3-hydroxy-3- (4-methoxyphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 255 The title compound was synthesized using 3,3-dimethylbutanamide. Yield 82%. Melting point 169-170 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.10 (9H, s), 1.54 (3H, s), 2.14-2.20 (8H, m), 3.79 (3H, s), 4.27 (1H , s), 6.71 (1H, br s), 6.82 (2H, d, J = 8.7 Hz), 6.93 (1H, s), 7.01 (2H, d, J = 8.7 Hz).

N- (3- (2,4-dimethoxyphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Example 271 Similarly to N- (3- (2,4-dimethoxyphenyl) -3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5 obtained in Example 253 The title compound was synthesized using -yl) -3,3-dimethylbutanamide. Yield 82%. Melting point 146-147 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, s), 1.09 (9H, s), 1.55 (3H, s), 2.14-2.19 (8H, m), 3.78 (3H, s), 3.82 (3H , s), 4.73 (1H, s), 6.35 (1H, dd, J = 8.4, 2.4 Hz), 6.45 (1H, d, J = 2.4 Hz), 6.66 (1H, d, J = 8.4 Hz), 6.76 (1H, br s), 6.90 (1H, s).

N- (3-Cyclohexyl-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide As in Example 271, N- (3-cyclohexyl-3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in 256. Used to synthesize the title compound. Yield 48%. Melting point 198-199 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.50-2.20 (35H, m), 2.24-2.35 (2H, m), 2.67 (1H, d, J = 2.7 Hz), 6.55 (1H, br s).

3,3-Dimethyl-N- (2,2,4,6,7-pentamethyl-3- (2-pyridyl) -2,3-dihydro-1-benzofuran-5-yl) butanamide
In the same manner as in Example 271, N- (3-hydroxy-2,2,4,6,7-pentamethyl-3- (2-pyridyl) -2,3-dihydro-1-benzofuran- obtained in Example 257 The title compound was synthesized using 5-yl) -3,3-dimethylbutanamide. Yield 52%. Mp 210-212 ° C.
¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, s), 1.12 (9H, s), 1.55 (3H, s), 1.79 (3H, s), 2.17 (6H, s), 2.26 (2H, s ), 4.41 (1H, s), 6.52 (1H, br s), 6.78 (1H, d, J = 7.6 Hz), 7.12 (1H, dd, J = 7.6, 4.4 Hz), 7.54-7.61 (1H, m ), 8.53 (1H, d, J = 4.4 Hz).

N- (3- (4-methoxyphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 271 N- (3-hydroxy-3- (4-methoxyphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 258- The title compound was synthesized using 3,3-dimethylbutanamide. Yield 40%. Melting point 175-176 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.12 (9H, s), 1.48 (3H, s), 1.77 (3H, s), 2.15 (6H, s), 2.24 (2H, s ), 3.76 (3H, s), 4.08 (1H, s), 6.48 (1H, s), 6.76 (1H, br d, J = 5.4 Hz), 6.83 (2H, br).

N- (3- (3-methoxyphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 271 N- (3-hydroxy-3- (3-methoxyphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-obtained in Example 259 The title compound was synthesized using 3,3-dimethylbutanamide. Yield 77%. Melting point 166-167 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, s), 1.12 (9H, s), 1.49 (3H, s), 1.79 (3H, s), 2.15 (6H, s), 2.25 (2H, s ), 3.76 (3H, s), 4.09 (1H, s), 6.25 (1H, br), 6.47 (1H, s), 6.60-6.85 (2H, m), 7.08 (1H, br).

N- (3- (4-Isopropylphenyl) -2,2,4,5,6-pentamethyl-2,3-dihydro-1-benzofuran-7-yl) -3,3-dimethylbutanamide Example 271 and Similarly, N- (3-hydroxy-3- (4-isopropylphenyl) -2,2,4,5,6-pentamethyl-2,3-dihydro-1-benzofuran-7- obtained in Example 260 Yl) -3,3-dimethylbutanamide was used to synthesize the title compound. Yield 53%. Melting point 152-153 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, s), 1.14 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.46 (3H, s), 1.83 (3H, s), 2.08 (3H, s), 2.17 (3H, s), 2.29 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.11 (1H, s), 6.40-7.15 (5H, m).

N- (3- (4-formylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 284 N- (3- (4-bromophenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (500 mg, 1.13 mmol) in THF (10 mL) was added dropwise n-butyllithium (1.59 M hexane solution, 1.56 mL, 2.48 mmol) at −78 ° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. DMF (90 mg, 1.24 mmol) was added to the reaction solution at the same temperature, and the mixture was stirred for 30 minutes, then warmed to room temperature and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 2: 3) and recrystallized from ethyl acetate-hexane to obtain 204 mg (yield 46%) of the title compound. Melting point 169-170 ° C.
¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, s), 1.09 (9H, s), 1.58 (3H, s), 2.04-2.20 (8H, m), 4.38 (1H, s), 6.74 (1H , br s), 6.99 (1H, s), 7.25 (2H, d, J = 8.4 Hz), 7.81 (2H, dd, J = 8.4 Hz), 9.99 (1H, s).

N- (3- (4-acetylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 292 N- (3- (4-bromophenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- obtained in Example 284 The title compound was synthesized using dimethylbutanamide and N, N-dimethylacetamide. Yield 20%. Melting point 195-196 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, s), 1.09 (9H, s), 1.57 (3H, s), 2.16-2.19 (8H, m), 2.59 (3H, s), 4.36 (1H , s), 6.73 (1H, br s), 6.97 (1H, s), 7.18 (2H, d, J = 8.0 Hz), 7.88 (2H, d, J = 8.0 Hz).

N- (3- (4- (hydroxymethyl) phenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples Like 21, N- (3- (4-formylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 292 , 3-Dimethylbutanamide was used to synthesize the title compound. Yield 80%. Melting point 162-163 ° C. (THF-diisopropyl ether).
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.09 (9H, s), 1.56 (3H, s), 1.65 (1H, t, J = 6.0 Hz), 2.15-2.19 (8H, m ), 4.32 (1H, s), 4.67 (2H, d, J = 6.0 Hz), 6.72 (1H, br s), 6.94 (1H, s), 7.09 (2H, d, J = 8.0 Hz), 7.29 ( 2H, d, J = 8.0 Hz).

N- (3- (4- (1-hydroxyethyl) phenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 21, N- (3- (4-acetylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) obtained in Example 293) The title compound was synthesized as an oil using -3,3-dimethylbutanamide. Yield 65%.
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.09 (9H, s), 1.48 (3H, d, J = 6.4 Hz), 1.55 (3H, s), 1.66 (1H, brs), 2.14-2.19 (8H, m), 4.30 (1H, s), 4.87 (1H, q, J = 6.4 Hz), 6.79 (1H, br s), 6.93 (1H, s), 7.07 (2H, d, J = 8.0 Hz), 7.29 (2H, d, J = 8.0 Hz).

N- (3- (2-Isopropylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide 1-bromo-2 -A solution of isopropylbenzene (1.20 g, 6.03 mmol) in THF (5 mL) was added dropwise to a mixture of magnesium (147 mg, 6.03 mmol) and a catalytic amount of iodine under an argon atmosphere, and the mixture was stirred at 70 ° C for 30 minutes. To the reaction solution, 3,3-dimethyl-N- (2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide (350) obtained in Reference Example 65 was added. mg, 1.15 mmol) in THF (3 mL) was added dropwise and heated to reflux for 12 hours. The reaction mixture was added to ice and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to give N- (3-hydroxy-3- (3-isopropylphenyl) -2,2,6,7-tetramethyl-2. , 3-Dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide was obtained in an amount of 79 mg (yield 16%). Triethylsilane (44 mg, 0.38 mmol) was added to a solution of this compound (79 mg, 0.19 mmol) in trifluoroacetic acid (1 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 2) to obtain 39 mg (yield 51%) of the title compound. Yield 51%. Melting point 188-189 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.09 (9H, s), 1.27 (3H, d, J = 7.0 Hz), 1.32 (3H, d, J = 7.0 Hz), 1.57 ( 3H, s), 2.15-2.20 (8H, m), 3.15-3.30 (1H, m), 4.67 (1H, s), 6.67 (1H, d, J = 7.8 Hz), 6.69 (1H, br s), 6.88 (1H, s), 7.02 (1H, t, J = 7.8 Hz), 7.17 (1H, t, J = 7.8 Hz), 7.29 (1H, d, J = 7.8 Hz).

3,3-Dimethyl-N- (2,2,4,6,7-pentamethyl-3-piperidin-1-yl-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in Example 234 , N- (3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (450 mg, 1.41 mmol) Triethylamine (0.79 mL, 5.64 mmol) was added to the methylene chloride (3 mL) solution, and then methanesulfonyl chloride (0.22 mL, 2.82 mmol) was added dropwise under ice cooling. The reaction solution was stirred for 30 minutes, piperidine (0.70 mL, 7.05 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 20: 1) to obtain 270 mg (yield 50%) of the title compound. Melting point 229-230 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.10-1.82 (22H, m), 2.08 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 2.22-2.43 (3H, m), 2.78 (1H, br s), 2.95 (1H, br s), 3.68 (1H, s), 6.56 (1H, s).

3,3-Dimethyl-N- (2,2,4,6,7-pentamethyl-3-pyrrolidin-1-yl-2,3-dihydro-1-benzofuran-5-yl) butanamide As in Example 297 N- (3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 234 And pyrrolidine were used to synthesize the title compound. Yield 36%. Melting point 197-198 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.16 (9H, s), 1.23 (3H, s), 1.49 (3H, s), 1.58-1.72 (4H, m), 2.09 (3H, s), 2.13 (6H , s), 2.30 (2H, s), 2.48-2.80 (4H, m), 4.02 (1H, s), 6.55 (1H, br s).

N- (3-anilino-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 297, Example 235 The title compound using N- (3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide and aniline obtained in 1 above Was synthesized. Yield 79%. Melting point 151-152 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.37 (3H, s), 1.53 (3H, s), 2.14 (6H, s), 2.22 (2H, s), 3.93 (1H, d , J = 8.7 Hz), 4.81 (1H, d, J = 8.7 Hz), 6.60 (2H, d, J = 7.8 Hz), 6.67-6.75 (2H, m), 7.17 (3H, t, J = 7.8 Hz ).

N- (3-((2-methoxyphenyl) amino) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples Similar to 297, N- (3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane obtained in Example 235 The title compound was synthesized using amide and (2-methoxyphenyl) amine. Yield 75%. Melting point 184-185 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.34 (3H, s), 1.53 (3H, s), 2.14 (6H, s), 2.22 (2H, s), 3.78 (3H, s ), 4.53 (1H, d, J = 8.1 Hz), 4.86 (1H, d, J = 8.1 Hz), 6.63-6.68 (2H, m), 6.75-6.77 (2H, m), 6.86 (1H, t, J = 9.0 Hz), 7.16 (1H, s).

N- (3-((2- (trifluoromethoxy) phenyl) amino) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 297, N- (3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 235, The title compound was synthesized using 3-dimethylbutanamide and (2- (trifluoromethoxy) phenyl) amine. Yield 73%. Melting point 196-197 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.35 (3H, s), 1.54 (3H, s), 2.15 (6H, s), 2.23 (2H, s), 4.32 (1H, d , J = 9.0 Hz), 4.85 (1H, d, J = 9.0 Hz), 6.67 (1H, t, J = 6.9 Hz), 6.70-6.80 (2H, m), 7.12-7.17 (3H, m).

(7-Bromo-2,2,4,6-tetramethyl-3- (pyrrolidin-1-yl) -2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl Similar to Example 297 (7-Bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl and pyrrolidine obtained in Example 236 Used to synthesize the title compound. Yield 43%. Melting point 128-130 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.28-1.57 (15H, m), 1.60-1.70 (4H, m), 2.14 (3H, s), 2.33 (3H, s), 2.40-2.67 (2H, m) 2.70-2.80 (2H, m), 4.13 (1H, s), 5.82 (1H, br s).

(7-Bromo-3- (dimethylamino) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl Performed as in Example 297. Using tert-butyl (7-bromo-3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) carbamate obtained in Example 236 and dimethylamine The title compound was synthesized. Yield 89%. Melting point 111-112 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, s), 1.36-1.60 (12H, m), 2.04-2.60 (12H, m), 3.86 (1H, s), 5.84 (1H, b rs).

Tert-Butyl (3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) carbamate Reference Example 59 The title compound was synthesized using 3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Example 120. Yield 24%. Melting point 119-120 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.21 (6H, d, J = 6.6 Hz), 1.25-1.58 (12H, m), 1.81 (3H, s), 2.16 (3H, s ), 2.17 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.08 (1H, s), 5.72 (1H, s), 6.64-7.10 (4H, m).

Tert-Butyl (2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) carbamate Reference Example 59 The title compound was synthesized using 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine obtained in Example 122. Yield 18%. Melting point 124-125 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.20-1.64 (9H, m), 1.48 (3H, s), 1.80 (3H, s), 2.16 (3H, s), 2.17 (3H , s), 2.30 (3H, s), 4.08 (1H, s), 5.71 (1H, br s), 6.20-7.60 (4H, m).

N- (7- (4-Isopropylbenzyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 238 (7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) carbamate tert-butyl (1.77 g, 4.78 mmol) in THF (20 mL) Under an argon atmosphere, n-butyllithium (1.60 M hexane solution, 6.25 mL, 10.0 mmol) was added dropwise at −78 ° C. and stirred for 30 minutes. To the reaction solution, a solution of 4-isopropylbenzaldehyde (815 mg, 5.50 mmol) in THF (5 mL) was added dropwise at -78 ° C. The reaction solution was warmed to room temperature and stirred for 1 hour, and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. . The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4), and (7- (hydroxy (4-isopropylphenyl) methyl) -2,2,4,6-tetramethyl-2,3 -Dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl 1.20 g (yield 59%) was obtained. Triethylsilane (1.0 mL, 6.4 mmol) was added to a mixture of this compound (1.00 g, 2.27 mmol) in trifluoroacetic acid (5 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, the aqueous layer was made alkaline, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-2,3-dihydro. A crude product of -1-benzofuran-5-amine was obtained. Triethylamine (0.16 mL, 1.12 mmol) was added to a methylene chloride (30 mL) solution of this compound (330 mg, about 1.02 mmol) and tert-butylacetyl chloride (0.16 mL, 1.12 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. did. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to obtain 273 mg (yield 17%) of the title compound. Melting point 170-171 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.19 (6H, d, J = 7.2 Hz), 1.46 (6H, s), 2.05 (3H, s), 2.08 (3H, s), 2.25 (2H, s), 2.82 (1H, septet, J = 7.2 Hz), 2.96 (2H, s), 3.89 (2H, s), 6.46 (1H, br s), 7.04 (2H, d, J = 8.1 Hz), 7.09 (2H, d, J = 8.1 Hz).

N- (7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-3- (pyrrolidin-1-yl) -2,3-dihydro-1-benzofuran-5-yl) -3, 3-Dimethylbutanamide (7-Bromo-2,2,4,6-tetramethyl-3- (pyrrolidin-1-yl) -2,3-dihydro-) obtained in Example 302 in the same manner as in Example 306 The title compound was synthesized using tert-butyl 1-benzofuran-5-yl) carbamic acid. Yield 61%. Melting point 179-180 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.18 (3H, s), 1.21 (3H, s), 1.25 (3H, s), 1.49 (3H, s), 1.62-1.72 (4H , m), 2.05 (3H, s), 2.14 (3H, s), 2.25 (2H, dd, J = 17.1, 13.2 Hz), 2.59 (2H, br), 2.70-2.90 (3H, m), 3.80- 3.95 (2H, br), 4.05 (1H, s), 6.48 (1H, s), 7.00-7.10 (4H, m).

N- (3- (dimethylamino) -7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide Similar to Example 306, (7-bromo-3- (dimethylamino) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-obtained in Example 303 was obtained. Yl) The title compound was synthesized using tert-butyl carbamate. Yield 33%. Melting point 138-139 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.18 (3H, s), 1.21 (3H, s), 1.24 (3H, s), 1.51 (3H, s), 2.03-2.06 (14H , m), 2.70-2.88 (1H, m), 3.78 (1H, s), 3.90 (2H, br s), 6.49 (1H, s), 6.98-7.05 (4H, m).

N- (2,2,6,7-tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Reference Example 63 The title compound (yield) was obtained using 2,2,6,7-tetramethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 139. 88%). Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.08 (9H, s), 1.54 (3H, s), 2.14 (3H, s), 2.17 (5H, s), 2.32 (3H, s ), 4.28 (1H, s), 6.75 (1H, brs), 6.90 (1H, s), 6.96 (2H, d, J = 7.9 Hz), 7.08 (2H, d, J = 7.9 Hz).

N- (2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) butanamide In the same manner as in Reference Example 63, Reference Example 122 The title compound was synthesized using 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine and butyryl chloride obtained in 1 above. Yield 50%. Melting point 138-139 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.74-2.41 (25H, m), 4.10 (1H, s), 6.54 (1H, br s), 7.03 (4H, br s).

N- (2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) pentanamide In the same manner as in Reference Example 63, Reference Example The title compound was synthesized using 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine obtained in 122 and pentanoyl chloride. . Yield 62%. Melting point 156-157 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.78-2.43 (27H, m), 4.10 (1H, s), 6.55 (1H, br s), 7.04 (4H, br s).

N- (2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl) hexanamide In the same manner as in Reference Example 63, Reference Example The title compound was synthesized using 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine obtained in 122 and hexanoyl chloride. . Yield 52%. Melting point 96-97 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.77-2.41 (29H, m), 4.10 (1H, s), 6.55 (1H, br s), 7.03 (4H, br s).

N- (3- (4-fluorophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Reference Example 63 Similarly, using 3- (4-fluorophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 123, the title compound was converted. Synthesized. Yield 60%. Melting point 194-195 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.12 (9H, s), 1.49 (3H, s), 1.77 (3H, s), 2.15 (6H, s), 2.25 (2H, s ), 4.11 (1H, s), 6.40-7.20 (5H, m).

3,3-Dimethyl-N- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) butanamide In the same manner as in Reference Example 63, Reference Example The title compound was synthesized using 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine obtained in 121. Yield 55%. Melting point 214-215 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.92-1.20 (12H, m), 1.50 (3H, s), 1.77 (3H, s), 2.16 (6H, s), 2.25 (2H, s), 4.13 (1H , s), 6.40-7.38 (6H, m).

N- (3- (4-bromophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Reference Example 63 Similarly, using 3- (4-bromophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 124, the title compound was converted. Synthesized. Yield 65%. Melting point 201-202 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.92-1.18 (12H, m), 1.49 (3H, s), 1.76 (3H, s), 2.15 (6H, s), 2.25 (2H, s), 4.09 (1H , s), 6.51-7.44 (5H, m).

N- (3- (4-tert-butylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Reference Example 3- (4-tert-butylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride (400 mg, 1.16 mmol) obtained in 76 Triethylamine (0.35 mL, 2.50 mmol) was added at room temperature to a solution of tert-butylacetyl chloride (0.17 mL, 1.22 mmol) in methylene chloride (10 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 8: 1) to obtain 110 mg (yield 41%) of the title compound. Amorphous.
¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.06 (9H, s), 1.12 (9H, s), 1.49 (3H, s), 1.78 (3H, s), 2.16 (6H, s ), 2.25 (2H, s), 4.10 (1H, s), 6.50 (1H, br s), 6.70-7.24 (4H, m).

N- (3- (4-Isopropylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 316 The title compound was prepared using 3- (4-isopropylphenyl) -2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride obtained in Reference Example 74. Synthesized. Yield 38%. Melting point 172-173 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.94 (3H, s), 1.06 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.55 (3H, s), 2.15 (3H, s), 2.18 (3H, s), 2.19 (2H, s), 2.87 (1H, septet, J = 6.6 Hz), 4.29 (1H, s), 6.71 (1H, br s), 6.94 (1H, s), 7.00 ( 2H, d, J = 7.8 Hz), 7.13 (2H, d, J = 7.8 Hz).

N- (3- (4-Isopropylphenyl) -2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Example 316 The title compound was prepared using 3- (4-isopropylphenyl) -2,2,4,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride obtained in Reference Example 75. Synthesized. Yield 23%. Melting point 118-119 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.10 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.48 (3H, s), 1.78 (3H, s), 2.19 (2H, s), 2.21 (3H, s), 2.85 (1H, septet, J = 6.9 Hz), 4.08 (1H, s), 6.52-7.24 (6H, m).

N- (3- (4-Isopropylphenyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Similar to Reference Example 63 The title compound was synthesized using 3- (4-isopropylphenyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 78. . Yield 52%. Amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.11 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.49 (3H, s), 1.79 (3H, s), 2.21 (3H, s), 2.23 (2H, s), 2.84 (1H, septet, J = 6.9 Hz), 4.08 (1H, s), 6.53 (1H, br s), 6.56 (1H, s), 6.70- 7.10 (4H, m).

N- (3- (4-Isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Reference Example 63, Reference Example The title compound was synthesized using 3- (4-isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in 86. Yield 52%. Melting point 126-127 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, s), 1.07 (9H, s), 1.24 (6H, d, J = 6.6 Hz), 1.56 (3H, s), 2.12 (2H, s), 2.88 (1H, septet, J = 6.6 Hz), 4.29 (1H, s), 6.75 (1H, d, J = 8.1 Hz), 6.91 (1H, br s), 6.99 (2H, d, J = 8.1 Hz) , 7.14 (2H, d, J = 8.1 Hz), 7.16-7.25 (2H, m).

N- (3- (4-Isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide In the same manner as in Reference Example 63, the 3- ( The title compound was synthesized using 4-isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran-5-amine and butyryl chloride. Yield 27%. Amorphous.
¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, s), 0.98 (3H, t, J = 7.2 Hz), 1.24 (6H, d, J = 6.9 Hz), 1.56 (3H, s), 1.60- 1.80 (2H, m), 2.26 (2H, t, J = 7.5 Hz), 2.88 (1H, septet, J = 6.9 Hz), 4.29 (1H, s), 6.75 (1H, d, J = 9.3 Hz), 6.90-7.05 (3H, m), 7.13 (2H, d, J = 8.1 Hz), 7.17-7.22 (2H, m).

N- (3- (4-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide In the same manner as in Reference Example 63, Reference Example 120 The title compound was synthesized using 3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and butyryl chloride obtained in 1 above. Yield 59%. Melting point 120-122 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.78-1.10 (6H, m), 1.21 (6H, d, J = 6.9 Hz), 1.60-1.90 (8H, m), 2.10-2.40 (8H, m), 2.84 (1H, septet, J = 6.9 Hz), 4.10 (1H, s), 6.50-7.20 (5H, m).

N- (3- (4-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) pentanamide In the same manner as in Reference Example 63, Reference Example The title compound was synthesized using 3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine obtained in 120 and pentanoyl chloride. . Yield 44%. Melting point 106-107 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.70-1.90 (22H, m), 2.05-2.41 (8H, m), 2.84 (1H, septet, J = 6.6 Hz), 4.10 (1H, s), 6.42-7.18 (5H, m).

N- (3- (4-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Reference Example 63 Similarly, using 3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 120, the title compound was obtained. Synthesized. Yield 41%. Amorphous.
¹ H-NMR (CDCl ₃ ) δ: 0.90-1.20 (12H, m), 1.21 (6H, d, J = 7.2 Hz), 1.48 (3H, s), 1.78 (3H, s), 2.15-2.27 (8H , m), 2.84 (1H, septet, J = 7.2 Hz), 4.09 (1H, s), 6.40-7.10 (5H, m).

N- (3- (4-Isopropylphenyl) -2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl) -3,3-dimethylbutanamide Reference Example 63 Similarly, using 3- (4-isopropylphenyl) -2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-amine obtained in Reference Example 77, the title compound was obtained. Synthesized. Yield 50%. Melting point 128-129 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.17 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.48 (3H, s), 1.83 (3H, s), 2.04 (3H, s), 2.12 (3H, s), 2.31 (2H, s), 2.84 (1H, septet, J = 7.2 Hz), 4.10 (1H, s), 6.50-7.18 (5H, m).

N- (3-Benzyl-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-yl) -3,3-dimethylbutanamide In the same manner as in Reference Example 63, The title compound was synthesized using 3-benzyl-2,2,4,5,7-pentamethyl-2,3-dihydro-1-benzofuran-6-amine obtained in Example 79. Yield 38%. Melting point 209-210 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.26 (3H, s), 1.40 (3H, s), 1.80 (3H, s), 2.01 (3H, s), 2.07 (3H, s ), 2.29 (2H, s), 2.75 (1H, dd, J = 14.7, 6.0 Hz), 2.89 (1H, dd, J = 14.7, 8.4 Hz), 3.29 (1H, dd, J = 8.4, 6.0 Hz) , 6.60 (1H, br s), 7.10-7.30 (5H, m).

N- (3- (4-Isopropylphenyl) -2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-yl) -3,3-dimethylbutanamide In the same manner as in Reference Example 63, The title compound was synthesized using 3- (4-isopropylphenyl) -2,2,5-trimethyl-2,3-dihydro-1-benzofuran-7-amine obtained in Reference Example 96. Yield 51%. Melting point 64-68 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.12 (9H, s), 1.24 (6H, d, J = 6.9 Hz), 1.57 (3H, s), 2.25 (3H, s), 2.27 (2H, s), 2.89 (1H, septet, J = 6.9 Hz), 4.30 (1H, s), 6.59 (1H, s), 6.99 (2H, d, J = 8.1 Hz), 7.14 (2H, d , J = 8.1 Hz), 7.17 (1H, br s), 7.98 (1H, s).

N- (3- (4-Isopropylphenyl) -5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-yl) -3,3-dimethylbutanamide Reference In the same manner as in Example 63, 3- (4-isopropylphenyl) -5-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-7-amine obtained in Reference Example 97 Was used to synthesize the title compound. Yield 67%. Melting point 140-141 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, s), 1.14 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.47 (3H, s), 1.83 (3H, s), 2.20 (3H, s), 2.28 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 3.64 (3H, s), 4.10 (1H, s), 6.40-7.18 (5H, m).

N- (3- (4-Isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -N, 3,3-trimethylbutanamide N-synthesized in Example 320 (3- (4-Isopropylphenyl) -2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (110 mg, 290 mmol) in DMF (3 mL ) Sodium hydride (60% liquid paraffin dispersion, 12.8 mg, 319 mmol) was added to the solution at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (8.0 g, 319 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted with diisopropyl ether. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 4: 1) to give 47 mg of the title compound (41% yield) ) Melting point 78-79 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 0.93 (9H, s), 1.00 (3H, s), 1.24 (6H, d, J = 7.0 Hz), 1.62 (3H, s), 1.94-2.10 (2H, m ), 2.90 (1H, septet, J = 7.0 Hz), 3.19 (3H, s), 4.36 (1H, s), 6.77-6.92 (3H, m), 6.98 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 8.0 Hz).

N- (3- (4-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3- (4-morpholinyl) propionamide hydrochloride 3- (4-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (350 mg, 1.08 mmol) obtained in Reference Example 120 and chloride 3 -Triethylamine (0.18 mL, 1.30 mmol) was added to a methylene chloride (15 mL) solution of -chloropropionyl (0.39 mL, 3.72 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. A crude product of N- (3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3-chloropropionamide is obtained. It was. An ethanol mixture of this compound, morpholine and potassium carbonate was heated to reflux for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane-ethyl acetate 10: 1) to obtain the free base of the title compound. This compound was crystallized from 4N hydrochloric acid-ethyl acetate to obtain 230 mg of the title compound (yield 42%). Melting point 158-161 ° C. (methanol-diethyl ether).
¹ H-NMR (DMSO-d ₆ ) δ: 0.94 (3H, s), 1.17 (6H, d, J = 6.9 Hz), 1.43 (3H, s), 1.66 (3H, s), 2.02 (3H, s ), 2.09 (3H, s), 2.77-2.98 (3H, m), 3.08-3.18 (2H, m), 3.25-3.47 (4H, m), 3.80 (2H, t, J = 12.0 Hz), 3.94 ( 2H, d, J = 11.4 Hz), 4.18 (1H, s), 4.42 (1H, br s), 6.60-7.20 (4H, m), 9.35 (1H, s).

Tert-butyl (2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamate 2,4,6-trimethyl- obtained in Reference Example 304 in the same manner as in Reference Example 59 The title compound was synthesized using 2,3-dihydro-1-benzofuran-5-amine. Yield quantitative. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, d, J = 6.3 Hz), 1.45 (9H, s), 2.12 (3H, s), 2.19 (3H, s), 2.69 (1H, dd, J = 7.5, 15.0 Hz), 3.21 (1H, dd, J = 8.7, 15.0 Hz), 4.80-4.97 (1H, m), 5.72 (1H, br s), 6.46 (1H, s).

(7-Bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid tert-butyl In a similar manner to Reference Example 66, the compound obtained in Example 331 (2,4 , 6-Trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid The title compound was synthesized using tert-butyl. Yield 75%. Melting point 115-116 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.35-1.58 (12H, m), 2.10 (3H, s), 2.31 (3H, s), 2.82 (1H, dd, J = 7.5, 15.0 Hz), 3.34 (1H , dd, J = 8.7, 15.0 Hz), 4.96-5.08 (1H, m), 5.83 (1H, br s).

Tert-Butyl (7- (hydroxy (4-isopropylphenyl) methyl) -2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid The title compound was synthesized using tert-butyl (7-bromo-2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamate obtained in Example 332. Yield 71%. Melting point 141-142 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 6.9 Hz), 1.38 (3H, d, J = 6.0 Hz), 1.49 (9H, s), 2.14 (6H, s), 2.71 ( 1H, dd, J = 7.5, 15.0 Hz), 2.80-2.90 (1H, septet, J = 6.9 Hz), 3.24 (1H, dd, J = 8.7, 15.0 Hz), 4.07 (1H, br d, J = 9.9 Hz), 4.93-5.08 (1H, m), 5.75 (1H, br s), 5.90 (1H, d, J = 9.9 Hz), 7.13 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz).

N- (7- (4-Isopropylbenzyl) -2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 224, Using tert-butyl (7- (hydroxy (4-isopropylphenyl) methyl) -2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) carbamic acid obtained in Example 333, The title compound was synthesized. Yield 32%. Melting point 179-180 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.44 (3H, d, J = 6.0 Hz), 2.06 (3H, s), 2.10 ( 3H, s), 2.26 (2H, s), 2.71-2.90 (2H, m), 3.27 (1H, dd, J = 8.7, 15.0 Hz), 3.91 (2H, s), 4.80-4.97 (1H, m) , 6.49 (1H, br s), 7.07 (4H, s).

N- (2- (hydroxymethyl) -7- (4-isopropylbenzyl) -2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Reference N- (4-hydroxy-3- (4-isopropylbenzyl) -2,6-dimethyl-5- (2-methylprop-2-en-1-yl) phenyl) -3,3-dimethyl obtained in Example 341 To a solution of butanamide (300 mg, 0.71 mmol) in methylene chloride (2 mL) was added a saturated aqueous sodium hydrogen carbonate solution (1 mL) and m-chloroperbenzoic acid (302 mg, 1.75 mmol) under ice cooling. The reaction solution was stirred at room temperature for 1 hour, added to water, and extracted with ethyl acetate. The combined organic layers were washed with 10% aqueous sodium sulfite solution and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane 3: 2) to obtain 61 mg (yield 20%) of the title compound. Melting point 186-187 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.42 (3H, s), 2.09 (6H, s), 2.27 (2H, s), 2.76-2.90 (2H, m), 3.14 (1H, d, J = 15.0 Hz), 3.56 (2H, m), 3.87 (1H, d, J = 15.6 Hz), 3.93 (1H, d, J = 15.6 Hz) ), 6.49 (1H, br s), 7.06 (2H, d, J = 8.1 Hz), 7.09 (2H, d, J = 8.1 Hz), 1H not confirmed.

N- (2- (iodomethyl) -7- (4-isopropylbenzyl) -2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Reference Example N- (4-hydroxy-3- (4-isopropylbenzyl) -2,6-dimethyl-5- (2-methylprop-2-en-1-yl) phenyl) -3,3-dimethylbutane obtained in 341 A solution of amide (300 mg, 0.71 mmol), benzyltrimethylammonium iododichloride (272 mg, 0.78 mmol), and calcium carbonate (92 mg, 0.92 mmol) in THF (5 mL) -methanol (5 mL) at room temperature for 12 hours. Stir. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium sulfite solution and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 380 mg (yield 98%) of the title compound. Oily substance.
¹ H-NMR (CDCl ₃ ) δ: 1.04 (9H, s), 1.19 (6H, d, J = 6.9 Hz), 1.65 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.21 (2H, s), 2.84 (1H, septet, J = 6.9 Hz), 2.98 (1H, d, J = 15.6 Hz), 3.26 (1H, d, J = 15.6 Hz), 3.41 (2H, s), 3.87 (2H, s), 6.68 (1H, br s), 7.05 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz).

N- (7- (4-Isopropylbenzyl) -2,4,6-trimethyl-2- (pyrrolidin-1-ylmethyl) -2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide N- (2- (iodomethyl) -7- (4-isopropylbenzyl) -2,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3 obtained in Example 336 , 3-Dimethylbutanamide (102 mg, 0.19 mmol) and pyrrolidine (1.5 mL) were reacted using a microwave apparatus (110 ° C., hold time 20 min, 250 W). Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 86 mg (yield 95%) of the title compound. Melting point 143-144 [deg.] C. (THF-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.19 (6H, d, J = 6.9 Hz), 1.43 (3H, s), 1.50-1.75 (4H, m), 2.07 (3H, s ), 2.09 (3H, s), 2.26 (2H, s), 2.42-2.63 (4H, m), 2.69 (2H, s), 2.73-2.90 (2H, m), 3.23 (1H, d, J = 15.0 Hz), 3.84 (1H, d, J = 15.3 Hz), 3.92 (1H, d, J = 15.3 Hz), 6.47 (1H, br s), 7.03 (2H, d, J = 8.1 Hz), 7.07 (2H , d, J = 8.1 Hz).

3,3-Dimethyl-N- (3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide In the same manner as in Example 234, Reference Example 342 The title compound was synthesized using 3,3-dimethyl-N- (2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in 1. did. Yield 82%. Melting point 217-218 [deg.] C. (THF-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.30 (3H, s), 1.49 (3H, s), 1.78 (1H, d, J = 9.0 Hz), 2.19 (3H, s), 2.25 (3H, s), 2.28 (2H, s), 4.69 (1H, d, J = 9.0 Hz), 6.51 (1H, s), 6.57 (1H, br s).

3,3-Dimethyl-N- (2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide 3,3-Dimethyl-N- (obtained in Example 338 Triethylsilane was added to a mixture of 3-hydroxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide (2.0 g, 6.55 mmol) in trifluoroacetic acid (3 mL). (2.09 g, 13.10 mmol) was added dropwise under ice cooling. After warming to room temperature and stirring for 30 minutes, the reaction mixture was added to water and extracted with ethyl acetate. The combined organic layers were washed with 1N aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.75 g (yield 92%) of the title compound. Melting point 181-182 ° C (THF-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.46 (6H, s), 2.08 (3H, s), 2.17 (3H, s), 2.27 (2H, s), 2.91 (2H, s ), 6.45 (1H, s), 6.48 (1H, br s).

N- (7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 20, The title compound was synthesized using 3,3-dimethyl-N- (2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) butanamide obtained in 339. Yield 85%. Melting point 180-181 ° C. (THF-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.52 (6H, s), 2.13 (3H, s), 2.20 (2H, s), 2.47 (3H, s), 2.92 (2H, s ), 6.54 (1H, br s), 10.33 (1H, s).

N- (7- (hydroxy (4-isopropylphenyl) methyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide magnesium (198 mg, 8.13 mmol) and a catalytic amount of iodine were added dropwise with THF (5 mL) solution of 1-bromo-4-isopropylbenzene (1.62 g, 8.13 mmol) at room temperature under argon atmosphere at room temperature. Was heated until the iodine color disappeared. The reaction mixture was stirred at room temperature with N- (7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-2,3-dihydro-1-benzofuran-5-yl obtained in Example 340. ) -3,3-dimethyl-butanamide (860 mg, 2.71 mmol) in THF (5 mL) was added dropwise and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to synthesize 1.15 g (97% yield) of the title compound. Amorphous powder.
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.21 (6H, d, J = 6.9 Hz), 1.42 (3H, s), 1.49 (3H, s), 2.07 (3H, s), 2.10 (3H, s), 2.27 (2H, s), 2.85 (1H, septet, J = 6.9 Hz), 2.92 (2H, s), 4.17 (1H, d, J = 10.2 Hz), 5.86 (1H, d , J = 10.2 Hz), 6.59 (1H, br s), 7.11 (2H, d, J = 8.1 Hz), 7.25 (2H, d, J = 8.1 Hz).

N- (7- (4-Isopropylbenzoyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 341 N- (7- (hydroxy (4-isopropylphenyl) methyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Manganese dioxide (415 mg, 4.8 mmol) was added to a solution of (209 mg, 0.48 mmol) in methylene chloride (7 mL), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 2: 3) to give 156 mg (yield 75%) of the title compound. Melting point 194-195 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.26 (6H, d, J = 7.0 Hz), 1.35 (6H, s), 2.00 (3H, s), 2.14 (3H, s), 2.30 (2H, s), 2.84-3.05 (3H, m), 6.62 (1H, br s), 7.25 (2H, d, J = 8.0 Hz), 7.80 (2H, d, J = 8.0 Hz).

N-(7- bromo -2,2,4,6- tetramethyl-2,3 Jihido Russia - 1-benzofuran-5-yl) -3,3-in the same manner as dimethylbutanamide Reference Example 66, carried out obtained in example 339 3,3-dimethyl-N-(2,2,4,6-tetramethyl-2,3 Jihido Russia - 1-benzofuran-5-yl) using butanamide, the title compound was synthesized . Yield 85%. Melting point 205-206 ° C. (methanol).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.51 (6H, s), 2.05 (3H, s), 2.28 (2H, s), 2.28 (3H, s), 3.02 (2H, s ), 6.58 (1H, br s).

N- (7- (4-Isopropylphenoxy) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 343 N- (7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide (500 mg, 1.36 mmol), 4 A mixture of isopropylphenol (556 mg, 4.08 mmol) and potassium carbonate (188 mg, 1.36 mmol) in pyridine (16 mL) was stirred at 140 ° C. for 1 hour under an argon atmosphere. Copper iodide (259 mg, 1.36 mmol) was added to the reaction solution, and the mixture was stirred at 140 ° C. for 60 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) and Gilson HPLC to obtain 230 mg (yield 40%) of the title compound. Melting point 148-149 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.14 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.42 (6H, s), 2.00 (3H, s), 2.11 (3H, s), 2.27 (2H, s), 2.84 (1H, septet, J = 6.9 Hz), 2.97 (2H, s), 6.56 (1H, br s), 6.77 (2H, d, J = 8.7 Hz), 7.06 (2H, d, J = 8.7 Hz).

3,3-Dimethyl-N- (2,2,4,6-tetramethyl-7- (4-methylphenoxy) -2,3-dihydro-1-benzofuran-5-yl) butanamide As in Example 344 N- (7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide obtained in Example 343 and 4 -The title compound was synthesized using methylphenol. Yield 19%. Melting point 182-184 ° C (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.35 (3H, s), 1.48 (3H, s), 1.98 (3H, br s), 2.08 (3H, s), 2.25 (2H, s), 2.86-2.97 (2H, m), 5.28 (1H, br s), 6.14 (1H, d, J = 3.84 Hz), 6.66 (1H, br s), 7.11-7.17 (2H, m), 7.54 -7.59 (1H, m), 8.51 (1H, d, J = 5.0 Hz).

N- (3-hydroxy-7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 234, N- (7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran- obtained in Reference Example 330 was used. The title compound was synthesized using 5-yl) -3,3-dimethylbutanamide. Yield 81%. M.p. 244-245 [deg.] C (THF-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.33 (3H, s), 1.51 (3H, s), 2.09 (3H, s), 2.26 (5H, m), 2.84 (1H, septet, J = 6.9 Hz), 3.91 (2H, d, J = 15.0 Hz), 4.76 (1H, d, J = 8.7 Hz), 6.53 (1H, br s) , 7.07 (4H, s) 1H unconfirmed.

N- (3-hydroxy-7- (4-isopropylbenzyl) -2,2,3,4,6-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 239, N- (7- (4-isopropylbenzyl) -2,2,4,6-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran obtained in Reference Example 330 The title compound was synthesized using -5-yl) -3,3-dimethylbutanamide and methylmagnesium bromide. Yield 92% Melting point 170-171 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.20 (6H, d, J = 6.9 Hz), 1.33 (3H, s), 1.41 (3H, s), 1.44 (3H, s), 2.08 (3H, s), 2.27 (2H, s), 2.32 (3H, s), 2.83 (1H, septet, J = 6.9 Hz), 3.91 (2H, br), 6.49 (1H, br s), 7.06 ( 4H, s) 1H unconfirmed.

N- (3- (4-Isopropylphenyl) -4,6,7-trimethyl-3H-spiro (1-benzofuran-2,1′-cyclopentane) -5-yl) -3,3-dimethylbutanamide In the same manner as in Example 1, 3- (4-isopropylphenyl) -4,6,7-trimethyl-3H-spiro (1-benzofuran-2,1′-cyclopentane) -5-amine obtained in Reference Example 325 Was used to synthesize the title compound. Yield 57%. Melting point 209-210 ° C. (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.06-1.38 (16H, m), 1.50-1.92 (9H, m), 1.99-2.08 (1H, m), 2.14 (3H, s), 2.15 (3H, s) , 2.24 (2H, s), 2.84 (1H, septet, J = 6.9 Hz), 4.16 (1H, s), 6.48 (1H, br s), 6.88 (2H, d, J = 8.1 Hz), 7.05 (2H , d, J = 8.1 Hz).

N-((cis) -3- (4-isopropylphenyl) -2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Example 316 and Similarly, (cis) -3- (4-isopropylphenyl) -2,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride obtained in Reference Example 351 and tert-butyl were used. The title compound was synthesized using acetyl chloride. Yield 83%. Melting point 94-95 ° C. (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, d, J = 7.0 Hz), 1.09 (9H, s), 1.22 (6H, d, J = 7.0 Hz), 2.15 (3H, s), 2.19 ( 2H, s), 2.21 (3H, s), 2.86 (1H, sept, J = 7.0 Hz), 4.31 (1H, d, J = 8.0 Hz), 4.96-5.05 (1H, m), 6.72 (1H, s ), 6.89 (2H, d, J = 8.0 Hz), 7.00 (1H, s), 7.11 (2H, d, J = 8.0 Hz).

(Cis) -3- (4-Isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-amine Obtained in Reference Example 352 in the same manner as Reference Example 23. (Cis) -3- (4-Isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran was used to give (cis) -5-bromo-3- (4 -Isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran was synthesized. Using this compound, in the same manner as in Reference Example 24, (cis) -N-benzyl-3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1- Benzofuran-5-amine was synthesized. Using this compound, the title compound was synthesized in the same manner as in Reference Example 30. Yield 83%.
Melting point 91-92 ° C. (hexane).
¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.06 (3H, d, J = 7.0 Hz), 1.21 (6H, d, J = 7.0 Hz), 1.84 (3H, s), 2.12 (3H, s) , 2.21 (3H, s), 2.85 (1H, septet, J = 7.0 Hz), 3.25 (2H, br s), 4.29 (1H, d, J = 8.0 Hz), 4.83-4.96 (1H, m), 6.83 (2H, d, J = 8.0 Hz), 7.07 (2H, d, J = 8.0 Hz).

N-((trans) -3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Reference In the same manner as in Example 199, using 3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran obtained in Reference Example 347, 3- (4-isopropylphenyl) -2, A mixture of cis form and trans form (3: 2) of 4,6,7-tetramethyl-2,3-dihydro-1-benzofuran was synthesized. This compound was used as a mixture in the same manner as in Reference Example 23. A mixture of body and trans body was obtained. Using this compound, in the same manner as in Reference Example 24, N-benzyl- (3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5 I) A mixture of cis and trans isomers of amine was obtained. (3- (4-Isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) amine was prepared using this compound in the same manner as in Reference Example 30. Was synthesized. N- (3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-2,3-dihydro-1 was prepared in the same manner as in Example 1 using this compound and tert-butylacetyl chloride. -Benzofuran-5-yl) -3,3-dimethylbutanamide cis- and trans-isomer mixture was obtained. The mixture was purified by silica gel column chromatography (ethyl acetate-hexane 1: 4) to synthesize the title compound. Yield 18%. Mp 143-144 ° C (hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 7.0 Hz), 1.46 (3H, d, J = 6.0 Hz), 1.76 (3H, s), 2.14 ( 3H, s), 2.17 (3H, s), 2.24 (2H, s), 2.86 (1H, sept, J = 7.0 Hz), 4.08 (1H, d, J = 6.0 Hz), 4.58-4.67 (1H, m ), 6.48 (1H, s), 7.05 (2H, d, J = 8.0 Hz), 7.13 (2H, d, J = 8.0 Hz).

N- (7- (hydroxy (pyridin-2-yl) methyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide N-Butyllithium (1.6 M, hexane solution, 2.13 mL, 3.4 mmol) was added dropwise to a solution of 2-bromopyridine (553 mg, 3.5 mmol) in diethyl ether (3.0 mL) at −70 ° C. under an argon atmosphere. Stir for 30 minutes. Obtained in Example 340 reaction solution N-(7- formyl -2,2,4,6- tetramethyl-2,3 Jihido Russia - 1-benzofuran-5-yl) -3,3-dimethyl butanamide A solution of (317 mg, 1.0 mmol) in THF (4.0 mL) was added dropwise at −70 ° C., stirred for 30 minutes, and then warmed to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate-hexane 1:10) and then silica gel column chromatography (ethyl acetate-hexane 1: 1) to give 270 mg (yield 68%) of the title compound. Melting point 176-177 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.35 (3H, s), 1.48 (3H, s), 1.98 (3H, br s), 2.08 (3H, s), 2.25 (2H, s), 2.86-2.97 (2H, m), 5.28 (1H, br s), 6.14 (1H, d, J = 3.84 Hz), 6.66 (1H, br s), 7.11-7.17 (2H, m), 7.54 -7.59 (1H, m), 8.51 (1H, d, J = 5.0 Hz).

N- (7- (1-hydroxy-2- (4-isopropylphenyl) ethyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3 -Dimethylbutanamide In the same manner as in Example 341, N- (7-formyl-2,2,4,6-tetramethyl-2,3-dihydro-2,3-dihydro-1-- obtained in Example 340 was used. The title compound was synthesized using benzofuran-5-yl) -3,3-dimethyl-butanamide and 4-isopropylbenzyl chloride. Yield 92%. Amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.12 and 1.17 (9H, sx 2), 1.20-1.25 (6H, m), 1.45 and 1.48 (6H, sx 2), 1.88 (3H, s), 2.05 and 2.07 ( 3H, sx 2), 2.24 and 2.25 (2H, sx 2), 2.79-3.11 (5H, m), 3.76 (1H, br d, J = 16.0 Hz), 4.87-5.00 (1H, m), 6.69 (1H , br s), 7.03-7.13 (4H, m).

N- (7- (2- (4-Isopropylphenyl) ethyl))-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane Amide In the same manner as in Example 271, N- (7- (1-hydroxy-2- (4-isopropylphenyl) ethyl) -2,2,4,6-tetramethyl-2,3 obtained in Example 353 was used. The title compound was synthesized using -dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide. Yield 64%. Melting point 144-145 [deg.] C (hexane-ethyl acetate).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (9H, s), 1.23 (3H, s), 1.25 (3H, s), 1.43 (6H, s), 2.07 (3H, s), 2.13 (3H, s ), 2.29 (2H, s), 2.69-2.88 (5H, m), 2.92 (2H, br s), 6.51 (1H, br s), 7.15 (4H, s).

N- (7- (1-hydroxy (phenyl) methyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples 239 in the same manner as was obtained in example 340 N-(7- formyl -2,2,4,6- tetramethyl-2,3 Jihido Russia - 1-benzofuran-5-yl) -3,3 The title compound was synthesized using dimethyl-butanamide and phenylmagnesium bromide. Yield quantitative. Amorphous.
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.38 (3H, s), 1.49 (3H, s), 2.07 (3H, s), 2.10 (3H, s), 2.27 (2H, s ), 2.92 (2H, s), 4.24 (1H, br d, J = 10.0 Hz), 5.91 (1H, d, J = 10.0 Hz), 6.68 (1H, br s), 7.20-7.36 (5H, m) .

N-((7-benzyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide In the same manner as in Example 271, N- (7- (1-hydroxy (phenyl) methyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3 obtained in Example 355 -The title compound was synthesized using dimethylbutanamide. Yield 74%. Melting point 129-130 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.46 (6H, s), 2.04 (3H, s), 2.08 (3H, s), 2.25 (2H, s), 2.96 (2H, br s), 3.93 (2H, br s), 6.49 (1H, br s), 7.10-7.20 (5H, m).

3,3-Dimethyl-N- (2,2,4,6-tetramethyl-7- (2-methylbenzyl) -2,3-dihydro-1-benzofuran-5-yl) butanamide As in Example 239 Te, N- obtained in example 340 (7-formyl -2,2,4,6- tetramethyl-2,3 Jihido Russia - 1-benzofuran-5-yl) -3,3-dimethyl - butanamide and Using 2-methylphenylmagnesium bromide, N- (7- (hydroxy (2-methylphenyl) methyl) -2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide was synthesized. The title compound was synthesized in the same manner as in Example 271. Yield 24%. Melting point 175-176 ° C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.13 (9H, s), 1.41 (6H, s), 1.94 (3H, s), 2.12 (3H, s), 2.27 (2H, s), 2.38 (3H, s ), 2.96 (2H, br s), 3.85 (2H, br s), 6.54 (1H, br s), 6.76 (1H, d, J = 7.0 Hz), 6.98-7.14 (3H, m).

N-((3R) -7- (2-furyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide In the same manner as in Example 107, (-)-N-((3R) -7-bromo-3- (4-isopropylphenyl) -4,6-dimethyl-2,3- The title compound was obtained using dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide and 2-furyl (diphenyl) methanol. Yield 6%. Melting point 214-217 [deg.] C. (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.12 (9H, s), 1.22 (6H, d, J = 6.9 Hz), 1.89 (3H, s), 2.27 (5H, s), 2.86 (1H, septet, J = 6.9 Hz), 4.46 (1H, dd, J = 4.9, 8.6 Hz), 4.56 (1H, dd, J = 4.9, 9.1 Hz), 4.87 (1H, dd, J = 8.6, 9.1 Hz), 6.51 (1H , dd, J = 1.6, 3.3 Hz), 6.53 (1H, s), 6.58 (1H, d, J = 3.3 Hz), 7.07 (2H, d, J = 8.2 Hz), 7.13 (2H, d, J = 8.2 Hz), 7.53 (1H, d, J = 1.6 Hz).

N-((3R) -7-benzoyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Examples (+)-N-((3R) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5 obtained in Example 37 in the same manner as in Example 38. Yl) -3,3-dimethylbutanamide and benzoyl chloride were used to give the title compound. Yield 74%. Mp 205-206 ° C (ethyl acetate-hexane).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (9H, s), 1.23 (6H, d, J = 6.9 Hz), 1.93 (3H, s), 2.07 (3H, s), 2.27 (2H, s), 2.87 (1H, septet, J = 6.9 Hz), 4.34 (1H, dd, J = 4.9, 8.6 Hz), 4.54 (1H, dd, J = 4.9, 9.1 Hz), 4.77 (1H, dd, J = 8.6, 9.1 Hz), 6.59 (1H, s), 7.06 (2H, d, J = 7.9 Hz), 7.14 (2H, d, J = 7.9 Hz), 7.46 (2H, dd, J = 7.4, 7.7 Hz), 7.57 (1H, t, J = 7.4 Hz), 7.92 (2H, d, J = 7.7 Hz).

  The structures of the compounds of Examples are shown in Tables 1 to 7 below.

The compound obtained in Example 1 is dissolved in physiological saline containing 30% (W / V) polyethylene glycol 400, and a 0.01% solution of the compound is prepared. Noted. Injections containing 1 mg of compound per vial were prepared.
[Formulation Example 2]

The compound obtained in Example 1 was dissolved in physiological saline containing 5% cyclodextrin to prepare a 0.1% solution of the compound, and after sterile filtration, 10 mL each was dispensed into a vial. Injections containing 10 mg of compound per vial were prepared.
[Formulation Example 3]

(1) 50 mg of the compound obtained in Example 1
(2) Lactose 34mg
(3) Corn starch 10.6mg
(4) Corn starch (paste) 5mg
(5) Magnesium stearate 0.4mg
(6) Carboxymethylcellulose calcium 20mg
120mg total
According to a conventional method, the above (1) to (6) were mixed and tableted with a tableting machine to obtain tablets.
[Experimental Example 1]

With human CB1 and CB2 receptor expressing cell membrane fraction ^[3 H] -CP55,940 binding assay ^[3 H] -CP55940 binding inhibition assays, CB1 receptor expressing CHO cell membrane fraction and the test compounds and 500 pM ^[3 H] -CP55940 was incubated in a reaction buffer (50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 2.5 mM EDTA, 0.5% BSA (fatty acid free)) at room temperature for 60 minutes. . The reaction solution was filtered through a GF / C filter, washed 4 times with 300 μl of a washing buffer (50 mM Tris-HCl (pH 7.4), 0.05% BSA (fatty acid free)), and then the radioactivity of the filter was determined. Measured with a top count scintillation counter (Packard). The test compound inhibited the binding of [ ³ H] -CP55940 to the membrane fraction in a concentration-dependent manner.

The [ ³ H] -CP55940 binding inhibitory activity of the test compound is 100% of the radioactivity when only 500 pM [ ³ H] -CP55940 is added, and the radioactivity when 500 pM [ ³ H] -CP55940 and 100 nM CP55940 are added simultaneously. The percentage was calculated as 0%. Furthermore, the IC ₅₀ value of the test compound was calculated by analyzing the test compound concentration and percentage value using PRISM 3.0 (Graphpad Software, Inc.).

The same test was performed for the CB2 receptor-expressing CHO cell membrane, and [ ³ H] -CP55940 binding inhibitory activity was calculated.

  The results are shown in Table 8.

［実験例２］

[Experiment 2]

In vivo CB1 receptor agonistic activity of the compounds of the present invention was evaluated by administering drugs to mice and then examining their effects on body temperature. In the experiment, Jcl: ICR male mice (5 weeks old) were used. After measuring rectal temperature with a thermometer (Physitemp BAT-12) connected to a body temperature measurement probe, a compound dissolved in 2.2% EtOH, 5% G2-β-cyclodextrin (solvent) was administered intraperitoneally. did. Only the solvent was administered to the control group. Rectal temperature was measured again 30 minutes after administration. Experiments were conducted with 4 cases per group.

  For the compounds of the invention, 1 mg / kg, i.e. p. Compared with the control group 30 minutes after administration, the test result was validated when a significant decrease in body temperature of 1 ° C. or more was observed.

  The results are shown in Table 9.

As shown in Table 9, the compounds of the present invention exerted a hypothermic effect based on CB1 receptor agonist activity at a very low dose.
[Experiment 3]

Effect of reducing cerebral infarction in experimental cerebral infarction model Jcl: SD male rats (8 weeks old) were used for the experiment. A cannula was inserted from the left common jugular vein under halothane anesthesia for continuous infusion. A silicone-coated nylon obturator is inserted from the left common carotid artery to occlude the middle cerebral artery (MCAO). After occlusion for 120 minutes, after light anesthesia with halothane again, the obturator was removed and reperfusion was performed. Rats were observed for neurological symptoms during MCAO and only rats that developed typical symptoms were used in the experiment. The drug was dissolved in 2.2% EtOH, 5% G2-β-cyclodextrin (solvent). The test compound was intraperitoneally administered 3 times the minimum dose at which a body temperature lowering effect was observed immediately after reperfusion, and the same amount was administered after 2, 4, and 6 hours. Here, as the test compound, one compound was selected from the compounds showing excellent activity in Experimental Example 1 and Experimental Example 2. The same amount of solvent was similarly administered to the control group. Two days after MCAO treatment, the rats were decapitated, the brains were removed, and six 2 mm thick forehead brain slices were prepared under ice cooling. Each section was stained with 1% TTC solution at 37 ° C. for 15 minutes and photographed with a digital camera. The area was measured by using the image analysis software (Photoshop (trade name)) with the white portion of each cross section as the infarct, and the infarct volume was obtained by multiplying the thickness of the section. As a result, when carried out at a dose of 0.5 mg / kg, a significant reduction in infarct volume of 30% or more was observed.

  As is apparent from the above, compound (I) and the like have an excellent cannabinoid receptor function regulating action. In addition, it exhibits a cerebral infarction protective action and has a medicinal action such as cerebrovascular disorder treatment. Furthermore, toxicity is extremely low, and it is thought that it is excellent in brain migration.

  As described above, according to the present invention, an excellent cannabinoid receptor modulator useful as a medicine is provided.

Claims (6)

N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
(+)-N-((3R) -3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide ,
N- (7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
N- (3- (4-Isopropylphenyl) -7-methoxy-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
(+)-N-((3R) -7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide,
(+)-N- (tert-butyl) -N ′-((3R) -3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl Urea,
N- (3- (4-isopropylphenyl) -4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
N- (7- (3-dimethylaminophenyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide ,
N- (3-hydroxypropyl) -N ′-(3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) urea,
N- ( 3- (4-Isopropyl-3- (2-methoxyethoxy) phenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutane Amide,
N- (7- (4-isopropylbenzyl) -3,4,6-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
N- (3- (4-tert-butylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
N- (3- (4-isopropylphenyl) -4,6,7-trimethyl-3H-spiro (1-benzofuran-2,1′-cyclopentane) -5-yl) -3,3-dimethylbutanamide,
N- (3- (4-isopropylphenyl) -4,6-dimethyl-7-propyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
(+)-N-((3R) -7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)- 3,3-dimethylbutanamide,
N- (7- (6-Fluoropyridin-3-yl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3- Dimethylbutanamide,
N- (7- (3-furyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide,
N- (7-hydroxy-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide, and N- (7 -Ethoxy-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide or a compound thereof salt.   (+)-N-((3R) -3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethylbutanamide Or its salt.   (+)-N-((3R) -7-acetyl-3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl) -3,3-dimethyl Butanamide or a salt thereof.   (+)-N- (tert-butyl) -N ′-((3R) -3- (4-isopropylphenyl) -4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl ) Urea or its salt.   (+)-N-((3R) -7- (1-hydroxyethyl) -3- (4-isopropylphenyl) -4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)- 3,3-dimethylbutanamide or a salt thereof.   A medicament comprising the compound according to claim 1.