JP5983713B2 - Pharmaceuticals containing prodrugs of fluorine-containing amino acids - Google Patents

Description

The present invention relates to (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (hereinafter referred to as a metabotropic glutamate receptor agonist). And a prodrug of the parent compound or compound (IV)). More specifically, for example, neuropsychiatric disorders such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorder, epilepsy, developmental disorders, sleep disorders, and drug addiction, cognitive disorders, Alzheimer's disease, Huntington's choreography Diseases associated with group 2 metabotropic glutamate receptors, such as neurological diseases such as Parkinson's disease, movement disorders associated with muscle stiffness, cerebral ischemia, brain failure, spinal cord disorder, and head disorders (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane- is a metabotropic glutamate receptor agonist expected to be useful as a therapeutic and prophylactic agent The present invention relates to a pharmaceutical composition containing a prodrug of 2,6-dicarboxylic acid.
In addition, the present invention provides a prodrug in which the parent compound, which is a compound that acts on a metabotropic glutamate receptor, has a mucosal absorbability such as oral absorbability increased by increasing the amount of exposure of the parent compound in vivo. It is related with the pharmaceutical composition to contain.

In recent years, the glutamate receptor gene has been cloned one after another, and it has become clear that there are many subtypes of glutamate receptors. At present, glutamate receptors are broadly classified into two types: “ion channel type in which the receptor has an ion channel type structure” and “metabolic type in which the receptor is coupled to G-protein”. Furthermore, ion channel glutamate receptors are classified into three types, NMDA, α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), and kainate (Non-patent Document 1). Metabotropic glutamate Receptors are classified into 8 types, mGluR1 to mGluR8 (Non-patent Documents 2 and 3). Group 2 metabotropic glutamate receptors are present in the presynapse of the glutamate nervous system and function as self-receptors, so that excessive release of glutamate is suppressed (Non-Patent Documents 4 and 5). Since the glutamate nervous system is involved in various neuropsychiatric functions, compounds that act on group 2 metabotropic glutamate receptors should be effective in the treatment or prevention of acute and chronic neuropsychiatric and neurological disorders .
(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid is disclosed as an agonist of group 2 metabotropic glutamate receptors. (Patent Document 1). The ED ₅₀ value of the agonist activity, are each 29.4 nm (mGluR2) and 45.4nM (mGluR3), the effect of suppressing also recognized the phencyclidine hyperkinetic rat schizophrenia model, the ED ₅₀ The value is reported to be 5.1 mg / kg. Furthermore, an effect of suppressing phencyclidine-induced swinging behavior and condition avoidance reaction, which is a schizophrenia model, has been recognized (Non-patent Documents 6 and 7).
However, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid has poor oral absorbability in monkeys. Therefore, there is a possibility that oral absorption is also poor for humans.
There are roughly two approaches for improving mucosal absorbability such as oral absorbability of compounds. One is a method for changing the chemical structure of the compound itself, and the other is a method for devising a formulation without changing the chemical structure. Among the former is prodrug formation in which a small modifying group such as an alkyl group or an acyl group is bonded to a reactive substituent such as a hydroxyl group or amino group of a compound.
The prodrug is stable as a prodrug before absorption, and the absorption is improved by prodrug formation, and in the small intestine, liver, and / or plasma during or after absorption, chemically or enzymatically A compound that is rapidly converted to the parent compound is desired.
However, it is difficult to develop an ideal prodrug that satisfies all the above conditions. For example, since a prodrug derivative having an ester bond may be susceptible to hydrolysis reaction, it may greatly affect the chemical stability before absorption. Prodrug derivatives having an amide bond may greatly affect mucosal absorbability such as oral absorbability due to large changes in the physical properties of the compound. In addition, since the amide bond is difficult to be hydrolyzed, it may greatly affect the conversion of the compound into the parent compound in vivo and the plasma concentration. In addition, enzymes that control biotransformation of prodrugs to parent compounds have substrate specificity, and in particular, the prodrug's body such as the enzyme cannot react due to steric hindrance of the substituent inserted to form a prodrug. It is difficult to predict dynamics. For these reasons, it is not easy to increase the plasma concentration of the parent compound by estimating the mucosal absorption such as oral absorption of the prodrug compound and the conversion to the parent compound.
In fact, Patent Document 1 generally describes a prodrug of (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid. However, there is no specific disclosure at all, and there has been no successful example of prodrug formation until 1999 after the filing of this document.

JP 11-279129 A

Science, 258, 597-603, 1992. J. et al. Neurosci. , 13, 1373-1378, 1993. Neuropharmacol. , 34, 1-26, 1995. Neuropharmacol. , 40, 20-27, 2001. Eur. J. et al. Pharmacol. 356, 149-157, 1998. J. et al. Med. Chem. 43, 4893-4909, 2000. Life Science, 73, 1721-1728, 2003.

  The object of the present invention is to treat and prevent neuropsychiatric diseases such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorder, epilepsy, developmental disorders, sleep disorders, etc., and drug dependence, cognitive disorders Group 2 metabotropic glutamate receptors such as Alzheimer's disease, Huntington's disease, Parkinson's disease, movement disorders associated with muscle stiffness, cerebral ischemia, brain failure, spinal cord disorder, and head disorders As a therapeutic or prophylactic agent for a disease that is said to be present, a pharmaceutical comprising a prodrug that enhances mucosal absorbability such as oral absorbability of a parent compound acting on a group 2 metabotropic glutamate receptor and increases in vivo exposure Is to provide.

We have (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid acting on group 2 metabotropic glutamate receptors. As a result of intensive investigations on prodrugs containing acid as the parent compound, it was found that certain derivatives, as prodrugs, increased mucosal absorbability such as oral absorption and increased in vivo exposure of the parent compound. It came to be completed.
Hereinafter, the present invention will be described in detail. Examples of the present invention (hereinafter referred to as “the compound of the present invention”) include the following.
(1) Formula (I)

［式（Ｉ）中、
Ｒ¹及びＲ²は、同一又は異なって、水素原子、式‐（ＣＲ⁴Ｒ⁴’）‐Ｏ‐ＣＯ‐Ｒ⁵、式‐（ＣＲ⁶Ｒ⁶’）‐Ｏ‐ＣＯ‐Ｏ‐Ｒ⁷、下記式（ＩＩａ）又は式（ＩＩｂ）を示し、

[In the formula (I),
R ¹ and R ² are the same or different and each represents a hydrogen atom, a formula — (CR ⁴ R ⁴ ′) —O—CO—R ⁵ , a formula — (CR ⁶ R ⁶ ′) —O—CO—O—R ⁷ Represents the following formula (IIa) or (IIb):

Ｒ³は、水素原子、式‐（ＡＡ）ｎ‐Ｈ、式‐ＣＯ‐Ｏ‐（ＣＲ⁹Ｒ⁹’）‐Ｏ‐ＣＯ‐Ｒ¹⁰、式‐ＣＯ‐Ｏ‐（ＣＲ⁹Ｒ⁹’）‐Ｏ‐ＣＯ‐Ｏ‐Ｒ¹¹、又は下記式（ＩＩＩ）を示し、

R ³ is a hydrogen atom, a formula — (AA) n—H, a formula —CO—O— (CR ⁹ R ⁹ ′) —O—CO—R ¹⁰ , a formula —CO—O— (CR ⁹ R ⁹ ′) -O-CO-O-R ¹¹ or the following formula (III):

Ｒ⁴及びＲ⁴’は、同一又は異なって、水素原子又はＣ_1-6アルキル基を示し、
Ｒ⁵は、Ｃ_1-10アルキル基、Ｃ_3-8シクロアルキル基（該Ｃ_3-8シクロアルキル基は、１〜３個のＣ_1-6アルキル基で置換されてもよい）、アダマンチル基（該アダマンチル基は、１〜３個のＣ_1-6アルキル基で置換されてもよい）、又はフェニル基（該フェニル基は、ハロゲン原子及びＣ_1-6アルキル基から選ばれる１〜３個の基で置換されてもよい）を示し、
Ｒ⁶及びＲ⁶’は、同一又は異なって水素原子又はＣ_1-6アルキル基を示し、
Ｒ⁷は、Ｃ_1-10アルキル基、Ｃ_3-8シクロアルキル基（該Ｃ_3-8シクロアルキル基は、１〜３個のＣ_1-6アルキル基で置換されてもよい）、アダマンチル基（該アダマンチル基は、１〜３個のＣ_1-6アルキル基で置換されてもよい）又はアリール基（該アリール基は、ハロゲン原子及びＣ_1-6アルキル基から選ばれる１〜３個の基で置換されてもよい）を示し、
Ｒ⁸は、Ｃ_1-6アルキル基又はフェニル基を示し、
Ｒ⁹及びＲ⁹’は、同一又は異なって、水素原子又はＣ_1-6アルキル基を示し、
Ｒ¹⁰は、Ｃ_1-10アルキル基、Ｃ_3-8シクロアルキル基（該Ｃ_3-8シクロアルキル基は、１〜３個のＣ_1-6アルキル基で置換されてもよい）、アダマンチル基（該アダマンチル基は、１〜３個のＣ_1-6アルキル基で置換されてもよい）又はフェニル基（該フェニル基は、ハロゲン原子及びＣ_1-6アルキル基から選ばれる１〜３個の基で置換されてもよい）を示し、
Ｒ¹¹は、Ｃ_1-10アルキル基、Ｃ_3-8シクロアルキル基（該Ｃ_3-8シクロアルキル基は、１〜３個のＣ_1-6アルキル基で置換されてもよい）、アダマンチル基（該アダマンチル基は、１〜３個のＣ_1-6アルキル基で置換されてもよい）又はアリール基（該アリール基は、ハロゲン原子及びＣ_1-6アルキル基から選ばれる１〜３個の基で置換されてもよい）を示し、
Ｒ¹²は、Ｃ_1-6アルキル基又はフェニル基を示し、
ＡＡは、アミノアシル基を示し、
ｎは、１〜３の整数を示す。
ただし、Ｒ¹、Ｒ²及びＲ³が全て水素原子である化合物を除く。］
で表される化合物、又はその医薬上許容される塩を含有する、統合失調症、不安障害及びその関連疾患、うつ病、双極性障害、てんかん、発達障害、睡眠障害等の精神神経疾患、並びに、薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患からなる群から選択される疾患の予防又は治療用医薬。
（２）式（Ｉ）中、
Ｒ³が、水素原子である（１）に記載の化合物、又はその医薬上許容される塩を含有する、統合失調症、不安障害及びその関連疾患、うつ病、双極性障害、てんかん、発達障害、睡眠障害等の精神神経疾患、並びに、薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患からなる群から選択される疾患の予防又は治療用医薬。
（３）式（Ｉ）中、
Ｒ¹が、式‐（ＣＲ⁴Ｒ⁴’）‐Ｏ‐ＣＯ‐Ｒ⁵（式中、Ｒ⁴、Ｒ⁴’及びＲ⁵は、（１）で定義した通りである）、式‐（ＣＲ⁶Ｒ⁶’）‐Ｏ‐ＣＯ‐Ｏ‐Ｒ⁷（式中、Ｒ⁶、Ｒ⁶’及びＲ⁷は、（１）で定義した通りである）、下記式（ＩＩａ）又は式（ＩＩｂ）、

R ⁴ and R ⁴ ′ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
R ⁵ represents a C _1-10 alkyl group, a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups), an adamantyl group (The adamantyl group may be substituted with 1 to 3 C _1-6 alkyl groups) or a phenyl group (the phenyl group is 1 to 3 groups selected from a halogen atom and a C _1-6 alkyl group) And may be substituted with a group of
R ⁶ and R ⁶ ′ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
R ⁷ represents a C _1-10 alkyl group, a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups), an adamantyl group (The adamantyl group may be substituted with 1 to 3 C _1-6 alkyl groups) or an aryl group (the aryl group is 1 to 3 selected from a halogen atom and a C _1-6 alkyl group) Which may be substituted with a group)
R ⁸ represents a C _1-6 alkyl group or a phenyl group,
R ⁹ and R ⁹ ′ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
R ¹⁰ represents a C _1-10 alkyl group, a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups), an adamantyl group (The adamantyl group may be substituted with 1 to 3 C _1-6 alkyl groups) or a phenyl group (the phenyl group is 1 to 3 selected from a halogen atom and a C _1-6 alkyl group) Which may be substituted with a group)
R ¹¹ represents a C _1-10 alkyl group, a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups), an adamantyl group (The adamantyl group may be substituted with 1 to 3 C _1-6 alkyl groups) or an aryl group (the aryl group is 1 to 3 selected from a halogen atom and a C _1-6 alkyl group) Which may be substituted with a group)
R ¹² represents a C _1-6 alkyl group or a phenyl group,
AA represents an aminoacyl group,
n shows the integer of 1-3.
However, compounds in which R ¹ , R ² and R ³ are all hydrogen atoms are excluded. ]
Comprising a compound represented by: or a pharmaceutically acceptable salt thereof, schizophrenia, anxiety disorder and related diseases, depression, bipolar disorder, epilepsy, developmental disorder, sleep disorder and other neuropsychiatric disorders, and Selected from the group consisting of neurological diseases such as addictive drugs, cognitive disorders, Alzheimer's disease, Huntington's disease, Parkinson's disease, movement disorders associated with muscle stiffness, cerebral ischemia, brain failure, spinal cord disorder, and head disorders A drug for the prevention or treatment of diseases.
(2) In formula (I),
Schizophrenia, anxiety disorder and related diseases, depression, bipolar disorder, epilepsy, developmental disorder containing the compound according to (1), wherein R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof , Neuropsychiatric disorders such as sleep disorders, as well as drug addiction, cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement disorders associated with muscle rigidity, cerebral ischemia, brain failure, spinal cord disorder, head disorders, etc. A medicament for preventing or treating a disease selected from the group consisting of neurological diseases.
(3) In formula (I),
R ¹ has the formula-(CR ⁴ R ⁴ ') -O-CO-R ⁵ (wherein R ⁴ , R ⁴ ' and R ⁵ are as defined in (1)), formula-(CR ⁶ R ⁶ ′) —O—CO—O—R ⁷ (wherein R ⁶ , R ⁶ ′ and R ⁷ are as defined in (1)), the following formula (IIa) or formula (IIb) ,

Ｒ⁸は、（１）で定義した通りである）
である（２）に記載の化合物、又はその医薬上許容される塩を含有する、統合失調症、不安障害及びその関連疾患、うつ病、双極性障害、てんかん、発達障害、睡眠障害等の精神神経疾患、並びに、薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患からなる群から選択される疾患の予防又は治療用医薬。
（４）式（Ｉ）中、
Ｒ¹が、式‐（ＣＲ⁴Ｒ⁴’）‐Ｏ‐ＣＯ‐Ｒ⁵（式中、Ｒ⁴、Ｒ⁴’及びＲ⁵は、（１）で定義した通りである）、式‐（ＣＲ⁶Ｒ⁶’）‐Ｏ‐ＣＯ‐Ｏ‐Ｒ⁷（式中、Ｒ⁶、Ｒ⁶’及びＲ⁷は、（１）で定義した通りである）、である（３）に記載の化合物、又はその医薬上許容される塩を含有する、統合失調症、不安障害及びその関連疾患、うつ病、双極性障害、てんかん、発達障害、睡眠障害等の精神神経疾患、並びに、薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患からなる群から選択される疾患の予防又は治療用医薬。
（５）式（Ｉ）中、
Ｒ¹が、式‐（ＣＲ⁴Ｒ⁴’）‐Ｏ‐ＣＯ‐Ｒ⁵または式‐（ＣＲ⁶Ｒ⁶’）‐Ｏ‐ＣＯ‐Ｏ‐Ｒ⁷であって、Ｒ⁵がアダマンチル基（該アダマンチル基は、１〜３個のメチル基で置換されてもよい）であり、Ｒ⁷が１〜３個のＣ_1-6アルキル基で置換されたＣ_3-8シクロアルキル基又はアダマンチル基（該アダマンチル基は、１〜３個のＣ_1-6アルキル基で置換されてもよい）であり、Ｒ⁴、Ｒ⁴’、 Ｒ⁶、及びＲ⁶’は（１）で定義した通りである、（４）に記載の化合物、又はその医薬上許容される塩を含有する、統合失調症、不安障害及びその関連疾患、うつ病、双極性障害、てんかん、発達障害、睡眠障害等の精神神経疾患、並びに、薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患からなる群から選択される疾患の予防又は治療用医薬。
（６）式（Ｉ）中、
Ｒ²が、水素原子である（２）〜（５）いずれか１つに記載の化合物、又はその医薬上許容される塩を含有する、統合失調症、不安障害及びその関連疾患、うつ病、双極性障害、てんかん、発達障害、睡眠障害等の精神神経疾患、並びに、薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患からなる群から選択される疾患の予防又は治療用医薬。
（７）式（Ｉ）中、
Ｒ¹及びＲ²が、共に水素原子であり、
Ｒ³が、式‐（ＡＡ）ｎ‐Ｈであり、
ＡＡが、アミノアシル基であり、
ｎが、１又は２である（１）に記載の化合物、又はその医薬上許容される塩を含有する、統合失調症、不安障害及びその関連疾患、うつ病、双極性障害、てんかん、発達障害、睡眠障害等の精神神経疾患、並びに、薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患からなる群から選択される疾患の予防又は治療用医薬。
（８）式（Ｉ）中、
Ｒ³が、式‐（ＡＡ）ｎ‐Ｈであり、
ＡＡが、天然型アミノ酸由来のアミノアシル基であり、
ｎが、１である（７）に記載の化合物、又はその医薬上許容される塩を含有する、統合失調症、不安障害及びその関連疾患、うつ病、双極性障害、てんかん、発達障害、睡眠障害等の精神神経疾患、並びに、薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患からなる群から選択される疾患の予防又は治療用医薬。

R ⁸ is as defined in (1))
A psychiatric disorder such as schizophrenia, anxiety disorder and related diseases, depression, bipolar disorder, epilepsy, developmental disorder, sleep disorder, etc., comprising the compound according to (2) or a pharmaceutically acceptable salt thereof It consists of neurological diseases and neurological diseases such as drug addiction, cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia, cerebral ischemia, brain failure, spinal cord disorder, head disorder A medicament for preventing or treating a disease selected from the group.
(4) In formula (I),
R ¹ has the formula-(CR ⁴ R ⁴ ') -O-CO-R ⁵ (wherein R ⁴ , R ⁴ ' and R ⁵ are as defined in (1)), formula-(CR ⁶ R ⁶ ′) —O—CO—O—R ⁷ , wherein R ⁶ , R ⁶ ′ and R ⁷ are as defined in (1), Or a pharmaceutically acceptable salt thereof, schizophrenia, anxiety disorder and related diseases, depression, bipolar disorder, epilepsy, developmental disorder, sleep disorder and other neuropsychiatric disorders, and drug dependence, cognition Prevention or treatment of a disease selected from the group consisting of disorders, Alzheimer's disease, Huntington's disease, Parkinson's disease, movement disorders associated with muscle rigidity, cerebral ischemia, brain failure, spinal cord disorder, head disorder, etc. Pharmaceuticals.
(5) In formula (I),
R ¹ is a formula — (CR ⁴ R ⁴ ′) —O—CO—R ⁵ or a formula — (CR ⁶ R ⁶ ′) —O—CO—O—R ⁷ , and R ⁵ is an adamantyl group An adamantyl group may be substituted with 1 to 3 methyl groups), and a C _3-8 cycloalkyl group or an adamantyl group (wherein R ⁷ is substituted with 1 to 3 C _1-6 alkyl groups) The adamantyl group may be substituted with 1 to 3 C _1-6 alkyl groups), and R ⁴ , R ⁴ ′, R ⁶ , and R ⁶ ′ are as defined in (1). , Neuropsychiatric disorders such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorder, epilepsy, developmental disorders, sleep disorders, etc., comprising the compound according to (4) or a pharmaceutically acceptable salt thereof Diseases, as well as drug addiction, cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement disorders associated with muscle stiffness, Ischemia, cerebral insufficiency, spinal cord injury, prophylactic or therapeutic medicament for a disease selected from the group consisting of neurological disorders such as head injury.
(6) In formula (I),
Schizophrenia, anxiety disorder and related diseases, depression, comprising the compound according to any one of (2) to (5), wherein R ² is a hydrogen atom, or a pharmaceutically acceptable salt thereof, Psychiatric and neurological diseases such as bipolar disorder, epilepsy, developmental disorder, and sleep disorder, as well as drug dependence, cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement disorder associated with muscle stiffness, cerebral ischemia, brain failure, A medicament for the prevention or treatment of a disease selected from the group consisting of neurological diseases such as spinal cord disorders and head disorders.
(7) In formula (I),
R ¹ and R ² are both hydrogen atoms,
R ³ is of the formula-(AA) nH,
AA is an aminoacyl group,
Schizophrenia, anxiety disorder and related diseases, depression, bipolar disorder, epilepsy, developmental disorder containing the compound according to (1), wherein n is 1 or 2, or a pharmaceutically acceptable salt thereof , Neuropsychiatric disorders such as sleep disorders, as well as drug addiction, cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement disorders associated with muscle rigidity, cerebral ischemia, brain failure, spinal cord disorder, head disorders, etc. A medicament for preventing or treating a disease selected from the group consisting of neurological diseases.
(8) In formula (I),
R ³ is of the formula-(AA) nH,
AA is an aminoacyl group derived from a natural amino acid,
Schizophrenia, anxiety disorder and related diseases, depression, bipolar disorder, epilepsy, developmental disorder, sleep, comprising the compound according to (7), wherein n is 1, or a pharmaceutically acceptable salt thereof Psychiatric and neurological disorders such as disorders, and neurology such as drug dependence, cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement disorders associated with muscle rigidity, cerebral ischemia, brain failure, spinal cord disorder, head disorders A medicament for the prevention or treatment of a disease selected from the group consisting of experimental diseases.

  The prodrug of the fluorinated amino acid of the present invention has improved mucosal absorbability such as oral absorbability and is a parent compound (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro immediately after absorption. It is converted to bicyclo [3.1.0] hexane-2,6-dicarboxylic acid, and the parent compound has an affinity for metabotropic glutamate receptors and acts as an agonist. Schizophrenia, anxiety disorder and its Related disorders, depression, bipolar disorder, epilepsy, developmental disorders, sleep disorders, and other neuropsychiatric disorders, as well as drug addiction, cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement disorders associated with muscle rigidity, brain It has become possible to provide a medicament for the prevention or treatment of a disease selected from the group consisting of neurological diseases such as ischemia, brain failure, spinal cord injury, and head injury.

  Hereinafter, the form for implementing this invention is demonstrated concretely.

The terms used in the present specification have the following meanings.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The “C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Examples include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl group and the like.
The “C _1-10 alkyl group” means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Examples include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl group, etc. be able to.
The “C _3-8 cycloalkyl group” is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl group.
The “aryl group” is a monocyclic to bicyclic aromatic hydrocarbon ring, and examples thereof include phenyl, 1-naphthyl, and 2-naphthyl groups.
“Aminoacyl group” refers to an aminoacyl group derived from a natural or non-natural amino acid. “Natural amino acids” include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine. All except glycine have L-form solids. Examples of the “non-natural amino acid” include isomers of the above-mentioned “natural amino acid” in the D form. Sarcosine, phenylglycine and the like.

  As used herein, “pharmaceutically acceptable salt” refers to a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or nitric acid, or acetic acid, benzoic acid, oxalic acid, lactic acid, Malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycolic acid, glutamic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 1 type of salt with organic acids, such as p-toluenesulfonic acid, camphorsulfonic acid, or naphthalene-2-sulfonic acid, lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion, etc. Salts with multiple metal ions, ammonia, arginine, lysine, piperazine, choline, die Triethanolamine, 4-phenylcyclohexylamine, 2-aminoethanol, salts with amines such as benzathine. Conversion from the educt to the salt can be performed by conventional methods.

Preferred embodiments of the compound of the present invention are listed below.
When R ³ is a hydrogen atom, R ¹ is represented by the formula-(CR ⁴ R ⁴ ') -O-CO-R ⁵ , formula-(CR ⁶ R ⁶ ') -O-CO-O-R ⁷ or compound that is IIa) are preferred, wherein ^{- (CR 6 R 6 ')} -O-CO-O-R 7 or the compound is of formula (IIa) is more preferable. When R ³ is a hydrogen atom, R ² is preferably a compound of formula — (CR ⁶ R ⁶ ′) —O—CO—O—R ⁷ or formula (IIa).
When R ² and R ³ are both hydrogen atoms, R ¹ is represented by the formula-(CR ⁴ R ⁴ ') -O-CO-R ⁵ , formula-(CR ⁶ R ⁶ ') -O-CO-O-R ⁷ , compounds of formula (IIa) or formula (IIb) are preferred and are of formula-(CR ⁴ R ⁴ ') -O-CO-R ⁵ or formula-(CR ⁶ R ⁶ ') -O-CO-O- a R ⁷ is compounds are more preferable.
When R ¹ and R ³ are both hydrogen atoms, R ² is preferably a compound of the formula — (CR ⁶ R ⁶ ′) —O—CO—O—R ⁷ or formula (IIa).
R ⁴ is preferably a hydrogen atom compound.
R ⁴ ′ is preferably a hydrogen atom or a C _1-6 alkyl group compound, and more preferably a hydrogen atom or a methyl group compound.
R ⁵ represents a C _1-10 alkyl group, a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups), an adamantyl group (The adamantyl group may be substituted with 1 to 3 C _1-6 alkyl groups) or a phenyl group (the phenyl group is 1 to 3 groups selected from a halogen atom and a C _1-6 alkyl group) And a C _1-10 alkyl group, an adamantyl group (the adamantyl group may be substituted with 1 to 3 C _1-6 alkyl groups), or A compound that is a phenyl group is more preferable, and a compound that is an adamantyl group (the adamantyl group may be substituted with 1 to 3 methyl groups) is more preferable.
R ⁶ is preferably a hydrogen atom compound.
R ⁶ ′ is preferably a hydrogen atom or a C _1-6 alkyl group compound, more preferably a hydrogen atom or a methyl group compound.
R ⁷ represents a C _1-6 alkyl group, a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups) or an adamantyl group. (the adamantyl group may be substituted with 1 to 3 C _1-6 alkyl group) is preferably a compound which is, C _3-8 cycloalkyl substituted with 1-3 C _1-6 alkyl groups A compound that is an alkyl group or an adamantyl group (the adamantyl group may be substituted with 1 to 3 C _1-6 alkyl groups) is more preferable.
R ⁸ is preferably a compound having a C _1-6 alkyl group.
When R ¹ and R ² are both hydrogen atoms, R ³ is preferably a compound of the formula — (AA) n—H.
AA is preferably a compound that is an aminoacyl group derived from a natural amino acid.
n is preferably a compound of 1 or 2, and more preferably a compound of 1.
Examples of preferred compounds among the compounds of the present invention include the following compounds or pharmaceutically acceptable salts thereof:
(1S, 2S, 3S, 5R, 6S) -6-(((adamantane-1-carbonyl) oxy) methoxy) carbonyl-2-amino-3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid ,
(1S, 2S, 3S, 5R, 6S) -6- (1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl-2-amino-3-fluorobicyclo [3.1.0] hexane-2- carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-Amino-3-fluoro-6-((1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl ) Oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy ) Methoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-amino-6- (1-((3,5-dimethyladamantane-1-carbonyl) oxy) ethoxy) carbonyl-3-fluorobicyclo [3.1.0 ] Hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((octanoyloxy) methoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-amino-6-(((benzoyloxy) methoxy) carbonyl) -3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-amino-6-((1-(((cyclohexyloxy) carbonyl) oxy) ethoxy) carbonyl) -3-fluorobicyclo [3.1.0] hexane- 2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-amino-6-((1-(((cyclooctyloxy) carbonyl) oxy) ethoxy) carbonyl) -3-fluorobicyclo [3.1.0] hexane -2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-amino-6-((1-((((4,4-dimethylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -3-fluorobicyclo [3 1.0] hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -6-(((((adamantan-1-yloxy) carbonyl) oxy) methoxy) carbonyl) -2-amino-3-fluorobicyclo [3.1.0] hexane -2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -6-((1-(((adamantan-1-yloxy) carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3.1.0 ] Hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-Amino-3-fluoro-6-(((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl) bicyclo [3 1.0] hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid 6- (3-phthalidyl) ester,
(1S, 2S, 3S, 5R, 6S) -2-((S) -2-Amino-4- (methylthio) butanamide) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid ,
(1S, 2S, 3S, 5R, 6S) -2-((S) -2-aminopropanamide) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2- (2-aminoacetamido) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-((S) -2-amino-4-methylbutanamide) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-((S) -2,6-diaminohexaneamide) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-((S) -2-amino-4-methylpentanamide) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-((S) -2-((S) -2-aminopropanamide) propanamide) -3-fluorobicyclo [3.1.0] hexane-2 , 6-dicarboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-((S) -2-amino-3-phenylpropanamide) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ) Oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((R) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ) Oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3.1. 0] hexane-2-carboxylic acid,
(1S, 2S, 3S, 5R, 6S) -6-(((R) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3.1. 0] hexane-2-carboxylic acid,
Is mentioned.

In addition, when this invention compound forms a hydrate or a solvate, they are also contained in the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.

The compound of the present invention includes all enantiomers, diastereomers, equilibrium compounds, mixtures of these in arbitrary proportions, racemates and the like.
The compounds of the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, and fluorine atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
The compound of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients and diluents to form a pharmaceutical preparation. Examples of the carrier, excipient, and diluent include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, and cellulose. And various oils such as water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like.
The compound of the present invention is mixed with these carriers, excipients or diluents, and additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary. Oral or parenteral drugs such as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections, skin patches, etc., especially group 2 metabolism It is prepared as a prodrug of a glutamate receptor agonist.
The compound of the present invention can be administered orally or parenterally in an amount of 0.01 to 500 mg once or several times a day for an adult patient. Administration is preferred. This dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
The compound (I) of the present invention does not affect the group 2 metabotropic glutamate receptors. However, it is enzymatically or chemically hydrolyzed in vivo and is converted into compound (IV), which is a compound having a strong action on group 2 metabotropic glutamate receptors. Therefore, the compound of the present invention exhibits a function as a drug acting on a group 2 metabotropic glutamate receptor.

That is, the compounds of the present invention include schizophrenia, anxiety disorders and related diseases, depression, bipolar disorder, epilepsy, developmental disorders, and neuropsychiatric disorders such as sleep disorders, as well as drug addiction, cognitive disorders, Alzheimer's disease, Group 2 metabotropic glutamate receptors are involved in neurologic diseases such as Huntington's disease, Parkinson's disease, movement disorders associated with muscle stiffness, cerebral ischemia, brain failure, spinal cord injury, head injury, etc. As a therapeutic or prophylactic agent for diseases, it acts as a prodrug that enhances mucosal absorbability such as oral absorbability of parent compound (IV) acting on group 2 metabotropic glutamate receptors, and increases in vivo exposure.
A typical production method of the compound (I) of the present invention is shown in the following schemes 1 to 7. The following method is an illustration of the production method of the compound of the present invention, and is not limited thereto. In the following examples of production methods, the compound may form a salt that does not hinder the reaction.
The compound of the present invention represented by the formula (I-1) can be produced by the synthesis method shown in Scheme 1.
Scheme 1

(In the formula, R ¹ has the same meaning as described above.)
Step 1: Protecting the amino group of compound (IV) with a general allyloxycarbonyl group {Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons , INC.)} To compound (1). For example, hydrocarbon solvents such as benzene, toluene and hexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, N, N-dimethylformamide In an inert solvent such as amides such as N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof, triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4- (N, N-dimethyl) Reaction with allyl chloroformate in the presence or absence of organic bases such as amino) pyridine, 2,6-di-t-butylpyridine, or inorganic salts such as potassium carbonate, sodium carbonate, sodium bicarbonate Can lead to compound (1) Yes.
Step 2: Compound (1) is, for example, a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. In an inert solvent such as a system solvent or a mixed solvent thereof, in the presence of an aldehyde such as paraformaldehyde, using an acid catalyst such as p-toluenesulfonic acid or oxalic acid, a dehydrator such as a Dean-Stark water separator The reaction can be conducted with or without use to lead to compound (2).
Step 3: Compound (2) has the formula LR ¹ (wherein L represents a leaving group, for example, a halogen atom, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc.) Hydrocarbon solvents such as benzene, toluene, hexane and cyclohexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, N, N- In an inert solvent such as amides such as dimethylformamide and N-methyl-2-pyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate , Cesium bicarbonate, sodium hydroxide, water Inorganic bases such as potassium iodide, metal amides such as lithium bis (trimethylsilyl) amide, lithium diisopropylamide, sodium amide, triethylamine, pyridine, diisopropylethylamine, 4- (N, N-dimethylamino) pyridine, 2,6- By reacting in the presence or absence of a suitable activator such as sodium iodide in the presence of an organic base such as di-t-butylpyridine and a base such as potassium t-butoxide, the compound (3) is led. be able to. Preferably, the compound (2) is added in N, N-dimethylformamide in the presence of potassium carbonate and sodium iodide and the formula Cl—R ¹ or formula Br—R ¹ at room temperature to 80 ° C. for 2 hours to 1 day. By reacting, it can be led to the compound (3). In addition, the compound (2) is reacted with N-N-dimethylformamide in the presence of cesium carbonate in the presence of cesium carbonate with the formula Cl-R ¹ or formula Br-R ¹ at room temperature to 80 ° C. for 2 hours to 1 day. It can also lead to (3).
Step 4: Amino group of compound (3) is converted into a general deprotection reaction (see Protective Groups in Organic Synthesis 4th Edition, John Wiley & Sons, Inc.). } Can lead to the compound [I-1] of the present invention. For example, hydrocarbon solvents such as benzene, toluene and hexane, for example, in the presence of a regenerative reagent for a zerovalent palladium catalyst such as tetrakistriphenylphosphine palladium (0) and a metal catalyst such as 1,3-dimethylbarbituric acid Deprotection of the α-amino acid moiety in an inert solvent such as halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, or mixed solvents thereof Thus, the compound (I-1) which is the compound of the present invention can be derived. Preferably, the compound (3) is reacted in the presence of tetrakistriphenylphosphine palladium (0) and 1,3-dimethylbarbituric acid in chloroform at room temperature to 50 ° C. for 2 to 8 hours. It can lead to compound (I-1).
The compound of the present invention represented by the formula (I-2) can be produced by the synthesis method shown in Scheme 2.
Scheme 2

(In the formula, R ² has the same meaning as described above.)
Step 5: The carboxy group of compound (1) can be converted to compound (4) by reacting allyl alcohol with time and / or reaction temperature in a general esterification reaction {complihen See Shimb Organic Transformations Second Edition 1999, John Wiley & Sons, Inc.}. Here, the esterification reaction is, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluro in an inert solvent in the presence or absence of a base. Nium hexafluorophosphoric acid (HATU), O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphoric acid (HBTU), N, N′-dicyclohexylcarbodiimide ( DCC), condensation reaction using a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), diphenylphosphoryl azide (DPPA) or carbonyldiimidazole (CDI), chloroformic acid Condensation reaction via mixed acid anhydride using ethyl, isobutyl chloroformate or trimethylacetyl chloride, thionyl chloride, salt A condensation reaction via an acid halide using oxalyl chloride, 1-chloro-N, N, 2-trimethyl-1-propenylamine, or the like. In the esterification reaction using a condensing agent, additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary. Preferably, the compound (1) is diluted with chloroform in the presence of diisopropylethylamine, 4- (N, N-dimethylamino) pyridine, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl). The compound (4) can be led by reacting with 1 to 1.5 equivalents of allyl alcohol at room temperature for 1 to 4 days.
Step 6: Compound (4) can be led to compound (5) in the same manner as in Step 3. Preferably, the compound (4) is used in N, N-dimethylformamide in the presence of potassium carbonate and sodium iodide and the formula Cl—R ² or formula Br—R ² at room temperature to 80 ° C. for 2 hours to 1 day. By reacting, it can be led to the compound (3). Further, the compound (4) is reacted with N-N-dimethylformamide in the presence of cesium carbonate in the presence of cesium carbonate at room temperature to 80 ° C. for 2 hours to 1 day with the compound Cl-R ² or formula Br-R ² . It can also lead to (5).
Step 7: Compound (5) is led to Compound (I-2) which is the compound of the present invention by deprotecting the protecting group of the amino group and the carboxyl group at the 6-position by the same method as in Step 4. Can do. Preferably, the compound (5) is reacted in the presence of tetrakistriphenylphosphine palladium (0) and 1,3-dimethylbarbituric acid in chloroform at room temperature to 50 ° C. for 2 to 8 hours. It can lead to compound (I-2).
The compound of the present invention represented by the formula (I-3) can be produced by the synthesis method shown in Scheme 3.
Scheme 3

(In the formula, R ¹ = R ² , and R ¹ and R ² are as defined above.)
Step 8: Compound (1) can be led to compound (6) in the same manner as in Step 3. Preferably, the compound (1) is prepared in N, N-dimethylformamide in the presence of potassium carbonate and sodium iodide and the formula Cl—R ¹ or formula Br—R ¹ at room temperature to 80 ° C. for 2 hours to 1 day. It can guide | induce to a compound (6) by reacting. The compound (1) is reacted with N-N-dimethylformamide in the presence of cesium carbonate in the presence of cesium carbonate at room temperature to 80 ° C. for 2 hours to 1 day with the compound Cl-R ¹ or formula Br-R ¹ . It can also lead to (6).
Step 9: Compound (6) can be led to Compound (I-3) which is a compound of the present invention by deprotecting the protecting group of amino group by the same method as in Step 4. Preferably, the compound (6) is reacted in the presence of tetrakistriphenylphosphine palladium (0) and 1,3-dimethylbarbituric acid in chloroform at room temperature to 50 ° C. for 2 to 8 hours. It can lead to compound (I-3).
The compound of the present invention represented by the formula (I-4) can be produced by the synthesis method shown in Scheme 4.
Scheme 4

(In the formula, AA and n are as defined above, and P represents an amino-protecting group.)
Step 10: Carboxyl group of compound (IV) is converted into general esterification reaction (see Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, INC.) } To the compound (7). Preferably, compound (IV) can be led to compound (7) by reacting in a methanol solution containing 5 to 10% hydrogen chloride at room temperature to 80 ° C. for 2 hours to 3 days.
Step 11: The amino group of compound (7) can be led to compound (8) by a general amidation reaction. For example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU) in an inert solvent in the presence or absence of a base , O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphoric acid (HBTU), N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3 -Condensation reaction using a condensing agent such as (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), diphenylphosphoryl azide (DPPA) or carbonyldiimidazole (CDI), ethyl chloroformate, isobutyl chloroformate or trimethylacetyl Condensation reaction via mixed acid anhydride using chloride, thionyl chloride, oxalyl chloride, 1-chloro- For example, a condensation reaction via an acid halide using N, N, 2-trimethyl-1-propenylamine or the like. Here, in the amidation reaction using the condensing agent, additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary. Preferably, compound (7) is reacted in chloroform in the presence of N-methylmorpholine, isobutyl chloroformate and compound HO- (AA) -P at -40 to 60 ° C for 20 minutes to 1 day. To compound (8).
Step 12: The methyl ester of compound (8) is converted to a carboxylic acid in a general hydrolysis reaction (see T. W. Greene, PGM M. Wuts, “Protective Groups in Organic Synthesis”). Compound (9) can be derived. Preferably, compound (8) can be led to compound (9) by reacting in tetrahydrofuran and 0.1 to 10 mol / L aqueous sodium hydroxide solution at −10 to 40 ° C. for 2 hours to 2 days. .
Step 13: Amino-protecting group of compound (9) is converted into a general deprotection reaction {Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, Inc. .) See} to lead to compound (I-4) which is a compound of the present invention.
The compound of the present invention represented by the formula (I-5) can be produced by the synthesis method shown in Scheme 5.
Scheme 5

(Wherein R ³ represents a formula —CO—O— (CR ⁹ R ⁹ ′) —O—CO—R ¹⁰ , a formula —CO—O— (CR ⁹ R ⁹ ′) —O—CO—O—R ¹¹ or a structure of formula (III), wherein R ⁹ , R ⁹ ′, R ¹⁰ , R ¹¹ and formula (III) are as defined above.)
Step 14: Compound (IV) can be converted to compound (10) in the same manner as in Step 1. Preferably, compound (IV) is reacted with 1 to 5 equivalents of di-tert-butoxycarbonyl (Boc ₂ O) in 1,4-dioxane in the presence of 1 mol / L aqueous sodium hydroxide solution at room temperature for 6 hours to 5 hours. By reacting for a day, the compound (10) can be derived.
Process 15: The carboxy group of a compound (10) can be guide | induced to a compound (11) by the method similar to the process 5. Preferably, compound (10) is reacted with 2 to 5 equivalents of allyl bromide in N, N-dimethylformamide in the presence of potassium carbonate and allyl bromide at 0 to 80 ° C. for 2 hours to 2 days. (11).
Step 16: Compound (11) is an amino group deprotection reaction, followed by a protection reaction with an acyl group similar to Step 14, {Protective Groups in Organic Synthesis, 4th edition, John Willy and Sons (See John Wiley & Sons, INC.)} Can lead to compound (12). Preferably, compound (11) is reacted in a 1 to 4 mol / L hydrogen chloride-ethyl acetate solution at −20 to 40 ° C. for 30 minutes to 1 day to remove the tert-butoxycarbonyl group, and then N, In N-dimethylformamide, the compound (12) can be derived by reacting with carbon dioxide and the compound LR ³ at −20 to 60 ° C. for 1 hour to 1 day in the presence of cesium carbonate. Alternatively, compound (11) is reacted in a 1 to 4 mol / L hydrogen chloride-ethyl acetate solution at −20 to 40 ° C. for 30 minutes to 1 day to remove the tert-butoxycarbonyl group, and then in chloroform. Compound (12) can also be derived by reacting with compound HO- (IIa) at −10 to 40 ° C. for 1 hour to 1 day in the presence of N, N-diisopropylethylamine and triphosgene.
Step 17: Compound (12) is led to Compound (I-5) which is the compound of the present invention by deprotecting the protecting groups of the 2-position and 6-position carboxy groups in the same manner as in Step 4. Can do. Preferably, the compound (6) is reacted in the presence of tetrakistriphenylphosphine palladium (0) and 1,3-dimethylbarbituric acid in chloroform at room temperature to 50 ° C. for 2 to 8 hours. To Compound (I-5).
The compound of the present invention represented by the formula (I-6) can be produced by the synthesis method shown in Scheme 6.
Scheme 6

Wherein R ¹ has the same meaning as described above, and R ³ has the formula —CO—O— (CR ⁹ R ⁹ ′) —O—CO—R ¹⁰ , the formula —CO—O— (CR ⁹ R ⁹ ′) —O—CO—O—R ¹¹ , or the structure of formula (III), wherein R ⁹ , R ⁹ ′, R ¹⁰ , R ¹¹ and formula (III) are as defined above.)
Step 18: Compound (I-1) can be led to compound (I-6) of the present invention by the same method as in Step 14. Preferably, compound (I-1) is a compound of the formula L- (CR ⁹ R ⁹ ') -O-CO-R ¹⁰ , formula L- (CR in the presence of cesium carbonate in N, N-dimethylformamide. ⁹ R ⁹ ′) -O—CO—O—R ¹¹ (wherein L is a leaving group as described above) and reaction at −20 to 60 ° C. for 1 hour to 1 day. It can lead to a compound (I-6). Alternatively, compound (I-1) is reacted with compound HO- (IIa) in chloroform in the presence of N, N-diisopropylethylamine and triphosgene at −10 ° C. to 40 ° C. for 1 hour to 1 day. It can also lead to the compound (I-6) of the present invention.
Scheme 7

(In the formula, R ¹ has the same meaning as described above. R ¹³ and R ¹⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, an aryl group, or Represents a heteroaryl group (the aryl group or heteroaryl group may be substituted with 1 to 3 groups selected from a halogen atom and a C _1-6 alkyl group), or R ¹³ and R ¹⁴ are , Together with adjacent boron atoms, a 5- to 8-membered saturated heterocycle (the 5- to 8-membered saturated heterocycle is bridged between two different carbon atoms in the ring with C _1-6 alkylene. May be.)
Step 19: Protecting the α-amino acid moiety of Compound (IV) with a general boron group {Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons , INC.)} To compound (13). For example, hydrocarbon solvents such as benzene, toluene and hexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, N, N-dimethylformamide In an inert solvent such as amides such as N-methyl-2-pyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof, triethylborane, sodium tetraphenylborate, 9-borabicyclo [3.3.1] nonane dimer, boron The compound (13) can be derived by reacting with a boron reagent such as trifluoride at -20 to 100 ° C for 1 hour to 2 days. Preferably, compound (IV) can be led to compound (13) by reacting with triethylborane in tetrahydrofuran at 0 ° C. to 80 ° C. for 2 hours to 1 day.
Step 20: Compound (13) has the formula LR ¹ (wherein L represents a leaving group, such as a halogen atom, p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc.) Hydrocarbon solvents such as benzene, toluene, hexane and cyclohexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, N, N- In an inert solvent such as amides such as dimethylformamide and N-methyl-2-pyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate , Cesium bicarbonate, sodium hydroxide Inorganic bases such as potassium hydroxide, metal amides such as lithium bis (trimethylsilyl) amide, lithium diisopropylamide, sodium amide, triethylamine, pyridine, diisopropylethylamine, 4- (N, N-dimethylamino) pyridine, 2,6 -Reacting in the presence or absence of a suitable activator such as sodium iodide or 18-crown-6 in the presence of an organic base such as di-t-butylpyridine or a base such as potassium t-butoxide. Can lead to the compound (14). Preferably, the compound (13) is reacted with formula Cl—R ¹ or formula Br—R ¹ at room temperature to 80 ° C. for 2 hours to 1 day in the presence of potassium carbonate and 18-crown-6 in dimethyl sulfoxide. This can lead to compound (14).
Step 21: The α-amino acid part of compound (14) is subjected to a general deprotection reaction {Protective Groups in Organic Synthesis 4th Edition, John Wiley & Sons, Inc. )} Can be led to the compound (I-1) of the present invention. For example, in the presence of acidic reagents such as hydrogen chloride, paratoluenesulfonic acid, benzenesulfonic acid, for example, hydrocarbon solvents such as benzene, toluene, hexane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl Ethers, ether solvents such as 1,2-dimethoxyethane, esters such as ethyl acetate and isopropyl acetate, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or these By deprotecting the α-amino acid moiety in an inert solvent such as a mixed solvent, the compound (I-1) as the compound of the present invention can be derived. Preferably, compound (14) leads to compound (I-1) of the present invention by reacting in ethyl acetate in the presence of benzenesulfonic acid or hydrogen chloride at room temperature to 50 ° C. for 2 hours to 1 day. be able to.

  Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples. However, the present invention is not limited to these examples, and may be changed without departing from the scope of the present invention.

In Reference Examples and Examples, Biotage (registered trademark) SNAPPartridge KP-Sil and HP-Sil manufactured by Biotage were used as the “silica gel cartridge” when purified using column chromatography. YMC-Actus Trial C18, 5.0 μm, φ30 × 50 mm was used for “reverse phase column chromatography when purified using reverse phase column chromatography”. Silica gel 60F254 (Merck) was used for TLC (silica gel plate) when purified using TLC.
Each instrument data described in the examples was measured with the following measuring instruments.
LCMS spectrum: Shimadzu LCMS-IT-TOF, Shimadzu LCMS-2010EV, micromass Platform LC, micromass GCT, Agilent 6150, Agilent 1290 Infinity and Agilent 1100
NMR spectrum: [ ¹ H-NMR] 600 MHz: JNM-ECA600 (JEOL), 500 MHz: JNM-ECA500 (JEOL)
X-ray structural analysis: R-AXIS RAPID II (Rigaku)
Melting point: differential thermal balance (TG-DTA): Thermo plus EVO TG8120 (Rigaku)
The compound names in the examples were named by ACD / Name (ACD / Labs 12.0, Advanced Chemistry Development Inc.).
Abbreviations in the nuclear magnetic resonance (NMR) spectra used in the examples are shown below.
s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, qd: quartet double, doublet Doublet (double doublet), ddt: double double triplet, ddd: double double doublet, mul: doublet, m: doublet Constant, Hz: Hertz, DMSO-d6: deuterated dimethyl sulfoxide Indicated by pm value.

Reference Example 1: (1S, 2S, 3S, 5R, 6S) -2-amino-6- (ethoxycarbonyl) -3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid (Reference Example 1) Synthesis (1) (1S, 2S, 3S, 5R, 6S) -3'-allyl 6-ethyl 3-fluoro-5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine]- 3 ′, 6-dicarboxylate (Reference Example 1-1)
(1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] obtained in Example A-1 below Cesium carbonate (261 mg) was added to a suspension of N, N-dimethylformamide (6 mL) in hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 200 mg), and the mixture was stirred at room temperature for 30 minutes. Ethyl tosylate (201 mg) was further added, and the mixture was stirred at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. After washing, the ethyl acetate layer was dried over anhydrous sodium sulfate, insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (silica gel cartridge, hexane: ethyl acetate). = 100: 0 to 50:50) and purified by (1S, 2S, 3S, 5R, 6S) -3'-allyl 6-ethyl 3-fluoro-5'-oxospiro [bicyclo [3.1.0] Hexane-2,4′-oxazolidine] -3 ′, 6-dicarboxylate (Reference Example 1-1, 68 mg) was obtained as a colorless amorphous substance.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.01-5.92 (m, 1H), 5.60 (d, J = 4.5 Hz, 1H), 5.37-5.30 (m 1H), 5.29-5.21 (m, 2H), 4.77-4.62 (m, 3H), 4.20-4.12 (m, 2H), 2.62-2.46. (M, 2H), 2.37-2.25 (m, 1H), 2.22-2.17 (m, 1H), 1.27 (t, J = 1.0 Hz, 3H).
MS m / z; 350 ([M + Na] ⁺ )
(2) (1S, 2S, 3S, 5R, 6S) -2-amino-6- (ethoxycarbonyl) -3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid (Reference Example 1)
(1S, 2S, 3S, 5R, 6S) -3′-allyl 6-ethyl 3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane in the same manner as in Example A-1 4 below The title compound (Reference Example 1, 28 mg) was obtained as a colorless solid from -2,4′-oxazolidine] -3 ′, 6-dicarboxylate (Reference Example 1-1, 68 mg).
¹ H NMR (600 MHz, DMSO-d6) δ = 4.90-4.72 (m, 1H), 4.12-3.95 (m, 2H), 2.65-2.51 (m, 1H) , 2.15-1.82 (m, 4H), 1.19 (t, J = 7.2 Hz, 3H).
MS m / z; 232 ([M + H] ⁺ )

Reference Example 2: Synthesis of (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (IV) (1) (1S, 2S, 3S, 5R, 6S) -Ethyl 2-amino-2-cyano-3-fluorobicyclo [3.1.0] hexane-6-carboxylate (Reference Example 2-1)
8 mol / L of (1S, 3S, 5R, 6S) -ethyl 3-fluoro-2-oxobicyclo [3.1.0] hexane-6-carboxylate (WO 2000/37410 pamphlet, 37.17 g) To an ammonia-methanol (250 mL) solution, tetraisopropyl orthotitanate (68.09 g) and trimethylsilylcyanide (23.03 g) were successively added dropwise with ice cooling. After stirring with ice cooling for 3.5 hours, a 12.4% disodium citrate aqueous solution (848 g) was added dropwise to the reaction solution. After extraction twice with toluene (743 ml), the combined organic layers were dried over anhydrous sodium sulfate. After insoluble matter was filtered off, the insoluble matter was washed with toluene (186 mL), and the filtrate was concentrated and purified without purification (1S, 2S, 3S, 5R, 6S) -ethyl 2-amino-2-cyano-3- A solution containing fluorobicyclo [3.1.0] hexane-6-carboxylate (Reference Example 2-1) was used for the next reaction.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 4.84 (dd, J = 5.6, 48.0 Hz, 1H), 4.13 (qd, J = 7.4, 2.5 Hz, 2H ), 2.59-2.49 (m, 1H), 2.46-2.45 (m, 1H), 2.36 (dd, J = 7.6, 15.9 Hz, 1H), 2. 09 (br s, 1H), 2.02 to 2.01 (m, 1H), 1.81 (br s, 2H), 1.27 (t, J = 7.4 Hz, 1H).
MS m / z; 213 ([M + H] ⁺ )
(2) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (IV)
Contains the obtained (1S, 2S, 3S, 5R, 6S) -ethyl 2-amino-2-cyano-3-fluorobicyclo [3.1.0] hexane-6-carboxylate (Reference Example 2-1) The solution was concentrated under reduced pressure. Water (30 ml), acetic acid (30 ml) and 35% hydrochloric acid (60 ml) were added, and the mixture was stirred at an external temperature of 105 ° C. for 22 hours. Activated carbon (3.0 g) was added to the reaction solution at room temperature, and the mixture was stirred for 1 hour. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by anion exchange column chromatography (Dowex 1 × 8, 0.5 mol / L acetic acid-water), and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] Hexane-2,6-dicarboxylic acid (IV, 25.48 g) was obtained as a colorless solid.
¹ H NMR (500 MHz, D 2 O) δ = 5.06 (dd, J = 5.8, 53.2 Hz, 1H), 2.65 (ddt, J = 15.5, 42.0, 4.5 Hz , 1H), 2.36 (dd, J = 16.0, 29.0 Hz, 1H), 2.21-2.17 (m, 1H), 2.10 (brs, 1H), 1.91 -1.89 (m, 1H).
MS m / z; 202 ([M−H] ⁻ )

Example A-1: (1S, 2S, 3S, 5R, 6S) -6-(((adamantane-1-carbonyl) oxy) methoxy) carbonyl-2-amino-3-fluorobicyclo [3.1.0] Synthesis of hexane-2-carboxylic acid (A-1).
(1) (1S, 2S, 3S, 5R, 6S) -2-(((allyloxy) carbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (A-1 -1)
(1S, 2S, 3S, 5R, 6S) -2-Amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (IV) (4.00 g) in dioxane (24 mL), saturated To a sodium hydrogen carbonate aqueous solution (48 mL) suspension, allyl chloroformate (0.42 mL) was added dropwise over 15 minutes, and the mixture was stirred at room temperature for 20 hours. 1 mol / L hydrochloric acid was added to the reaction solution to adjust the pH to 1, followed by extraction with ethyl acetate three times. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give (1S, 2S, 3S, 5R, 6S) -2-(((allyloxy) carbonyl) amino. ) -3-Fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (A-1-1, 6.23 g) was obtained as colorless amorphous.
¹ H NMR (600 MHz, DMSO-d6) δ = 8.27 (s, 1H), 5.98-5.81 (m, 1H), 5.43-5.03 (m, 3H), 4.59 -4.36 (m, 2H), 2.48-1.36 (m, 1H), 2.22-1.93 (m, 3H), 1.79 (brs, 1H), 1.71 ( t, J = 3.1 Hz, 1H).
MS m / z; 310 ([M + Na] ⁺ )
(2) (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′- Oxazolidine] -6-carboxylic acid (A-1-2)
The obtained (1S, 2S, 3S, 5R, 6S) -2-(((allyloxy) carbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (A-1 -1,6.23 g), paraformaldehyde (3.00 g), p-toluenesulfonic acid monohydrate (45 mg) in toluene (150 mL) was heated with a Dean-Stark water separator for 34 hours. Refluxed. The mixture was allowed to cool, diluted with ethyl acetate, and the organic layer was washed twice with saturated brine. After drying over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5 ′. -Oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine] -6-carboxylic acid (A-1-2, 5.65 g) was obtained as a colorless solid.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 5.89-5.78 (m, 1H), 5.49 (d, J = 4.5 Hz, 1H), 5.25-5.10 (m 3H), 4.65-4.48 (m, 3H), 2.54-2.35 (m, 2H), 2.27-2.11 (m, 2H), 1.96 (dd, J = 3.3, 6.6 Hz, 1H).
MS m / z; 300 ([M + H] ⁺ )
(3) (1S, 2S, 3S, 5R, 6S) -6-(((adamantane-1-carbonyl) oxy) methyl) 3'-allyl 3-fluoro-5'-oxospiro [bicyclo [3.1.0] ] Hexane-2,4'-oxazolidine] -3 ', 6-dicarboxylate (A-1-3)
The resulting (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′- Cesium carbonate (1.37 g) was added to a solution of oxazolidine] -6-carboxylic acid (A-1-2, 1.05 g) in N, N-dimethylformamide (30 mL), and the mixture was stirred at 60 ° C. for 10 minutes. After bringing the liquid to room temperature, chloromethyl adamantane-1-carboxylate (see J. Med. Chem., 23, 474 (1980)) (1.70 g) was added and stirred for 1 hour at 60 ° C. After standing to cool. A saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed once with water and twice with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. Insoluble matter The resulting residue was purified by silica gel column chromatography (silica gel cartridge, hexane: ethyl acetate = 90: 10-50: 50) and (1S, 2S, 3S, 5R). , 6S) -6-(((adamantane-1-carbonyl) oxy) methyl) 3'-allyl 3-fluoro-5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine]- 3 ′, 6-dicarboxylate (A-1-3, 894 mg) was obtained as a colorless amorphous.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 5.95 (s, 1H), 5.79-5.71 (m, 2H), 5.61 (d, J = 5.0 Hz, 1H), 5.37-5.30 (m, 1H), 5.30-5.24 (m, 2H), 4.77-4.60 (m, 3H), 2.68-1.61 (m, 1H) ), 2.61-2.48 (m, 1H), 2.38-2.28 (m, 1H), 2.27-2.21 (m, 1H), 2.12-2.07 (m) , 1H), 2.02 (br s, 3H), 1.93-1.84 (m, 6H), 1.77-1.65 (m, 6H).
MS m / z; 514 ([M + Na] ⁺ )
(4) (1S, 2S, 3S, 5R, 6S) -6-(((adamantane-1-carbonyl) oxy) methoxy) carbonyl-2-amino-3-fluorobicyclo [3.1.0] hexane-2 -Carboxylic acid (A-1)
The resulting (1S, 2S, 3S, 5R, 6S) -6-(((adamantane-1-carbonyl) oxy) methyl) 3′-allyl 3-fluoro-5′-oxospiro [bicyclo [3.1.0] ] Hexane-2,4'-oxazolidine] -3 ', 6-dicarboxylate (A-1-3, 894 mg) in chloroform (30 mL) under a nitrogen atmosphere, 1,3-dimethylbarbituric acid (828 mg) ), Tetrakistriphenylphosphine palladium (102 mg) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, acetonitrile was added to the residue, and the mixture was stirred at room temperature for 20 min. The obtained solid was collected by filtration and washed with water to give the title compound (A-1, 588 mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 5.59 (m, 2H), 4.82-4.65 (m, 1H), 2.58-2.45 (m, 1H), 2.07 -1.96 (m, 1H), 1.95-1.92 (m, 1H), 1.90 (brs, 3H), 1.86 (brs, 2H), 1.76-1.69 (M, 6H), 1.65-1.51 (m, 6H).
MS m / z; 396 ([M + H] ⁺ )
[Α] _D ²⁵ 37.6 (c 0.25, EtOH)

Example A-2:
(1S, 2S, 3S, 5R, 6S) -6- (1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl-2-amino-3-fluorobicyclo [3.1.0] hexane-2- Synthesis of carboxylic acid (A-2) (1) 1-chloroethyl adamantane-1-carboxylate (A-2-1)
Sodium carbonate (3.53 g) was added to a suspension of 1-adamantanecarboxylic acid (1.50 g) in water (22 mL), and the mixture was stirred at 100 ° C. for 20 minutes. After cooling to 0 ° C., tetrabutylammonium hydrogen sulfate (1.00 g), chloroform (30 mL), and 1-chloroethyl sulfochloridate (1.94 g) were added to the reaction solution, and then at 0 ° C. for 1 hour at room temperature. Stir for 12 hours. Water was added to the reaction solution, and extracted twice with chloroform. The combined organic layers were washed with saturated brine and then dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0-50: 50), and 1-chloroethyl adamantane-1-carboxylate (A-2-1, 1.10 g). ) Was obtained as a colorless oil.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.54 (q, J = 5.8 Hz, 1H), 2.03 (br s, 4H), 1.97-1.63 (m, 14H) .
(2) 1-bromoethyl adamantane-1-carboxylate (A-2-2)
Tetrabutylammonium bromide (25.2 mg) and trimethylsilyl bromide (0.80 mL) were added to a solution of the obtained 1-chloroethyl adamantane-1-carboxylate (A-2-1, 500 mg) in benzene (5 mL). Stir at 18 ° C. for 18 hours. The reaction solution was concentrated under reduced pressure and diluted with chloroform. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccant was filtered off and concentrated under reduced pressure to give 1-bromoethyl adamantane-1-carboxylate (A-2-2, 498 mg) as a pale yellow oil.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.72 (q, J = 5.8 Hz, 1H), 2.08-1.96 (m, 6H), 1.96-1.84 (m , 6H), 1.81-1.67 (m, 6H).
(3) (1S, 2S, 3S, 5R, 6S) -1-(((adamantane-1-carbonyl) oxy) ethyl) 3′-allyl 3-fluoro-5′-oxospiro [bicyclo [3.1.0] ] Hexane-2,4'-oxazolidine] -3 ', 6-dicarboxylate (A-2-3)
In the same manner as in Example A-1 (3), (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1 0.0] hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 800 mg) and 1-chloroethyl adamantane-1-carboxylate (A-2-1, 1.62 g), (1S, 2S, 3S, 5R, 6S) -1-(((adamantane-1-carbonyl) oxy) ethyl) 3′-allyl 3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane- 2,4′-oxazolidine] -3 ′, 6-dicarboxylate (A-2-3, 500 mg) was obtained as colorless amorphous.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.87-6.76 (m, 1H), 6.03-5.92 (m, 1H), 5.64-5.57 (m, 1H) , 5.39-5.22 (m, 3H), 4.79-4.58 (m, 3H), 2.62-2.47 (m, 2H), 2.39-2.27 (m, 1H), 2.6-2.18 (m, 1H), 2.11-1.05 (m, 1H), 2.04-1.97 (m, 3H), 1.92-1.80 ( m, 6H), 1.77-1.64 (m, 6H), 1.49-1.41 (m, 3H).
MS m / z; 528 ([M + Na] ⁺ )
(4) (1S, 2S, 3S, 5R, 6S) -6-(((adamantane-1-carbonyl) oxy) ethoxy) carbonyl-2-amino-3-fluorobicyclo [3.1.0] hexane-2 -Carboxylic acid (A-2)
Similar to Example A-1 (4), (1S, 2S, 3S, 5R, 6S) -1-(((adamantane-1-carbonyl) oxy) ethyl) 3′-allyl 3-fluoro-5 ′ -Oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine] -3 ', 6-dicarboxylate (A-2-3, 700 mg) was used to give the title compound (A-2, 330 mg). Obtained as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.70-6.65 (m, 1H), 4.89-4.75 (m, 1H), 2.66-2.51 (m, 1H) , 2.14-2.04 (m, 1H), 1.97 (m, 4H), 1.93 (m, 2H), 1.78 (br s, 6H), 1.72-1.61 ( m, 6H), 1.42-1.37 (m, 3H).
MS m / z; 410 ([M + H] ⁺ )

Example A-3: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-((1-((((((1R, 2S, 5R) -2-isopropyl-5- Synthesis of methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (A-3) (1) (1S, 2S, 3S, 5R, 6S) -3 '-Allyl 6-((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethyl) 3-fluoro-5'-oxospiro [bicyclo [3.1.0] Hexane-2,4′-oxazolidine] -3 ′, 6-dicarboxylate (A-3-1)
In the same manner as in Example A-1 (3), (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1 .0] hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 350 mg) and 1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (768 mg) to (1S, 2S, 3S, 5R, 6S) -3′-allyl 6-((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethyl ) 3-Fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -3 ′, 6-dicarboxylate (A-3-1, 260 mg) was colorless. It was obtained as Jo products.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.79-6.69 (m, 1H), 6.01-5.91 (m, 1H), 5.63-5.57 (m, 1H) , 5.38-5.30 (m, 1H), 5.30-5.22 (m, 2H), 4.78-4.59 (m, 3H), 4.58-4.49 (m, 1H), 2.64-2.47 (m, 2H), 2.37-2.20 (m, 2H), 2.13-2.05 (m, 2H), 1.97-1.88 ( m, 1H), 1.73-1.64 (m, 2H), 1.54-1.36 (m, 5H), 1.05 (dd, J = 2.1, 11.1 Hz, 2H) , 0.96-0.82 (m, 7H), 0.82-0.73 (m, 3H).
MS m / z; 548 ([M + Na] ⁺ )
(2) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-((1-((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) Oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (A-3)
Similar to Example A-1 (4), (1S, 2S, 3S, 5R, 6S) -3′-allyl 6-((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ) Oxy) carbonyl) oxy) ethyl) 3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -3 ′, 6-dicarboxylate (A-3-1) 260 mg) gave the title compound (A-3, 133 mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.65-6.51 (m, 1H), 4.91-4.74 (m, 1H), 4.53-4.37 (m, 1H) 2.69-2.53 (m, 1H), 2.15-1.99 (m, 2H), 1.98-1.87 (m, 3H), 1.86-1.75 (m, 1H), 1.68-1.57 (m, 2H), 1.52-1.39 (m, 4H), 1.39-1.29 (m, 1H), 1.11-0.95 ( m, 2H), 0.93-0.80 (m, 7H), 0.78-0.68 (m, 3H).
MS m / z; 430 ([M + H] ⁺ )

Example A-4: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl )) Oxy) carbonyl) oxy) methoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (A-4) synthesis In the same manner as in Example A-1 (3) and (4), 1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -6 -From the carboxylic acid (A-1-2, 350 mg) and 1-chloromethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (727 mg), the title compound (A-4, 140 mg) As a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 5.74-5.64 (m, 2H), 4.91-4.74 (m, 1H), 4.53-4.42 (m, 1H) , 2.67-1.53 (m, 1H), 2.15-2.02 (m, 2H), 2.00-1.93 (m, 3H), 1.86-1.77 (m, 1H), 1.68-1.59 (m, 2H), 1.53-1.42 (m, 1H), 1.41-1.33 (m, 1H), 1.04 (s, 2H) , 0.94-0.80 (m, 7H), 0.75 (d, J = 7.0 Hz, 3H).
MS m / z; 416 ([M + H] ⁺ )

Example A-5: (1S, 2S, 3S, 5R, 6S) -2-amino-6- (1-((3,5-dimethyladamantane-1-carbonyl) oxy) ethoxy) carbonyl-3-fluorobicyclo [3.1.0] Synthesis of hexane-2-carboxylic acid (A-5) (1) 1-chloroethyl 3,5-dimethyladamantane-1-carboxylate (A-5-1)
In the same manner as in Example A-2 (1), from 3,5-dimethyladamantane-1-carboxylic acid (2.00 g) and 1-chloroethyl sulfochloridate (2.58 g), 1-chloroethyl 3,5 -Dimethyladamantane-1-carboxylate (A-5-1, 1.48 g) was obtained as a colorless oil.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.59-6.48 (m, 1H), 2.17-2.08 (m, 4H), 1.79 (d, J = 5.8 Hz 3H), 1.76-1.69 (m, 1H), 1.60-1.43 (m, 5H), 1.40-1.29 (m, 4H), 1.21-1.11. (M, 2H), 0.90-0.82 (m, 6H).
(2) (1S, 2S, 3S, 5R, 6S) -2-amino-6-(((3,5-dimethyladamantane-1-carbonyl) oxy) ethoxy) carbonyl-3-fluorobicyclo [3.1. 0] Hexane-2-carboxylic acid (A-5)
In the same manner as in Example A-1 (3) and (4), (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] Hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 500 mg) and 1-chloroethyl 3,5-dimethyladamantane-1-carboxylate (A-5) -1,1.13 g) gave the title compound (A-5, 70 mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.69-6.58 (m, 1H), 4.91-4.70 (m, 1H), 2.65-2.50 (m, 1H) , 2.16-1.94 (m, 2H), 1.94-1.75 (m, 1H), 1.57 (brs, 2H), 1.47-1.19 (m, 7H), 1.16-1.03 (m, 2H), 0.84-0.69 (m, 6H).
MS m / z; 438 ([M + H] ⁺ )

Example A-6: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((octanoyloxy) methoxy) carbonyl) bicyclo [3.1.0] hexane-2 Synthesis of carboxylic acid (A-6) (1S, 2S, 3S, 5R, 6S) -3 '-(((allyloxy) carbonyl)- From 3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 300 mg) and chloromethyl octanoate (483 mg), The title compound (A-6, 95 mg) was obtained as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 5.72-5.63 (m, 2H), 4.90-4.75 (m, 1H), 2.67-2.51 (m, 1H) , 2.35 (t, J = 7.4 Hz, 2H), 2.14-2.00 (m, 2H), 1.98-1.91 (m, 2H), 1.56-1.47. (M, 2H), 1.32-1.18 (m, 8H), 0.89-0.82 (m, 3H).
MS m / z; 360 ([M + H] ⁺ )

Example A-7: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-((((pivaloyloxy) methoxy) carbonyl) bicyclo [3.1.0] hexane-2- Synthesis of carboxylic acid (A-7) (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3 -Fluoro-5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine] -6-carboxylic acid (A-1-2, 400 mg) and chloromethyl pivalate (193 mg) The compound (A-7, 60 mg) was obtained as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 5.72-5.66 (m, 2H), 4.89-4.74 (m, 1H), 2.67-2.53 (m, 1H) , 2.14-2.04 (m, 1H), 2.04-1.99 (m, 1H), 1.97-1.92 (m, 2H), 1.15 (s, 9H).
MS m / z; 318 ([M + H] ⁺ )

Example A-8: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-((1- (isobutyloxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane- Synthesis of 2-carboxylic acid hydrochloride (A-8) (1) (1S, 2S, 3S, 5R, 6S) -3′-allyl 6- (1- (isobutyryloxy) ethyl) 3-fluoro-5 '-Oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine] -3', 6-dicarboxylate (A-8-1)
In the same manner as in Example A-1 (3), (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1 .0] hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 1.43 g) and 1-chloroethyl isobutyrate (1.80 g), (1S, 2S, 3S, 5R, 6S) -3′-allyl 6- (1- (isobutyryloxy) ethyl) 3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -3 ′, 6-Dicarboxylate (A-8-1, 307 mg) was obtained as a pale yellow oil.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.84 (dd, J = 5.4, 11.1 Hz, 1H), 6.03-5.87 (m, 1H), 5.47-5 .43 (m, 1H), 5.43-5.29 (m, 1H), 5.29-5.22 (m, 2H), 4.79-4.58 (m, 3H), 2.66 -2.42 (m, 3H), 2.39-2.27 (m, 1H), 2.26-2.18 (m, 1H), 2.05 (s, 1H), 1.48 (d , J = 5.4 Hz, 3H), 1.24-1.12 (m, 13H).
MS m / z; 436 ([M + Na] ⁺ )
(2) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-((1- (isobutyloxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic Acid hydrochloride (A-8)
(1S, 2S, 3S, 5R, 6S) -3′-allyl 6- (1- (isobutyryloxy) ethyl) 3-fluoro-5′-oxospiro as in Example A-1 (4) From [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -3 ′, 6-dicarboxylate (A-8-1, 403 mg), (1S, 2S, 3S, 5R, 6S) — A pale yellow oil (278 mg) containing 2-amino-3-fluoro-6-((1- (isobutyloxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid was obtained. Ethyl acetate (3 mL) was added to the obtained oil and stirred, and then a 4 mol / L hydrogen chloride-ethyl acetate solution (3 mL) was added under ice cooling. The mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure and dried to give the title compound (A-8, 200 mg) as a pale yellow solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 8.82-8.64 (m, 1H), 6.80-6.63 (m, 1H), 5.19-4.99 (m, 1H) 3.49-3.30 (m, 2H), 2.68-1.43 (m, 1H), 2.37-2.18 (m, 2H), 2.18-2.01 (m, 2H), 1.49-1.38 (m, 3 H), 1.16-1.01 (m, 6H).
MS m / z; 318 ([M + H] ⁺ )

Example A-9: (1S, 2S, 3S, 5R, 6S) -2-amino-6-(((benzoyloxy) methoxy) carbonyl) -3-fluorobicyclo [3.1.0] hexane-2- Synthesis of carboxylic acid (A-9) (1S, 2S, 3S, 5R, 6S) -3 '-(((allyloxy) carbonyl) -3 was carried out in the same manner as in Examples A-1 (3) and (4) -From fluoro-5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine] -6-carboxylic acid (A-1-2, 500 mg) and chloromethyl benzoate (712 mg), the title The compound (A-9, 198 mg) was obtained as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 8.03-7.94 (m, 2H), 7.77-7.68 (m, 1H), 7.62-7.51 (m, 2H) , 6.00-5.89 (m, 2H), 4.97-4.77 (m, 1H), 2.67-1.53 (m, 1H), 2.17-2.06 (m, 2H), 2.05-1.95 (m, 2H).
MS m / z; 338 ([M + H] ⁺ )

Example A-10: (1S, 2S, 3S, 5R, 6S) -2-amino-6-((1-(((cyclohexyloxy) carbonyl) oxy) ethoxy) carbonyl) -3-fluorobicyclo [3. 1.0] Synthesis of hexane-2-carboxylic acid (A-10) In the same manner as in Examples A-1 (3) and (4), (1S, 2S, 3S, 5R, 6S) -3 ′-( ((Allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 1.35 g) , 1-chloroethyl cyclohexyl carbonate (2.06 mL) gave the title compound (A-10, 113 mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.68-6.52 (m, 1H), 4.92-4.75 (m, 1H), 4.62-4.49 (m, 1H) , 2.70-2.52 (m, 1H), 2.19-1.89 (m, 4H), 1.89-1.78 (m, 2H), 1.70-1.58 (m, 2H), 1.53-1.12 (m, 7H).
MS m / z; 374 ([M + H] ⁺ )

Example A-11: (1S, 2S, 3S, 5R, 6S) -2-amino-6-((1-(((cyclooctyloxy) carbonyl) oxy) ethoxy) carbonyl) -3-fluorobicyclo [3 1.0] Synthesis of hexane-2-carboxylic acid (A-11) (1) 1-chloroethyl cyclooctyl carbonate (A-11-1)
After adding pyridine (1.13 mL) to a solution of cyclooctanol (1.79 g) in chloroform (40 mL), the reaction solution was cooled to −60 ° C. 1-Chloroethyl carbonochloridate (1.53 mL) was added to the reaction solution at the same temperature over 10 minutes. Thereafter, the reaction solution was warmed to room temperature and stirred at the same temperature for 3 hours. Chloroform was added to the reaction solution, and the organic layer was washed 3 times with saturated brine and then dried over magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 1-chloroethyl cyclooctyl carbonate (A-11-1, 3.70 g) as a colorless oil.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.48-6.37 (m, 1H), 4.96-4.81 (m, 1H), 1.97-1.66 (m, 7H) , 1.64-1.42 (m, 7H).
(2) (1S, 2S, 3S, 5R, 6S) -2-amino-6-((1-(((cyclooctyloxy) carbonyl) oxy) ethoxy) carbonyl) -3-fluorobicyclo [3.1. 0] Hexane-2-carboxylic acid (A-11)
In the same manner as in Example A-1 (3) and (4), (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo From [3.1.0] hexane-2,4′-oxazolidine] -6-carboxylic acid [A-1-2] 380 mg and 1-chloroethyl cyclooctyl carbonate (A-11-1, 745 mg), the title compound (A-11, 93 mg) was obtained as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.64-6.53 (m, 1H), 4.92-4.76 (m, 2H), 4.76-4.66 (m, 1H) , 2.68-1.53 (m, 1H), 2.17-2.00 (m, 2H), 2.00-1.89 (m, 2H), 1.85-1.57 (m, 6H), 1.57-1.36 (m, 11H).
MS m / z; 402 ([M + H]) ⁺

Example A-12: (1S, 2S, 3S, 5R, 6S) -2-amino-6-((1-((((4,4-dimethylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl)- Synthesis of 3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid (A-12) (1) 1-chloroethyl (4,4-dimethylcyclohexyl) carbonate (A-12-1)
In the same manner as in Example A-11 (1), from 1-chloroethyl carbonochloridate (1.19 mL) and 4,4-dimethyl-1-cyclohexanol (2.00 g), 1-chloroethyl (4, 4-Dimethylcyclohexyl) carbonate (A-12-1, 4.37 g) was obtained as a colorless oil.
¹ H NMR (200 MHz, CHLOROFORM-d) δ = 6.49-6.36 (m, 1H), 4.68 (dddd, J = 4.4, 4.4, 8.8, 8.8 Hz , 1H), 1.94-1.38 (m, 9H), 1.35-1.16 (m, 2H), 0.94 (s, 3H), 0.92 (s, 3H).
(2) (1S, 2S, 3S, 5R, 6S) -2-amino-6-((1-((((4,4-dimethylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -3-fluoro Bicyclo [3.1.0] hexane-2-carboxylic acid (A-12)
In the same manner as in Example A-1 (3) and (4), (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] Hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 300 mg) and 1-chloroethyl (4,4-dimethylcyclohexyl) carbonate (A-12-1) 588 mg) gave the title compound (A-12, 70 mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.64-6.55 (m, 1H), 4.89-4.73 (m, 1H), 4.60-4.50 (m, 1H) , 2.67-1.51 (m, 1H), 2.15-1.99 (m, 2H), 1.99-1.89 (m, 2H), 1.78-1.70 (m, 2H), 1.61-1.50 (m, 2H), 1.47-1.41 (m, 3H), 1.40-1.32 (m, 2H), 1.28-1.18 ( m, 2H), 0.94-0.84 (m, 6H).
MS m / z; 402 ([M + H] ⁺ )

Example A-13: (1S, 2S, 3S, 5R, 6S) -6-(((((adamantan-1-yloxy) carbonyl) oxy) methoxy) carbonyl) -2-amino-3-fluorobicyclo [3 1.0] Synthesis of hexane-2-carboxylic acid (A-13) (1S, 2S, 3S, 5R, 6S) -3′- in the same manner as in Examples A-1 (3) and (4) (((Allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 500 mg), The title compound (A-13, 120 mg) was obtained as a pale yellow solid from adamantan-1-yl (chloromethyl) carbonate (1.02 g).
¹ H NMR (600 MHz, DMSO-d6) δ = 5.67-5.60 (m, 2H), 4.94-4.77 (m, 1H), 2.67-2.54 (m, 1H) , 2.21-1.94 (m, 13H), 1.62 (br s, 6H).
MS m / z; 412 ([M + H] ⁺ )

Example A-14: (1S, 2S, 3S, 5R, 6S) -6-((1-(((adamantan-1-yloxy) carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3.1.0] Synthesis of hexane-2-carboxylic acid (A-14) (1S, 2S, 3S, 5R, 6S) -3 in the same manner as in Examples A-1 (3) and (4). '-(((Allyloxy) carbonyl) -3-fluoro-5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine] -6-carboxylic acid (A-1-2, 500 mg) Then, the title compound (A-14, 164 mg) was obtained as a pale yellow solid from adamantan-1-yl (1-chloroethyl) carbonate (1.08 g).
¹ H NMR (600 MHz, DMSO-d6) δ = 6.60-6.48 (m, 1H), 4.92-4.72 (m, 1H), 2.69-2.42 (m, 1H) , 2.20-1.86 (m, 13H), 1.61 (br s, 6H), 1.41 (dd, J = 1.7, 5.4 Hz, 3H).
MS m / z; 426 ([M + H]) ⁺

Example A-15: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-((1-((isopropyloxycarbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1. 0] Synthesis of hexane-2-carboxylic acid trifluoroacetate salt (A-15) (1) (1S, 2S, 3S, 5R, 6S) -3'-allyl 6- (1-(((isopropyloxycarbonyl) Oxy) ethyl) 3-fluoro-5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine] -3 ', 6-dicarboxylate (A-15-1)
In the same manner as in Example A-1 (3), (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1 0.0] hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 400 mg) and 1-chloroethyl isopropyl carbonate (204 mg), (1S, 2S, 3S, 5R, 6S) — 3′-allyl 6- (1-((((isopropyloxycarbonyl) oxy) ethyl) 3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -3 ′, 6-Dicarboxylate (A-15-1, 95 mg) was obtained as a colorless oil.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.79-6.70 (m, 1H), 6.02-5.90 (m, 1H), 5.63-5.56 (m, 1H) , 5.38-5.30 (m, 1H), 5.27 (m, 2H), 4.94-4.84 (m, 1H), 4.78-4.57 (m, 3H), 2 .63 -2.47 (m, 2H), 2.38-2.20 (m, 2H), 2.13-2.05 (m, 1H), 1.52 (m, 3H), 1.33 -1.29 (m, 6H).
MS m / z; 452 ([M + Na]) ⁺
(2) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-((1-((isopropyloxycarbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane -2-Carboxylic acid trifluoroacetate (A-15)
(1S, 2S, 3S, 5R, 6S) -3′-allyl 6- (1-(((isopropyloxycarbonyl) oxy) ethyl) 3-fluoro-5 in the same manner as in Example A-1 (4) From '-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine] -3', 6-dicarboxylate (A-15-1, 95 mg), (1S, 2S, 3S, 5R, A solid containing 6S) -2-amino-3-fluoro-6-((1-((isopropyloxycarbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid was obtained. Dimethyl sulfoxide was added to the obtained solid, and this solution was purified by reverse phase column chromatography (mobile phase: 0.1% TFA MeCN / H ₂ O = 10/90 to 90/10; v / v). Frac The ® down and neutralized with saturated aqueous sodium bicarbonate solution, extracted with chloroform, and filtered through Phase Separator. The filtrate was concentrated under reduced pressure to give the title compound (A-15,65mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.66-6.58 (m, 1H), 5.14-5.01 (m, 1H), 4.82-4.75 (m, 1H) , 2.65-2.51 (m, 1H), 2.33-2.05 (m, 4H), 1.48-1.41 (m, 3H), 1.26-1.20 (m, 6H).
MS m / z; 334 ([M + H]) ⁺

Example A-16: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy ) Synthesis of carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (A-16) In the same manner as in Example A-1 (3) and (4), (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1- 2, 660 mg) and 4- (bromomethyl) -5-methyl-1,3-dioxol-2-one (639 mg), the title compound (A-16, 188 mg) was obtained as a pale yellow solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 4.96 (s, 2H), 4.93-4.78 (m, 1H), 2.68-2.52 (m, J = 14.9 Hz) , 1H), 2.19-2.01 (m, 5H), 2.01-1.89 (m, 2H).
MS m / z; 316 ([M + H] ⁺ )

Example A-17: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid 6- (3-phthalidyl) ester hydrochloric acid Synthesis of salt (A-17) (1) (1S, 2S, 3S, 5R, 6S) -3′-allyl 6- (3-oxo-1,3-dihydroisobenzofuran-1-yl) 3-fluoro- 5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -3 ′, 6-dicarboxylate (A-17-1)
In the same manner as in Example A-1 (3), (1S, 2S, 3S, 5R, 6S) -3 ′-(((allyloxy) carbonyl) -3-fluoro-5′-oxospiro [bicyclo [3.1 0.0] hexane-2,4′-oxazolidine] -6-carboxylic acid (A-1-2, 640 mg) and 3-bromophthalide (456 mg), (1S, 2S, 3S, 5R, 6S) -3 ′ -Allyl 6- (3-oxo-1,3-dihydroisobenzofuran-1-yl) 3-fluoro-5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazolidine] -3 ' , 6-dicarboxylate (A-17-1, 380 mg) was obtained as a pale yellow amorphous.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 7.98-7.89 (m, J = 7.4 Hz, 1H), 7.83-7.55 (m, 3H), 7.46-7 .40 (m, 1H), 5.92-5.82 (m, 1H), 5.65-5.58 (m, 1H), 5.30-5.25 (m, 1H), 5.25 -5.19 (m, 1H), 5.18-5.10 (m, 1H), 4.77-4.54 (m, 3H), 2.74-2.65 (m, 1H), 2 64-4-2.50 (m, 1H), 2.39-2.28 (m, 2H), 2.21-2.16 (m, 1H).
MS m / z; 454 ([M + Na] ⁺ )
(2) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid 6- (3-phthalidyl) ester hydrochloride (A -17)
(1S, 2S, 3S, 5R, 6S) -3′-allyl 6- (3-oxo-1,3-dihydroisobenzofuran-1-yl) 3- From fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazolidine] -3 ′, 6-dicarboxylate (A-17-1, 380 mg), the title compound (A-17 120 mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 7.98-7.73 (m, 4H), 7.53-7.47 (m, 1H), 5.18-5.03 (m, 1H) , 2.67-1.51 (m, 1H), 2.40-2.24 (m, 3H), 2.21-2.15 (m, 1H).
MS m / z; 336 ([M + H] ⁺ )

Example A-18: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2- Synthesis of Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (A-18) (1) (1S, 2S, 3S, 5R, 6S) -6-carboxyl-2,2′-diethyl-3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazaborolidine] -3′-ium-8 -Wid (A-18-1)
(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (IV) (70.0 g) in 1 mol / L triethylborane -Tetrahydrofuran solution (362 mL) was added dropwise over 20 minutes under ice-cooling and stirred for 4 hours under water-cooling. The reaction solution was added dropwise to heptane (4200 mL) over 1 hour and stirred at room temperature for 30 minutes. The obtained solid was collected by filtration, washed with heptane (140 mL), and (1S, 2S, 3S, 5R, 6S) -6-carboxyl-2,2′-diethyl-3-fluoro-5′-oxospiro [bicyclo [ 3.1.0] Hexane-2,4′-oxazaborolidine] -3′-ium-8-wide (A-18-1, 89.68 g) was obtained as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.89-6.80 (m, 1H), 6.15-6.04 (m, 1H), 4.95-4.81 (m, 1H) , 3.33 (s, 1H), 2.53-2.37 (m, 1H), 2.25-2.15 (m, 1H), 2.06-2.02 (m, 1H), 2 0.00-1.93 (m, 1H), 1.82-1.76 (m, 1H), 0.77-0.69 (m, 6H), 0.35-0.22 (m, 4H) .
MS m / z; 272 ([M + H] ⁺ )
(2) (S) -1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (A-18-2-1), and (R) -1-chloroethyl ((1R , 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (A-18-2-2)
1-Chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) Carbonate (146 g) in heptane (146 mL) was stirred at −25 ° C. for 1.5 hours. The obtained solid was collected by filtration to give a colorless solid containing (S) -1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate. A solution of the resulting colorless solid (46.8 g) containing (S) -1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate in heptane (94 mL) at −40 ° C. Stir for 1.5 hours. The obtained solid was collected by filtration, and (S) -1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (A-18-2-1, 37.87 g) was colorless. Obtained as a solid. Alternatively, 1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate (300 mg) was separated by chiral column chromatography (CHIRALCEL OD, hexane), and (S) -1-chloroethyl was used. ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) Carbonate (A-18-2-1, 117 mg) as a colorless solid, (R) -1-chloroethyl ((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) carbonate (A-18-2-2, 129 mg) was obtained as a colorless oil. The absolute configuration of the obtained compound (A-18-2-1) was determined by X-ray structural analysis.
Spectrum of Compound (A-18-2-1) ¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.43 (q, J = 5.8 Hz, 1H), 4.58 (dt, J = 4. 5, 10.9 Hz, 1H), 2.15-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.83 (d, J = 2.8 Hz, 3H ), 1.72-1.66 (m, 2H), 1.52-1.41 (m, 2H), 1.12-1.02 (m, 2H), 0.94-0.86 (m , 7H), 0.79 (d, J = 7.0 Hz, 3H).
Spectrum of Compound (A-18-2-2) ¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.43 (q, J = 5.8 Hz, 1H), 4.60 (dt, J = 4. 1, 10.9 Hz, 1H), 2.10-2.05 (m, 1H), 1.98-1.91 (m, 1H), 1.83 (d, J = 5.8 Hz, 3H) ), 1.72-1.67 (m, 2H), 1.53-1.40 (m, 2H), 1.11-1.03 (m, 2H), 0.94-0.86 (m , 7H), 0.81 (d, J = 7.0 Hz, 3H).
(3) (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((((1R, 2S, 5R) -2 -Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine] -3'-ium- 8-Wide (A-18-3)
(1S, 2S, 3S, 5R, 6S) -6-carboxyl-2,2′-diethyl-3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2 obtained in (1) , 4′-oxazaborolidine] -3′-ium-8-wide (A-18-1,25.0 g) in dimethyl sulfoxide (475 mL) was added potassium carbonate (13.38 g) at room temperature. Stir for 30 minutes. To this reaction solution, (S) -1-chloroethyl ((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) carbonate obtained in (2) (A-182-1, 2.9.08 g) was added. And 18-crown-6 (25.60 g) were added while washing with dimethyl sulfoxide (25 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with ethyl acetate (750 mL) under ice-cooling, and the ice-cooled reaction mixture was added to a solution of saturated aqueous ammonium chloride (250 mL) and water (250 mL) over 20 minutes. The reaction vessel was washed with ethyl acetate (250 mL) and was also combined. After separating the combined reaction liquid, heptane (500 mL) was added to the obtained organic layer. The obtained organic layer was washed once with saturated brine, and then the organic layer was dried over anhydrous sodium sulfate. After filtering off insoluble matter, the filtrate was concentrated and purified without purification (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1 -((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2, The solution containing 4′-oxazaborolidine] -3′-ium-8-weide (A-18-3) was used for the next reaction.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.94-6.85 (m, 1H), 6.64-6.54 (m, 1H), 6.19-6.09 (m, 1H) , 4.99-4.84 (m, 1H), 4.51-4.43 (m, 1H), 2.49-1.39 (m, 1H), 2.24-2.15 (m, 1H), 2.14-2.09 (m, 1H), 2.08-2.02 (m, 1H), 1.98-1.92 (m, 1H), 1.83-1.72 ( m, 2H), 1.67-1.58 (m, 2H), 1.50-1.42 (m, 4H), 1.39-1.30 (m, 1H), 1.08-0. 98 (m, 2H), 0.91-0.84 (m, 7H), 0.78-0.67 (m, 9H), 0.37-0.21 (m, 4H).
MS m / z; 520 ([M + Na] ⁺ )
(4) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-isopropyl-5 -Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (A-18-4)
(1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S) -1-(((((1R, 2S, 5R) -2-Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine] -3 Benzenesulfonic acid monohydrate (19.50 g) was added to a solution of '-ium-8-weed (A-18-3), and the mixture was stirred at room temperature for 18 hours. Washing with a mixed solvent of ethyl and heptane (50 mL, 25 mL) and (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((( 1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) cal Nyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (A-18-4, 33.0 g) was obtained as a colorless solid. The absolute configuration of -18-4) was determined by X-ray structural analysis.
¹ H NMR (600 MHz, DMSO-d6) δ = 7.62-7.56 (m, 2H), 7.34-7.27 (m, 3H), 6.61-6.57 (m, 1H) , 5.17-5.05 (m, 1H), 4.50-4.44 (m, 1H), 2.65-2.51 (m, 1H), 2.29-2.18 (m, 2H), 2.15-2.10 (m, 1H), 2.10-2.06 (m, 1H), 1.97-1.92 (m, 1H), 1.83-1.74 ( m, 1H), 1.67-1.59 (m, 2H), 1.50-1.43 (m, 4H), 1.38-1.31 (m, 1H), 1.09-0. 98 (m, 2H), 0.91-0.81 (m, 7H), 0.75 (d, J = 7.0 Hz, 3H).
MS m / z; 428 ([M−H] ⁻ )
[Α] _D ²⁴ -5.8 (c 1.02, EtOH)
Melting point 178 ° C (decomposition)
(5) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-isopropyl-5 -Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (A-18)
(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2 -Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (A-18-4, 33.0 g) in acetone ( (125 mL) To the suspension, water (25 mL) was added and dissolved. The resulting solution was added dropwise to water (1225 mL) over 30 minutes and stirred at room temperature for 2 hours. The obtained solid was collected by filtration and washed with water (50 ml) to give the title compound (A-18, 24.08 g) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.61-6.55 (m, 1H), 4.90-4.77 (m, 1H), 4.50-4.43 (m, 1H) , 2.67-2.54 (m, 1H), 2.11-2.00 (m, 2H), 1.97-1.89 (m, 3H), 1.83-1.75 (m, 1H), 1.66-1.59 (m, 2H), 1.51-1.41 (m, 4H), 1.38-1.31 (m, 1H), 1.09-0.97 ( m, 2H), 0.91-0.80 (m, 7H), 0.75 (d, J = 7.0 Hz, 3H).
MS m / z; 428 ([M−H] ⁻ )
Melting point 175 ° C (decomposition)
(6) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-isopropyl-5 -Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid methanesulfonate (A-18-6)
In the same manner as in Example A-18 (4), (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S ) -1-((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane -2,4′-oxazaborolidine] -3′-ium-8-ide (A-18-3) and methanesulfonic acid, (1S, 2S, 3S, 5R, 6S) -2-amino- 3-Fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1 .0] hexane-2-carboxylic acid methanesulfonate (A- 18-6) was obtained as a colorless solid.
Melting point 160 ° C (decomposition)
(7) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-isopropyl-5 -Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid ethanesulfonate (A-18-7)
In the same manner as in Example A-18 (4), (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S ) -1-((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane -2,4′-oxazaborolidine] -3′-ium-8-weide (A-18-3) and ethanesulfonic acid, (1S, 2S, 3S, 5R, 6S) -2-amino- 3-Fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1 .0] hexane-2-carboxylic acid ethanesulfonate (A- 18-7) was obtained as a colorless solid.
Melting point 195 ° C (decomposition)
(8) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-isopropyl-5 -Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid p-toluenesulfonate (A-18-8)
In the same manner as in Example A-18 (4), (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S ) -1-((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane -2,4′-oxazaborolidine] -3′-ium-8-weide (A-18-3) and p-toluenesulfonic acid monohydrate, (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) Carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid p-tolu The enesulfonate (A-18-8) was obtained as a colorless solid.
Melting point 175 ° C (decomposition)
(9) (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-((((((1R, 2S, 5R) -2-isopropyl-5 -Methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (-)-10-camphorsulfonate (A-18-9)
In the same manner as in Example A-18 (4), (1S, 2S, 3S, 5R, 6S) -2,2′-diethyl-3-fluoro-6-((((S ) -1-((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) -5'-oxospiro [bicyclo [3.1.0] hexane -2,4′-oxazaborolidine] -3′-ium-8-weid (A-18-3) and (−)-10-camphorsulfonic acid, (1S, 2S, 3S, 5R, 6S ) -2-Amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl ) Bicyclo [3.1.0] hexane-2-carboxylic acid (-) -10-camphorsulfonic acid salt (A-18-9) was obtained as a colorless solid.
Melting point 174 ° C (decomposition)

Example A-19: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((R) -1-(((((1R, 2S, 5R) -2- Synthesis of Isopropyl-5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (A-19)
In the same manner as in Example A-18 (3)-(5), (1S, 2S, 3S, 5R, 6S) -6-carboxyl-2,2′-diethyl-3-fluoro-5′-oxospiro [bicyclo [3.1.0] Hexane-2,4′-oxazaborolidine] -3′-ium-8-wide (A-18-1, 33 mg) and (R) -1-chloroethyl ((1R, 2S , 5R) -2-isopropyl-5-methylcyclohexyl) Carbonate (A-18-2-2, 51 mg) gave the title compound (A-19, 7.0 mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.60 (m, 1H), 4.89-4.71 (m, 1H), 4.44 (dt, J = 4.1, 10.9 Hz) , 1H), 2.56-2.40 (m, 1H), 2.11-2.01 (m, 2H), 1.98-1.93 (m, 1H), 1.91 (br s, 2H), 1.85-1.77 (m, 1H), 1.90-1.60 (m, 2H), 1.49-1.42 (m, 4H), 1.39-1.31 ( m, 1H), 1.08-0.98 (m, 2H), 0.91-0.83 (m, 7H), 0.74 (d, J = 7.0 Hz, 3H).
MS m / z; 428 ([M−H] −)

Example A-20: (1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluoro Synthesis of bicyclo [3.1.0] hexane-2-carboxylic acid (A-20) (1) (S) -1-chloroethyl adamantane-1-carboxylate (A-20-1-1), and (R) ) -1-Chloroethyl adamantane-1-carboxylate (A-20-1-2)
1-Chloroethyl adamantane-1-carboxylate (A-2-1, 600 mg) is eluted first by fractionation by chiral column chromatography (CHIRALPAK AD-H, hexane / ethanol = 95/5) (S) -1 -Chloroethyl adamantane-1-carboxylate (A-20-1-1, 230 mg) as a colorless solid, later eluting (R) -1-chloroethyl adamantane-1-carboxylate (A-20-1-2, 200 mg) ) Was obtained as a colorless solid. The absolute configuration of the obtained compound (A-20-1-2) was determined by X-ray structural analysis.
Spectrum of Compound (A-20-1-1) ¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.54 (q, J = 5.8 Hz, 1H), 2.03 (br s, 4H), 1.97-1.63 (m, 14H).
[Α] _D ²² 112.7 (c 1.11. EtOH)
Spectrum of Compound (A-20-1-2) ¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.54 (q, J = 5.8 Hz, 1H), 2.03 (br s, 4H), 1.97-1.63 (m, 14H).
^{_{[Α] D 23 -111.7 (c}} 1.09, EtOH)
(2) (1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3 1.0] Hexane-2-carboxylic acid (A-20)
In the same manner as in Example A-18 (3) to (5), (1S, 2S, 3S, 5R, 6S) -6-carboxyl-2,2′-diethyl-3-fluoro-5′-oxospiro [bicyclo [3.1.0] Hexane-2,4′-oxazaborolidine] -3′-ium-8-weide (A-18-1, 1.85 g) and (S) -1-chloroethyl adamantane-1 -Carboxylate (A-2-1, 1.10 g) gave the title compound (A-20, 636 mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.70-6.65 (m, 1H), 4.88-4.75 (m, 1H), 2.66-2.51 (m, 1H) , 2.14-2.05 (m, 1H), 2.02-1.95 (m, 4H), 1.95-1.90 (m, 2H), 1.79-1.76 (m, 6H), 1.71-1.62 (m, 6H), 1.42-1.38 (m, 3H).
MS m / z; 408 ([M−H] ⁻ )
[Α] _D ²⁵ 42.9 (c 0.57, MeOH)
(3) (1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3 1.0] hexane-2-carboxylic acid methanesulfonate (A-20-3)
Similar to Example A-18 (6), (1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl)- 2-Amino-3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid methanesulfonate (A-20-3) was obtained as a colorless solid.
Melting point 154 ° C (decomposition)
(4) (1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3 1.0] Hexane-2-carboxylic acid ethanesulfonate (A-20-4)
Similar to Example A-18 (7), (1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl)- 2-Amino-3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid ethanesulfonate (A-20-4) was obtained as a colorless solid.
Melting point 171 ° C (decomposition)
(5) (1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3 1.0] hexane-2-carboxylic acid benzenesulfonate (A-20-5)
In the same manner as in Example A-18 (4), (1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl)- 2-Amino-3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid benzenesulfonate (A-20-5) was obtained as a colorless solid.
Melting point 147 ° C (decomposition)
(6) (1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3 1.0] Hexane-2-carboxylic acid p-toluenesulfonate (A-20-6)
In the same manner as in Example A-18 (8), (1S, 2S, 3S, 5R, 6S) -6-(((S) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl)- 2-Amino-3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid p-toluenesulfonate (A-20-6) was obtained as a colorless solid.
Melting point 146 ° C (decomposition)

Example A-21: (1S, 2S, 3S, 5R, 6S) -6-(((R) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluoro Synthesis of bicyclo [3.1.0] hexane-2-carboxylic acid (A-21) (1) (1S, 2S, 3S, 5R, 6S) -6-(((R) -1-((adamantane- 1-carbonyl) oxy) ethoxy) carbonyl) -2,2′-diethyl-3-fluoro-5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazaborolidine] -3 ′ -Ium-8-weid (A-21-1)
(1S, 2S, 3S, 5R, 6S) -6-carboxyl-2,2′-diethyl-3-fluoro-5′-oxospiro [bicyclo [3.1] as in Example A-18 (3). .0] hexane-2,4′-oxazaborolidine] -3′-ium-8-weide (A-18-1, 1.45 g) and (R) -1-chloroethyl adamantane-1-carboxylate ( A-20-1-2, 2.08 g) from (1S, 2S, 3S, 5R, 6S) -6-(((R) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2,2'-diethyl-3-fluoro-5'-oxospiro [bicyclo [3.1.0] hexane-2,4'-oxazaborolidine] -3'-ium-8-weid (A-21) A solution containing -1) was obtained and used for the next reaction.
(2) (1S, 2S, 3S, 5R, 6S) -6-(((R) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3 1.0] Hexane-2-carboxylic acid hydrochloride (A-21-2)
The resulting (1S, 2S, 3S, 5R, 6S) -6-(((R) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2,2′-diethyl-3-fluoro In a solution of -5′-oxospiro [bicyclo [3.1.0] hexane-2,4′-oxazaborolidine] -3′-ium-8-weid (A-21-1) at room temperature, 4 mol / L Hydrogen chloride-ethyl acetate solution (2.7 mL) was added, and the mixture was stirred at room temperature for 7 hr. The obtained solid was collected by filtration, washed with a mixed solvent of ethyl acetate and heptane (10 mL, 10 mL), and (1S, 2S, 3S, 5R, 6S) -6-(((R) -1-((adamantane- 1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid hydrochloride (A-21-2, 1.20 g) was obtained as a colorless solid. It was.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.72-6.68 (m, 1H), 5.14-5.02 (m, 1H), 2.61-2.51 (m, 1H) , 2.32-2.20 (m, 2H), 2.13-2.04 (m, 2H), 1.98 (br s, 3H), 1.80-1.76 (m, 6H), 1.71-1.62 (m, 6H), 1.42 (d, J = 5.4 Hz, 3H).
MS m / z; 410 ([M + H] +)
Melting point 164 ° C (decomposition)
(3) (1S, 2S, 3S, 5R, 6S) -6-(((R) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [3 1.0] Hexane-2-carboxylic acid (A-21)
In the same manner as in Example A-18 (5), (1S, 2S, 3S, 5R, 6S) -6-(((R) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl)- 2-Amino-3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid From the hydrochloride (A-21-2, 2.20 g), the title compound (A-21, 1.36 g) was obtained as a colorless solid. Got as.
¹ H NMR (600 MHz, DMSO-d6) δ = 6.68 (q, J = 5.6 Hz, 1H), 4.90-4.74 (m, 1H), 2.66-2.52 (m , 1H), 2.12-2.04 (m, 1H), 2.01 (dd, J = 2.9, 6.6 Hz, 1H), 1.97 (br s, 3H), 1.96 -1.90 (m, 1H), 1.88 (m, 1H), 1.78 (d, J = 2.5 Hz, 6H), 1.71-1.61 (m, 6H), 40 (d, J = 5.4 Hz, 3H).
MS m / z; 410 ([M + H] +)
[Α] _D ²⁴ 24.0 (c 0.53, MeOH)

Example B-1: (1S, 2S, 3S, 5R, 6S) -2-amino-2-((1-(((cyclohexyloxy) carbonyl) oxy) ethoxy) carbonyl) -3-fluorobicyclo [3. 1.0] Synthesis of hexane-6-carboxylic acid (B-1) (1) (1S, 2S, 3S, 5R, 6S) -6-((allyloxy) carbonyl) 2-(((allyloxy) carbonyl) amino ) -3-Fluorobicyclo [3.1.0] hexane-2-carboxylic acid (B-1-1)
(1S, 2S, 3S, 5R, 6S) -2-(((allyloxy) carbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (A-1-1, A solution of 1.41 g), allyl alcohol (336 μL), N, N-diisopropylethylamine (837 μL) and N, N-dimethylaminopyridine (60 mg) in chloroform (30 mL) was cooled to 0 ° C. To this solution was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (837 mg), and the mixture was warmed to room temperature and stirred for 2 days. Chloroform was added to the reaction solution, and the organic layer was washed successively with 0.25 mol / L-hydrochloric acid twice, water once, and saturated brine once. The organic layer was dried over anhydrous magnesium sulfate, the insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and (1S, 2S, 3S, 5R, 6S) -6-((allyloxy) carbonyl) 2-(((allyloxy)) Carbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid (B-1-1, 1.30 g) was obtained as a colorless amorphous.
(2) (1S, 2S, 3S, 5R, 6S) -2-amino-2-((1-(((cyclohexyloxy) carbonyl) oxy) ethoxy) carbonyl) -3-fluorobicyclo [3.1.0 ] Hexane-6-carboxylic acid (B-1)
In the same manner as in Example A-8 (2), (1S, 2S, 3S, 5R, 6S) -6-((allyloxy) carbonyl) 2-(((allyloxy) carbonyl) amino) -3-fluorobicyclo [ 3.1.0] The title compound (B-1, 115 mg) was obtained as a yellow solid from hexane-2-carboxylic acid (B-1-1, 701 mg) and 1-chloroethyl cyclohexyl carbonate (664 mg).
¹ H NMR (600 MHz, DMSO-d6) δ = 6.79-6.64 (m, 1H), 5.26-4.93 (m, 1H), 4.64-4.51 (m, 1H) , 2.38-2.13 (m, 2H), 2.13-1.94 (m, 2H), 1.91-1.80 (m, 2H), 1.73-1.58 (m, 2H), 1.53 (dd, J = 5.4, 8.3 Hz, 7H), 1.38-1.17 (m, 3H).
MS m / z; 374 ([M + H] ⁺ )

Example B-2: (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-2-(((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy )) Carbonyl) Synthesis of bicyclo [3.1.0] hexane-6-carboxylic acid (B-2) In the same manner as in Examples A-1 (3) and (4), (1S, 2S, 3S, 5R, 6S) -6-((allyloxy) carbonyl) 2-(((allyloxy) carbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid (B-1-1, 650 mg) and , 4- (bromomethyl) -5-methyl-1,3-dioxol-2-one (384 mg) gave the title compound (B-2, 262 mg) as a pale yellow solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 5.05 (s, 2H), 4.84-4.68 (m, 1H), 2.42-2.27 (m, 1H), 2.18 (S, 3H), 2.16-2.07 (m, 1H), 2.07-1.99 (m, 1H), 1.83-1.76 (m, 1H), 1.76-1 .70 (m, 3H).
MS m / z; 316 ([M + H]) ⁺

Example C-1: (1S, 2S, 3S, 5R, 6S) -bis ((1-(((cyclohexyloxy) carbonyl) oxy) ethyl 2-amino-3-fluorobicyclo [3.1.0] hexane Synthesis of -2,6-dicarboxylate (C-1) (1S, 2S, 3S, 5R, 6S) -2-(((allyloxy) in the same manner as in Examples A-1 (3) and (4). )) Carbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (A-1-1, 573 mg) and 1-chloroethyl cyclohexyl carbonate (905 mg) to give the title compound (C -1,124 mg) as a yellow oil.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.84-6.75 (m, 1H), 6.75-6.69 (m, 1H), 4.85-4.55 (m, 3H) , 2.55-2.37 (m, 1H), 2.37-2.20 (m, 2H), 2.10-1.88 (m, 6H), 1.79-1.70 (m, 4H), 1.66-1.42 (m, 13H), 1.42-1.30 (m, 4H), 1.30-1.20 (m, 2H).
MS m / z; 544 ([M + H] ⁺ )

Example C-2: (1S, 2S, 3S, 5R, 6S) -bis (((5-methyl-2-oxo-1,3-dioxol-4-yl) methyl) 2-amino-3-fluorobicyclo [3.1.0] Synthesis of hexane-2,6-dicarboxylate (C-2) In the same manner as in Examples A-1 (3) and (4), (1S, 2S, 3S, 5R, 6S ) -2-(((allyloxy) carbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (A-1-1, 660 mg) and 4- (bromomethyl)- The title compound (C-2, 207 mg) was obtained as a pale yellow oil from 5-methyl-1,3-dioxol-2-one (639 mg).
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 4.95 (d, J = 8.3 Hz, 2H), 4.82 (s, 2H), 4.80-4.65 (m, 1H), 2.56-2.40 (m, 1H), 2.38-2.25 (m, 2H), 2.20 (s, 3H), 2.17 (s, 3H), 2.07-1. 98 (m, 2H), 1.87-1.77 (m, 1H).
MS m / z; 428 ([M + H] ⁺ )

  The structural formulas of Examples A-1 to A-21, B-1, B-2, C-1, C-2 and Reference Example 1 are shown in Table 1-1 to Table 1-6.

Example D-1: (1S, 2S, 3S, 5R, 6S) -2-((S) -2-amino-4- (methylthio) butanamide) -3-fluorobicyclo [3.1.0] hexane- Synthesis of 2,6-dicarboxylic acid hydrochloride (D-1) (1) (1S, 2S, 3S, 5R, 6S) -dimethyl 2-amino-3-fluorobicyclo [3.1.0] hexane-2, 6-Dicarboxylate (D-1-1)
Thionyl chloride (3.59 mL) was added dropwise to methanol (40 mL) at −20 ° C., and the mixture was stirred at the same temperature for 30 minutes. Then (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (IV, 2.00 g) was added for 4 hours. Heated to reflux. After allowing to cool, the reaction mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and (1S, 2S, 3S, 5R, 6S) -dimethyl 2-amino-3-fluorobicyclo [3.1. 0] Hexane-2,6-dicarboxylate (D-1-1, 2.03 g) was obtained as a yellow oil.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 4.86-4.71 (m, 1H), 3.81 (s, 3H), 3.67 (s, 3H), 2.57-2.42 (M, 1H), 2.33-2.23 (m, 2H), 2.05-1.96 (m, 2H).
MS m / z; 232 ([M + H] ⁺ )
(2) (1S, 2S, 3S, 5R, 6S) -dimethyl 2-((S) -2-((tert-butoxycarbonyl) amino) -4- (methylthio) butanamide) -3-fluorobicyclo [3. 1.0] Hexane-2,6-dicarboxylate (D-1-2)
To a suspension of (S) -2-((tert-butoxycarbonyl) amino) -4- (methylthio) butanoic acid (600 mg) in chloroform (6 mL) was added N-methylmorpholine (0.265 mL), and −20 At ° C, isobutyl chloroformate (0.312 mL) was added dropwise and stirred at the same temperature for 15 minutes. To the reaction solution at −20 ° C., (1S, 2S, 3S, 5R, 6S) -dimethyl 2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D- 1-1, 464 mg) in chloroform (4 mL) was added dropwise, and the mixture was stirred at room temperature for 40 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layers were washed once with saturated brine and then dried over anhydrous sodium sulfate. Insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 0: 100), and (1S, 2S, 3S, 5R). , 6S) -dimethyl 2-((S) -2-((tert-butoxycarbonyl) amino) -4- (methylthio) butanamide) -3-fluorobicyclo [3.1.0] hexane-2,6-di Carboxylate (D-1-2, 895 mg) was obtained as a colorless amorphous.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 5.37-5.20 (m, 1H), 4.36-4.28 (m, 1H), 3.76 (s, 3H), 3.69 (S, 3H), 2.64-2.51 (m, 2H), 2.38-2.25 (m, 2H), 2.12 (s, 4H), 2.00 (br s, 2H) 1.95-1.88 (m, 1H), 1.60-1.51 (m, 1H), 1.46 (s, 9H), 1.26 (s, 2H).
MS m / z; 485 ([M + Na] ⁺ )
(3) (1S, 2S, 3S, 5R, 6S) -2-((S) -2-((tert-butoxycarbonyl) amino) -4- (methylthio) butanamide) -3-fluorobicyclo [3.1 .0] hexane-2,6-dicarboxylic acid (D-1-3)
(1S, 2S, 3S, 5R, 6S) -dimethyl 2-((S) -2-((tert-butoxycarbonyl) amino) -4- (methylthio) butanamide) -3-fluorobicyclo [3.1.0 ] To a solution of hexane-2,6-dicarboxylate (D-1-2, 895 mg) in tetrahydrofuran (10 mL) was added 2 mol / L aqueous sodium hydroxide solution (2.92 mL) at room temperature, and the mixture was stirred at the same temperature for 6 hours. . The reaction mixture was washed with tert-butyl methyl ether, 1 mol / L hydrochloric acid was added at 0 ° C to acidify the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give (1S, 2S, 3S, 5R, 6S) -2-((S) -2-((tert-butoxycarbonyl) amino) -4- (methylthio). Butanamide) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (D-1-3, 795 mg) was obtained as a colorless amorphous.
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 5.43-5.22 (m, 1H), 4.40-4.30 (m, 1H), 2.60-2.46 (m, 2H) , 2.40-2.19 (m, 1H), 2.18-2.06 (m, 4H), 2.02-1.90 (m, 1H), 1.45 (br s, 9H), 1.26 (t, J = 7.0 Hz, 2H).
MS m / z; 433 ([M−H] ⁻ )
(4) (1S, 2S, 3S, 5R, 6S) -2-((S) -2-Amino-4- (methylthio) butanamide) -3-fluorobicyclo [3.1.0] hexane-2,6 -Dicarboxylic acid hydrochloride (D-1)
(1S, 2S, 3S, 5R, 6S) -2-((S) -2-((tert-butoxycarbonyl) amino) -4- (methylthio) butanamide) -3-fluorobicyclo [3.1.0] To a suspension of hexane-2,6-dicarboxylic acid (D-1-3, 795 mg) in ethyl acetate (5 mL) was added a 4 mol / L hydrogen chloride-ethyl acetate solution (11.0 mL) at 0 ° C. and brought to room temperature. And stirred for 4 hours. Thereafter, the resulting solid was collected by filtration and dried to obtain the title compound (D-1, 543 mg) as a white solid.
¹ H NMR (600 MHz, DEUTERIUM OXIDE) δ = 5.30-5.14 (m, 1H), 4.25-4.13 (m, 1H), 2.73-2.50 (m, 3H), 2.50-2.42 (m, 1H), 2.39-2.26 (m, 1H), 2.26-2.16 (m, 2H), 2.16-2.09 (m, 4H) ), 1.95-1.84 (m, 2H).
MS m / z; 335 ([M + H] ⁺ )

Example D-2: (1S, 2S, 3S, 5R, 6S) -2-((S) -2-aminopropanamide) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic Synthesis of acid hydrochloride (D-2) In the same manner as in Examples D-1 (2), (3) and (4), (1S, 2S, 3S, 5R, 6S) -dimethyl 2-amino-3- Fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-1-1, 1.27 g) and (S) -2-((tert-butoxycarbonyl) amino) propanoic acid (1 .10 g) gave the title compound (D-2, 1.50 g) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 9.12 (s, 1H), 5.36-5.12 (m, 1H), 3.97-3.82 (m, 1H), 2.63 -2.52 (m, 1H), 2.25-2.11 (m, 1H), 2.11-2.02 (m, 1H), 1.89-1.82 (m, 1H), 1 .76-1.69 (m, 1H), 1.40 (d, J = 7.0 Hz, 3H).
MS m / z; 275 ([M + H] ⁺ )

Example D-3: (1S, 2S, 3S, 5R, 6S) -2- (2-aminoacetamido) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid hydrochloride (D -3) Synthesis In the same manner as in Example D-1 (2), (3) and (4), (1S, 2S, 3S, 5R, 6S) -dimethyl 2-amino-3-fluorobicyclo [3. 1.0] From the hexane-2,6-dicarboxylate (D-1-1, 500 mg) and 2-((tert-butoxycarbonyl) amino) acetic acid (455 mg), the title compound (D-3, 300 mg) Was obtained as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 9.18 (s, 1H), 8.21-8.04 (m, 1H), 5.35-5.12 (m, 1H), 3.62. (S, 2H), 2.58-2.39 (m, 1H), 2.24-2.11 (m, 1H), 2.11-1.03 (m, 1H), 1.87 (br s, 1H), 1.77-1.69 (m, 1H).
MS m / z; 261 ([M + H] ⁺ )

Example D-4: (1S, 2S, 3S, 5R, 6S) -2-((S) -2-amino-4-methylbutanamide) -3-fluorobicyclo [3.1.0] hexane-2 Synthesis of 1,6-dicarboxylic acid hydrochloride (D-4) In the same manner as in Example D-1 (2), (3) and (4), (1S, 2S, 3S, 5R, 6S) -dimethyl 2- Amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-1-1, 500 mg) and (S) -2-((tert-butoxycarbonyl) amino) 3- The title compound (D-4, 133 mg) was obtained as a colorless solid from methylbutanoic acid (564 mg).
¹ H NMR (600 MHz, DMSO-d6) δ = 9.09 (s, 1H), 5.32-5.13 (m, 1H), 3.74 (d, J = 4.1 Hz, 2H), 2.65-2.35 (m, 1H), 2.31-2.12 (m, 2H), 2.12-2.03 (m, 1H), 1.93-1.82 (m, 1H) ), 1.80-1.70 (m, 1H), 1.05-0.90 (m, 6H).
MS m / z; 303 ([M + H] ⁺ )

Example D-5: (1S, 2S, 3S, 5R, 6S) -2-((S) -2,6-diaminohexanamide) -3-fluorobicyclo [3.1.0] hexane-2,6 Synthesis of dicarboxylic acid hydrochloride (D-5) In the same manner as in Example D-1 (2), (3) and (4), (1S, 2S, 3S, 5R, 6S) -dimethyl 2-amino- 3-Fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-1-1, 200 mg) and (S) -2,6-bis ((tert-butoxycarbonyl) amino) hexane The title compound (D-5, 281 mg) was obtained as a colorless solid from the acid (360 mg).
¹ H NMR (600 MHz, DMSO-d6) δ = 9.21 (s, 1H), 8.27 (br s, 1H), 8.03 (br s, 1H), 5.32-5.13 (m , 1H), 3.95-3.85 (m, 1H), 2.81-2.70 (m, 2H), 2.62-2.40 (m, 1H), 2.27-2.10. (M, 1H), 2.07 (dd, J = 2.7, 6.4 Hz, 1H), 1.95-1.69 (m, 4H), 1.66-1.51 (m, 2H ), 1.47-1.36 (m, 2H), 1.17 (t, J = 7.2 Hz, 2H).
MS m / z; 332 ([M + H] ⁺ )

Example D-6: (1S, 2S, 3S, 5R, 6S) -2-((2S, 3S) -2-amino-3-methylpentanamide) -3-fluorobicyclo [3.1.0] hexane Synthesis of 2,6-dicarboxylic acid hydrochloride (D-6) (1S, 2S, 3S, 5R, 6S) -dimethyl was carried out in the same manner as in Example D-1 (2), (3) and (4). 2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-1-1, 500 mg) and (2S, 3S) -2-((tert-butoxycarbonyl) The title compound (D-6, 662 mg) was obtained as a colorless solid from amino) -3-methylpentanoic acid (600 mg).
¹ H NMR (600 MHz, METHANOL-d4) δ = 5.40-5.21 (m, 1H), 3.84 (d, J = 4.5 Hz, 1H), 2.75-2.53 (m , 1H), 2.37-2.17 (m, 2H), 2.08-1.86 (m, 3H), 1.76-1.57 (m, 1H), 1.32-1.17 (M, 1H), 1.10 (d, J = 7.0 Hz, 3H), 1.04-0.93 (m, 3H).
MS m / z; 317 ([M + H]) ⁺

Example D-7: (1S, 2S, 3S, 5R, 6S) -2-((S) -2-amino-4-methylpentanamide) -3-fluorobicyclo [3.1.0] hexane-2 Synthesis of 1,6-dicarboxylic acid hydrochloride (D-7) In the same manner as in Example D-1 (2), (3) and (4), (1S, 2S, 3S, 5R, 6S) -dimethyl 2- Amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-1-1, 300 mg) and (S) -2-((tert-butoxycarbonyl) amino) -4 -The title compound (D-7, 240 mg) was obtained as a colorless solid from methylpentanoic acid (360 mg).
¹ H NMR (600 MHz, METHANOL-d4) δ = 5.42-5.23 (m, 1H), 4.01-3.91 (m, 1H), 2.74-2.56 (m, 1H) , 2.34-2.19 (m, 2H), 2.00-1.89 (m, 2H), 1.86-1.75 (m, 2H), 1.73-1.63 (m, 1H), 1.03 (d, J = 6.2 Hz, 3H), 1.01 (d, J = 6.2 Hz, 3H).
MS m / z; 317 ([M + H] ⁺ )

Example D-8: (1S, 2S, 3S, 5R, 6S) -2-((S) -2-((S) -2-aminopropanamide) propanamide) -3-fluorobicyclo [3.1 0.0] Synthesis of hexane-2,6-dicarboxylic acid hydrochloride (D-8) In the same manner as in Examples D-1 (2), (3) and (4), (1S, 2S, 3S, 5R, 6S) -dimethyl 2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-1-1, 300 mg) and (S) -2-((S)- The title compound (D-8, 452 mg) was obtained as a colorless solid from 2-((tert-butoxycarbonyl) propanamide) propanoic acid (405 mg).
¹ H NMR (600 MHz, METHANOL-d4) δ = 5.37-5.20 (m, 1H), 4.57 (d, J = 7.0 Hz, 1H), 3.91 (d, J = 7 0.0 Hz, 1H), 2.70-2.54 (m, 1H), 2.31-2.18 (m, 2H), 1.97-1.86 (m, 2H), 1.48 ( d, J = 7.0 Hz, 3H), 1.39 (d, J = 7.0 Hz, 3H).
MS m / z; 346 ([M + H]) ⁺

Example D-9: (1S, 2S, 3S, 5R, 6S) -2-((S) -2-amino-3-phenylpropanamide) -3-fluorobicyclo [3.1.0] hexane-2 Synthesis of 1,6-dicarboxylic acid hydrochloride (D-9) In the same manner as in Example D-1 (2), (3) and (4), (1S, 2S, 3S, 5R, 6S) -dimethyl 2- Amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-1-1, 150 mg) and (S) -2-((S) -2-((tert- The title compound (D-9, 205 mg) was obtained as a colorless solid from butoxycarbonyl) -3-phenylpropanoic acid (207 mg).
¹ H NMR (600 MHz, METHANOL-d4) δ = 7.43-7.28 (m, 5H), 5.41-5.25 (m, 1H), 4.24-4.15 (m, 1H) 3.46-3.37 (m, 1H), 3.05-2.95 (m, 1H), 2.73-2.58 (m, 1H), 2.38-2.21 (m, 2H), 2.04-1.92 (m, 2H).
MS m / z; 351 ([M + H] ⁺ )

Example D-10: (1S, 2S, 3S, 5R, 6S) -3-fluoro-2-((S) -pyrrolidine-2- (carboxamido) bicyclo [3.1.0] hexane-2,6 Synthesis of dicarboxylic acid hydrochloride (D-10) In the same manner as in Example D-1 (2), (3) and (4), (1S, 2S, 3S, 5R, 6S) -dimethyl 2-amino- 3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-1-1, 150 mg) and (S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid ( From 168 mg) to give the title compound (D-10, 182 mg) as a colorless solid.
¹ H NMR (600 MHz, METHANOL-d4) δ = 5.40-5.23 (m, 1H), 4.32 (dd, J = 6.6, 8.7 Hz, 1H), 3.46-3 37 (m, 1H), 3.34-3.25 (m, 1H), 2.73-2.59 (m, 1H), 2.51-2.41 (m, 1H), 2.33 -2.22 (m, 2H), 2.21-2.13 (m, 1H), 2.11-2.00 (m, 2H), 2.00-1.95 (m, 1H), 1 .94-1.89 (m, 1H).
MS m / z; 301 ([M + H] ⁺ )

Example D-11: (1S, 2S, 3S, 5R, 6S) -2-((R) -2-amino-4- (methylthio) butanamide) -3-fluorobicyclo [3.1.0] hexane- Synthesis of 2,6-dicarboxylic acid hydrochloride (D-11) In the same manner as in Examples D-1 (2), (3) and (4), (1S, 2S, 3S, 5R, 6S) -dimethyl 2 -Amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-1-1, 200 mg) and (R) -2-((tert-butoxycarbonyl) amino)- The title compound (D-11, 54.0 mg) was obtained as a colorless solid from 4- (methylthio) butanoic acid (258 mg).
¹ H NMR (600 MHz, DMSO-d6) δ = 9.28 (s, 1H), 5.35-5.12 (m, 1H), 4.01-3.93 (m, 1H), 2.66 -2.36 (m, 3H), 2.29-2.10 (m, 2H), 2.08-1.82 (m, 6H), 1.73-1.64 (m, 1H).
MS m / z; 335 ([M + H] ⁺ )

Example D-12: (1S, 2S, 3S, 5R, 6S) -2-((R) -2-aminopropanamide) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic Synthesis of acid hydrochloride (D-12) (1S, 2S, 3S, 5R, 6S) -dimethyl 2-amino-3-like the same manner as in Examples D-1 (2), (3) and (4) From fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-1-1, 200 mg) and (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (196 mg) The title compound (D-12, 128 mg) was obtained as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 9.15 (s, 1H), 5.34-5.11 (m, 1H), 3.98-3.85 (m, 1H), 2.56 -2.40 (m, 1H), 2.23-2.05 (m, 2H), 1.91-1.83 (m, 1H), 1.75-1.65 (m, 1H), 1 .35 (d, J = 7.0 Hz, 3H).
MS m / z; 275 ([M + H] ⁺ )

Example D-13: (1S, 2S, 3S, 5R, 6S) -2-(((1-(((cyclohexyloxy) carbonyl) oxy) ethoxy) carbonyl) amino-3-fluorobicyclo [3.1. 0] Synthesis of hexane-2,6-dicarboxylic acid (D-13) (1) (1S, 2S, 3S, 5R, 6S) -2-((tert-butoxycarbonyl) amino) -3-fluorobicyclo [3 1.0] Hexane-2,6-dicarboxylic acid (D-13-1)
(1S, 2S, 3S, 5R, 6S) -2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (IV) as in Example A-1 (1) 1.00 g) and di-tert-butoxycarbonyl (4.30 g), (1S, 2S, 3S, 5R, 6S) -2-((tert-butoxycarbonyl) amino) -3-fluorobicyclo [3 1.0] Hexane-2,6-dicarboxylic acid (D-13-1, 1.30 g) was obtained as a colorless amorphous.
(2) (1S, 2S, 3S, 5R, 6S) -diallyl 2-((tert-butoxycarbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D -13-2)
(1S, 2S, 3S, 5R, 6S) -2-((tert-butoxycarbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (D-13-1, To a solution of 1.30 g) in N, N-dimethylformamide (25 mL) were added allylalbromide (1.09 mL) and potassium carbonate (1.18 g) at room temperature, and the mixture was stirred at the same temperature for 18 hours. Water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were sequentially washed 3 times with 5% brine and once with saturated brine. The organic layer is dried over anhydrous sodium sulfate, insoluble matter is filtered off, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 60:40). , (1S, 2S, 3S, 5R, 6S) -diallyl 2-((tert-butoxycarbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-13 -2, 1.49 g) as a colorless oil.
(3) (1S, 2S, 3S, 5R, 6S) -diallyl 2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-13-3)
(1S, 2S, 3S, 5R, 6S) -Diallyl 2-((tert-butoxycarbonyl) amino) -3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-13 2, 1.49 g) was added 4 mol / L hydrogen chloride-ethyl acetate solution (24 mL) at 0 ° C., and the mixture was stirred at room temperature for 18 hours. Thereafter, the reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed once with saturated brine, dried over anhydrous sodium sulfate, insolubles were filtered off, the filtrate was concentrated under reduced pressure, and (1S, 2S, 3S, 5R, 6S) -diallyl 2 -Amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-13-3, 949 mg) was obtained.
(4) (1S, 2S, 3S, 5R, 6S) -Dialyl 2-((((1-(((cyclohexyloxy) carbonyl) oxy) ethoxy) carbonyl) amino-3-fluorobicyclo [3.1.0] Hexane-2,6-dicarboxylate (D-13-4)
(1S, 2S, 3S, 5R, 6S) -diallyl 2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-13-3, 880 mg) N, N -To a dimethylformamide (20 mL) solution were added cesium carbonate (4.05 g) and cyclohexyl (1-iodoethyl) carbonate (2.23 g) at room temperature, and the mixture was stirred at the same temperature for 2 hours while blowing carbon dioxide. Thereafter, blowing of carbon dioxide was stopped, and the mixture was stirred at the same temperature for 18 hours. Water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed successively with 5% brine and once with saturated brine, dried over anhydrous sodium sulfate, insolubles were filtered off, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. (1S, 2S, 3S, 5R, 6S) -diallyl 2-(((1-(((cyclohexyloxy) carbonyl)) by chromatography (silica gel cartridge, hexane: ethyl acetate = 100: 0 to 50:50) ) Oxy) ethoxy) carbonyl) amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-13-4, 840 mg) was obtained as a yellow oil.
(5) (1S, 2S, 3S, 5R, 6S) -2-(((1-(((cyclohexyloxy) carbonyl) oxy) ethoxy) carbonyl) amino-3-fluorobicyclo [3.1.0] hexane -2,6-dicarboxylic acid (D-13)
(1S, 2S, 3S, 5R, 6S) -diallyl 2-((((1-(((cyclohexyloxy) carbonyl) oxy) ethoxy) carbonyl) amino-3 as in Example A-1 (4) -The title compound (D-13, 537 mg) was obtained as a colorless amorphous form from fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate (D-13-4, 958 mg).
¹ H NMR (600 MHz, CHLOROFORM-d) δ = 6.79-6.62 (m, 1H), 5.85 (br s, 1H), 5.36-5.14 (m, 1H), 4. 73-4.55 (m, 1H), 2.69-2.46 (m, 1H), 2.45-2.26 (m, 1H), 2.20-1.84 (m, 4H), 1.80-1.68 (m, 2H), 1.59-1.42 (m, 5H), 1.41-1.18 (m, 6H).
MS m / z; 440 ([M + Na] ⁺ )

Example D-14: (1S, 2S, 3S, 5R, 6S) -3-fluoro-2-(((1- (isobutyloxy) ethoxy) carbonyl) aminobicyclo [3.1.0] hexane-2, Synthesis of 6-dicarboxylic acid (D-14) In the same manner as in Examples D-13 (4) and (5), (1S, 2S, 3S, 5R, 6S) -diallyl 2-amino-3-fluorobicyclo [ 3.1.0] From hexane-2,6-dicarboxylate (D-13-3, 800 mg) and 1-iodoethyl isobutyrate (1.37 g), (1S, 2S, 3S, 5R, 6S) -3 -Fluoro-2-(((1- (isobutyloxy) ethoxy) carbonyl) aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (D-14, 87 mg) was obtained as colorless amorphous.
¹ H NMR (600 MHz, DMSO-d6) δ = 8.51 (br s, 1H), 6.69-6.49 (m, 1H), 5.25-4.98 (m, 1H), 2. 49-2.36 (m, 1H), 2.22-2.06 (m, 1H), 2.05-1.90 (m, 1H), 1.79 (br s, 1H), 1.75 -1.62 (m, 1H), 1.45-1.34 (m, 3H), 1.05 (m, 6H).
MS m / z; 384 ([M + Na] ⁺ )

Example D-15: (1S, 2S, 3S, 5R, 6S) -3-fluoro-2-((((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl) Synthesis of (amino) bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (D-15) (1) (1S, 2S, 3S, 5R, 6S) -diallyl 3-fluoro-2-((( (5-Methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl) amino) bicyclo [3.1.0] hexane-2,6-dicarboxylate (D-15-1)
To a solution of triphosgene (35 mg) in chloroform (4 mL), a solution of N, N-diisopropylethylamine (0.18 mL) in tetrahydrofuran (4 mL) and 4- (hydroxymethyl) -5-methyl-1,3-dioxol-2-one 45.9 mg was added at room temperature. After stirring at the same temperature for 30 minutes, (1S, 2S, 3S, 5R, 6S) -diallyl 2-amino-3-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylate ( A solution of D-13-3, 100 mg) in chloroform (4 mL) was added, and the mixture was stirred at the same temperature for 3 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed once with water and once with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel cartridge, hexane: ethyl acetate = 90: 10 to 70:30) (1S , 2S, 3S, 5R, 6S) -diallyl 3-fluoro-2-((((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl) amino) bicyclo [3.1 .0] hexane-2,6-dicarboxylate (D-15-1, 60.0 mg) was obtained as a colorless amorphous.
(2) (1S, 2S, 3S, 5R, 6S) -3-fluoro-2-((((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl) amino) bicyclo [3.1.0] Hexane-2,6-dicarboxylic acid (D-15)
In the same manner as in Example A-1 (4), (1S, 2S, 3S, 5R, 6S) -diallyl 3-fluoro-2-(((((5-methyl-2-oxo-1,3-dioxole- 4-yl) methoxy) carbonyl) amino) bicyclo [3.1.0] hexane-2,6-dicarboxylate (D-15-1, 1.25 g) gave the title compound (D-15, 94 mg). Obtained as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 5.25-5.07 (m, 1H), 4.88 (s, 2H), 2.55-2.44 (m, 1H), 2.21 -2.07 (m, 4H), 2.02-1.94 (m, 1H), 1.83-1.75 (m, 1H), 1.72-1.65 (m, 1H).
MS m / z; 382 ([M + Na] ⁺ )

Example D-16: (1S, 2S, 3S, 5R, 6S) -3-fluoro-6-(((1- (isobutyloxy) ethoxy) carbonyl) -2-(((1- (isobutyloxy) ethoxy ) Carbonyl) amino) bicyclo [3.1.0] hexane-2-carboxylic acid (D-16) Synthesis (1S, 2S, 3S, D) In analogy to Examples D-13 (4) and (5) 5R, 6S) -2-Amino-3-fluoro-6-((1- (isobutyloxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid hydrochloride (A-8, 152 mg) From 1-iodoethyl isobutyrate (208 mg), the title compound (D-16, 108 mg) was obtained as a colorless amorphous substance.
¹ H NMR (600 MHz, DMSO-d6) δ = 8.68-8.51 (m, 1H), 6.76-6.65 (m, 2H), 6.65-6.57 (m, 2H) , 5.23-5.05 (m, 1H), 2.61-2.39 (m, 3H), 2.27-2.13 (m, 1H), 2.11-1.97 (m, 1H), 1.95-1.82 (m, 1H), 1.81-1.69 (m, 1H), 1.46-1.35 (m, 6H), 1.13-0.98 ( m, 12H).
MS m / z; 498 ([M + Na]) ⁺

Example D-17: (1S, 2S, 3S, 5R, 6S) -3-fluoro-6-((((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl) -2-((((5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy) carbonyl) amino) bicyclo [3.1.0] hexane-2-carboxylic acid (D-17) In the same manner as in Synthesis Example D-15 (1), (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((5-methyl-2-oxo-1, 3-dioxol-4-yl) methoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid (A-16, 340 mg) and 4- (hydroxymethyl) -5-methyl-1,3- From dioxol-2-one (154 mg), the title Compound with (D-17,53.0mg) as a colorless solid.
¹ H NMR (600 MHz, DMSO-d6) δ = 5.25-5.09 (m, 1H), 4.99-4.86 (m, 4H), 2.56-2.43 (m, 1H) , 2.23-2.10 (m, 7H), 2.08-2.01 (m, 1H), 1.95-1.87 (m, 1H), 1.81-1.73 (m, 1H).
MS m / z; 494 ([M + Na] ⁺ )

Examples D-1 to D-17 are shown in Table 2-1 to Table 2-2.

Test Example 1: Solution stability test With respect to the compound (I) of the present invention, the stability in a solution assuming the following digestive juices of the stomach and small intestine was tested.
The residual rate of each of the hydrochloric acid solution (pH 1.2) and 20 mM phosphate buffer (pH 6.5) of the compound (I) of the present invention was measured according to the following test method.
A test compound is dissolved in a hydrochloric acid solution (pH 1.2) containing hydrochloric acid and sodium chloride or a 20 mM phosphate buffer (pH 6.5) containing disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium chloride, and about 50 μg / A solution having a concentration of mL (around solubility when not dissolved) was prepared. This solution was incubated at 37 ° C. for 1 hour, the compound concentration before and after the incubation was quantified by high performance liquid chromatography, and the residual ratio was calculated.
The residual ratios of typical compounds in hydrochloric acid solution (pH 1.2) and 20 mM phosphate buffer (pH 6.5) are shown in Table 3 below.

以上より、本発明化合物は、胃及び小腸の消化液を想定した溶液での安定性が良く、消化管ではプロドラッグ体で安定して存在することが想定できた。

From the above, it can be assumed that the compound of the present invention has good stability in a solution assuming digestive juices of the stomach and small intestine, and stably exists in a prodrug form in the digestive tract.

Test Example 2: Production Test of Compound (IV) in Liver Microsomes About the compound (I) of the present invention, the production rate test of compound (IV) in human and monkey liver microsomes was performed according to the following method. As a comparative control, ethyl ester of compound (IV) (Reference Example 1) was used.
The test compound was prepared in the presence of NADPH production system (0.16 mM NADP ⁺ , 2.4 mM MgCl ₂ , 1.5 mM glucose-6-phosphate), human liver microsome (Ms) fraction (Xenotech / H630B / lot.0810472), Or it incubated in the 0.250M phosphate buffer (pH7.4) containing 69 mM KCl with the monkey liver Ms fraction (BD Biosciences / 452413 / lot.94518) (37 degreeC, 15 minutes). The final concentrations of the test compound and liver Ms protein were 3 μM and 1 mg protein / mL, respectively. The reaction mixture after the incubation was added with 2 volumes of DMSO, stirred, and then centrifuged at 3000 rpm (4 ° C., 10 minutes). The obtained supernatant was subjected to analysis by a liquid chromatography tandem mass spectrometry (LC-MS / MS) system. The lower limit of quantification was 0.3 μM for both the test compound and compound (IV).
Table 4 below shows the results of the production rate of compound (IV) in human and monkey liver microsomes for typical compounds.

ＮＴ：試験せず
ヒト肝ミクロソームによる参考例１化合物から化合物（ＩＶ）への変換率は低く、ほぼ100％未変化体（参考例1）のままであった。一方、本発明化合物は、化合物（ＩＶ）への変換率が高く、ヒト肝ミクロソーム及びサル肝ミクロソームで変換が進行し、プロドラッグから親化合物への変換が想定できた。

NT: Not tested, conversion rate from compound of Reference Example 1 to compound (IV) by human liver microsome was low and remained almost 100% unchanged (Reference Example 1). On the other hand, the compound of the present invention has a high conversion rate to compound (IV), and the conversion progressed in human liver microsomes and monkey liver microsomes, and conversion from a prodrug to the parent compound could be assumed.

Test Example 3: Production Test of Compound (IV) in Serum With respect to the compound (I) of the present invention, the production rate test of compound (IV) in human and monkey serum was performed according to the following method. As a comparative control, ethyl ester of compound (IV) (Reference Example 1) was used.
The test compound was added to human or monkey serum to a concentration of 3 μM and incubated at 37 ° C. for a predetermined time. Next, 200 μL of an acetonitrile / methanol mixture containing an internal standard substance was added to 50 μL of the sample after incubation and stirred, followed by centrifugation (4 ° C., 10 minutes). The obtained supernatant was subjected to LC-MS / MS analysis. The lower limit of quantification was 0.03 μM for both the test compound and compound (IV).
The results of the production rate of compound (IV) in human and monkey serum for representative compounds are shown in Table 5 below.

ＮＴ：試験せず
参考例１化合物はヒト血清による化合物（ＩＶ）への変換率が低かった。一方、本発明化合物は、化合物（ＩＶ）への変換率が高く、ヒト血清及びサル血清で変換が進行し、プロドラッグから親化合物への変換が想定できた。

NT: Not tested The compound of Reference Example 1 had a low conversion rate to compound (IV) by human serum. On the other hand, the compound of the present invention has a high conversion rate to compound (IV), and the conversion progressed in human serum and monkey serum, and conversion from a prodrug to a parent compound could be assumed.

Test Example 4: Production rate test of compound (IV) in human small intestine S9 With respect to the compound (I) of the present invention, the production rate test of compound (IV) in human small intestine S9 was performed according to the following method.
The compound of the present invention is mixed with 0.1 M of the human small intestine S9 fraction (XenoTech, LLC / CP710571 / Lot.710571) in the presence of Mg ²⁺ (5 mM), Ca ²⁺ (5 mM), Zn ²⁺ (0.1 mM). Incubation was carried out in phosphate buffer (pH 7.4) (37 ° C., 1 hour). The final concentrations of the compound of the present invention and the small intestine S9 protein were 3 μM and 1 mg protein / mL, respectively. After the incubation, the reaction mixture was added with 3 volumes of DMSO, stirred and then centrifuged at 3000 rpm (4 ° C., 10 minutes). The obtained supernatant was subjected to analysis by a liquid chromatography tandem mass spectrometry (LC-MS / MS) system. The lower limit of quantification was 0.3 μM for both Compound (I) and Compound (IV) of the present invention.
Waters XBridge Amide (3.5 μm, 50 mm × 4.6 mm ID), Waters Atlantis T3 (3 μm, 50 mm × 4.6 mm ID) or Shimadzu Shim-pack XR-ODS (2.2 μm) as separation columns LC-MS / MS system equipped with ID) was used for the measurement. A 0.1% formic acid / acetonitrile solution or a 0.1% formic acid / methanol solution (flow rate: 0.7 to 1.3 mL / min) was used as the mobile phase, and the measurement object was eluted in a linear gradient mode. The MS / MS detection of the compound (I) and the compound (IV) of the present invention was performed in the positive or negative ion detection mode using an API4000 or Triple quad 5500 system (both manufactured by AB SCIEX) equipped with a TurboIonSpray interface. .
Table 6 below shows the production rate of compound (IV) in human small intestine S9 for the compounds of the present invention.

試験した本発明化合物（Ｉ）は、化合物（ＩＶ）への変換がヒト小腸Ｓ９で進行することが分かった。

The compound (I) of the present invention that was tested was found to be converted to compound (IV) in human small intestine S9.

Test Example 5: Measurement of Compound (IV) Plasma Concentration in Monkeys Compound (IV) and compound (IV) plasma concentration measurement test by oral administration of Compound (IV) of the present invention (I) was carried out according to the following method.
Compound (IV) and invention compound (I) were orally administered to male cynomolgus monkeys (satiated) at a dose of 4.92 μmol / kg (base: 0.5% methylcellulose (MC) solution, administration volume 5 mL / kg).
About 0.7 mL of blood was collected from the cephalic vein 2 hours and 4 hours after oral administration (anticoagulant: EDTA-2K). Plasma obtained by centrifugation (3000 rpm, 4 ° C., 10 minutes) was stored frozen at −80 ° C. until analysis. At the time of analysis, 200 μL of an acetonitrile / methanol mixture containing an internal standard substance was added to 50 μL of a plasma sample thawed under ice-cooling, stirred and then centrifuged (4 ° C., 10 minutes), and the resulting supernatant Was subjected to LC-MS / MS analysis. The lower limit of quantification of the compound (I) of the present invention and the compound (IV) was 1 ng / mL and 3 ng / mL, respectively.
The results of plasma concentrations of compound (IV) after oral administration of representative compounds are shown in Table 7 below.

以上より、本発明化合物（Ｉ）は、化合物（ＩＶ）の経口投与時に比べ、化合物（ＩＶ）の血漿中濃度が飛躍的に向上した。

From the above, the compound (I) of the present invention has dramatically improved the plasma concentration of the compound (IV) compared to the oral administration of the compound (IV).

It was shown that the compound of the present invention is extremely useful as a prodrug of compound (IV) having a strong action on a group 2 metabotropic glutamate receptor. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used for diseases regulated by group 2 metabotropic glutamate receptor agonists such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorder, epilepsy. And neurological disorders such as drug dependence, cognitive impairment, Alzheimer's disease, Huntington's disease, Parkinson's disease, movement disorder associated with muscle stiffness, cerebral ischemia, brain failure, spinal cord disorder, head injury, etc. It can be used as a therapeutic or prophylactic agent for diseases.

Claims (9)

Formula (I)

[In the formula (I),
R ¹ represents the formula — (CR ⁴ R ⁴ ′) —O—CO—R ⁵ or the formula — (CR ⁶ R ⁶ ′) —O—CO—O—R ⁷ ,
R ² represents a hydrogen atom,
R ³ represents a hydrogen atom,
R ⁴ and R ⁴ ′ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
R ⁵ is a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups), or an adamantyl group (the adamantyl group is 1 to 3 C _1-6 alkyl groups may be substituted)
R ⁶ and R ⁶ ′ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group,
R ⁷ is a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups), or an adamantyl group (the adamantyl group is 1 to 3 C _1-6 alkyl groups may be substituted). ]
Or an pharmaceutically acceptable salt thereof as an active ingredient, and one or more lactose, dextrose, fructose, sucrose, sorbitol, mannitol, starch, gum, gelatin, alginate, Schizophrenia, anxiety disorder comprising a pharmaceutically acceptable carrier, excipient or diluent selected from the group consisting of calcium silicate, calcium phosphate, cellulose, methylcellulose, polyvinylpyrrolidone, talc, magnesium stearate and stearic acid And related diseases, depression, bipolar disorder, epilepsy, developmental disorders, sleep disorders, and neuropsychiatric disorders, as well as drug addiction, cognitive impairment, Alzheimer's disease, Huntington's chorea, Parkinson's disease, movement disorders associated with muscle stiffness , Cerebral ischemia, brain failure, spinal cord disorder, head disorder neurological disease Used in the treatment or prevention of a disease selected from the group consisting of tablets, pills, capsules, granules or oral manufactured agent is powder. A compound according to claim 1 which comprises, as an active ingredient, or oral made agent according to claim 1 dose per day 0.01~500mg a pharmaceutically acceptable salt thereof. The active ingredient is (1S, 2S, 3S, 5R, 6S) -6-(((adamantane-1-carbonyl) oxy) methoxy) carbonyl-2-amino-3-fluorobicyclo [3.1.0] hexane- 2-carboxylic acid, or oral made agent according to claim 1 or 2, a pharmaceutically acceptable salt thereof. The active ingredient is (1S, 2S, 3S, 5R, 6S) -6- (1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl-2-amino-3-fluorobicyclo [3.1.0] hexane-2-carboxylic acid, or oral made agent according to claim 1 or 2, a pharmaceutically acceptable salt thereof. The active ingredient is (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-((1-((((((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl ) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid, or oral made agent according to claim 1 or 2, a pharmaceutically acceptable salt thereof. The active ingredient is (1S, 2S, 3S, 5R, 6S) -2-amino-6-((1-(((cyclohexyloxy) carbonyl) oxy) ethoxy) carbonyl) -3-fluorobicyclo [3.1. 0] hexane-2-carboxylic acid, or oral made agent according to claim 1 or 2, a pharmaceutically acceptable salt thereof. The active ingredient is (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((S) -1-(((((1R, 2S, 5R) -2-isopropyl- The oral use according to claim 1 or 2, which is 5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid, or a pharmaceutically acceptable salt thereof . Ltd. agent. The active ingredient is (1S, 2S, 3S, 5R, 6S) -2-amino-3-fluoro-6-(((R) -1-(((((1R, 2S, 5R) -2-isopropyl- The oral use according to claim 1 or 2, which is 5-methylcyclohexyl) oxy) carbonyl) oxy) ethoxy) carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid, or a pharmaceutically acceptable salt thereof . Ltd. agent. The active ingredient is (1S, 2S, 3S, 5R, 6S) -6-(((R) -1-((adamantane-1-carbonyl) oxy) ethoxy) carbonyl) -2-amino-3-fluorobicyclo [ 3.1.0] hexane-2-carboxylic acid, or oral made agent according to claim 1 or 2, a pharmaceutically acceptable salt thereof.