JP2002348239A - Growth and differentiation stimulator for stem cell and neuronal precursor cell - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an improved growth and differentiation stimulator for stem cells and neuronal precursor cells. SOLUTION: The growth and differentiation stimulator for stem cells and/or neuronal precursor cells contains a compound represented by formula (1) or its salt or its prodrug [wherein, R<1> and R<2> are each independently H, a hydrocarbon group or a heterocyclic group, or form a ring with adjacent carbon atoms; R<3> is H, a hydrocarbon group or a heterocyclic group; W is formula (2) (wherein, A ring is a benzene ring which may have substituents; B ring is a five- or seven-membered nitrogen-containing heterocycle which may have substituents; R<4> is an aliphatic hydrocarbon group which has an aromatic substituent and may further have substituents, or an acyl group having an aromatic group; R<5> is H, a C1-6 alkyl group or an acyl group; R<4c> is an aromatic group, an aliphatic hydrocarbon group or an acyl group; X is O or S); Y is O, S or NH; C ring is a benzene ring which may have substituents].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for promoting proliferation and differentiation of stem cells and / or neural progenitor cells, comprising a benzofuran derivative.

[0002]

2. Description of the Related Art A neurodegenerative disease is a disease in which selective nerve cell death occurs progressively.
Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease are known. As a current drug treatment method, replacement therapy which compensates for neurotransmitter depletion accompanying neurodegeneration is mainstream. For Parkinson's disease, dopamine agonists such as L-dopa, which is a precursor of dopamine, and for Alzheimer's disease, acetylcholine degrading enzyme inhibitors are used as replacement or symptomatic treatments, respectively. However, these replacement therapeutic agents and symptomatic therapeutic agents do not suppress the progression of neurodegeneration, and the effect gradually decreases as the disease progresses. Therefore, it is desired to develop a drug that suppresses the progression of neurodegeneration and promotes the regeneration of remaining nerve endings, but at present, no drug having such an effect has been found. Furthermore, in neurodegenerative diseases, it is thought that most of the nerve cells are degenerated at the time of onset, and it is thought that suppression of degeneration or promotion of regeneration of nerve endings alone cannot achieve sufficient functional regeneration. On the other hand, in recent years, the concept of regeneration of the central nervous system has changed significantly. Conventionally, it has been considered that when neurodegeneration occurs in the central nervous system, recovery of function is difficult because nerves are not newly produced and replenished. However, it is only recently discovered that the central nervous system of mature mammals, including humans, has neural stem cells and neural progenitors that can generate new nerves, and activates endogenous neural stem cells. The possibility of regenerating impaired nerve tissue and function
[Nature Medicine, Volume 4, 1313
-1317, 1998, Nature Medicine
cine), 6, 271-277, 2000]. In addition, the preparation of neural stem cells from embryonic stem cells, and aborted fetal brain and even the patient's own tissue, and the study of neural regenerative medicine by transplantation has begun. (Nature, 405, 951-95)
5 pages, 2000, European Journal of Neuroscience (Eur.J. Neurosci.), Volume 10, 2026 2036 1
998]. In addition, benzofuran derivatives having a nerve regeneration promoting action and useful as a medicament for preventing and treating neurodegenerative diseases are described in WO 98/55454 and WO 00/3426.
2, there is no description in these publications to promote the growth and differentiation of neural stem cells and neural progenitor cells.

[0003]

At present, substances that proliferate and differentiate neural stem cells and neural progenitor cells are high molecular in vivo factors, and it is considered that treatment requires injection into the brain by surgery. In the present invention, a compound which is excellent in localization into the brain, enhances proliferation (self-renewal) of neural stem cells or neural progenitor cells, promotes differentiation into neural cells, and regenerates destroyed neural cells after neurodegeneration By developing
The objective is to treat neurodegenerative diseases, cerebrovascular disorders and head trauma. Such compounds are also useful for preparing embryonic stem cells and neural stem cells and neural progenitor cells from neural tissue, while promoting engraftment and differentiation after transplantation.

[0004]

Means for Solving the Problems The present inventors have conducted intensive searches and found that the formula:

Embedded image [Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent; ¹
And R ² may form a 3- to 8-membered homo- or heterocyclic ring which may have a substituent together with an adjacent carbon atom, and R ³ may be a hydrogen atom or a substituent have a good hydrocarbon group or a substituent shown also heterocyclic group, - - - represents a single bond or a double bond, W is (i)
formula:

Embedded image Wherein, in the formula, ring A represents a benzene ring which may have a substituent, and ring B represents a 5- to 7-membered nitrogen-containing heterocyclic ring which may have a substituent. (Ii) Formula:

Embedded image [In the formula, R ⁴ is (1) an aliphatic hydrocarbon group optionally substituted with an aromatic group, and further optionally having a substituent or (2) a substituent. An acyl group containing an aromatic group which may be substituted, R ⁵ represents a hydrogen atom,
A C _1-6 alkyl or acyl group] or a group represented by the formula (iii): [Wherein, R ^4c represents an aromatic group which may have a substituent,
X represents an aliphatic hydrocarbon group or an acyl group which may have a substituent, X represents an oxygen atom or a sulfur atom which may be oxidized], Y represents an oxygen atom,
It represents a sulfur atom which may be oxidized or an imino which may have a substituent, and the ring C represents a benzene ring which may further have a substituent in addition to the group represented by W. ] Or a salt thereof or a prodrug thereof is unexpectedly found to have an excellent stem cell / neural progenitor cell proliferation / differentiation promoting action, based on this finding,
As a result of further studies, the present invention has been completed.

That is, the present invention relates to (1) an agent for promoting proliferation and differentiation of stem cells and / or neural progenitor cells comprising a compound represented by the formula (I) or a salt thereof or a prodrug thereof; The agent according to the above (1), wherein the stem cell is an embryonic stem cell or a neural stem cell, (3) engraftment in neural stem cell, neural progenitor cell and / or neural cell transplantation.
The agent according to the above (1), which is an agent for promoting differentiation, (4) the agent according to the above (1), which is an agent for promoting proliferation / differentiation of neural stem cells, neural progenitor cells and / or nerve cells for transplantation, (5) The agent according to the above (1), which is an agent for promoting proliferation / differentiation of endogenous neural stem cells; (6) the agent according to the above (1), which is used for prevention / treatment of a central nervous system disease; agent of a (1) wherein, (8) the a neurogenic agent (1), wherein the agent, (9) - - - is agent of (1) wherein is a single bond, is (10) Y The agent according to the above (1), which is an oxygen atom; (11) the agent according to the above (1), wherein W is a group represented by the formula (Wa); (12) R ¹ and R ² are each C _1-6. In the alkyl group, R ³ represents a substituent selected from C _1-6 alkyl and a halogen atom by 1 to 3
A phenyl group which may have one or more C
_A benzene ring optionally having 1 to 3 substituents selected from _1-6 alkyl and C _1-6 alkoxy,
- - - is a single bond, Y is an oxygen atom, a group represented by formula (Wa) has the formula:

Embedded image [In the formula, ring A ¹ represents a benzene ring which may have 1 to 3 substituent (s) selected from halogen, C _1-6 alkoxy and C _1-6 alkylenedioxy. The agent according to the above (11), which is a group represented by the formula (13):
The agent according to the above (12), wherein the group represented by a) is substituted at the 5-position of the benzofuran ring, (14) 2- [2,2,
4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] isoindoline, 5,6-dimethoxy-2-
[2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-
5-yl] isoindoline, 5,6-dimethoxy-2
-[3- (4-isopropylphenyl) -2,2,4
6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] isoindoline, 5,6-dimethoxy-2- [2,2,4,6,7-pentamethyl-3-
(4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -2H-isoindole, 6-
[3- (4-isopropylphenyl) -2,2,4
6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -6,7-dihydro-5H- [1,
3] dioxolo [4,5-f] isoindole, 6-
[2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-
5-yl] -6H- [1,3] dioxolo [4,5-
f] isoindole, 6- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -6,7-dihydro-5H-
[1,3] dioxolo [4,5-f] isoindole,
(R) -5,6-dimethoxy-2- [2,2,4
6,7-pentamethyl-3- (4-methylphenyl)-
2,3-dihydro-1-benzofuran-5-yl] isoindoline or (R) -5,6-dimethoxy-2-
[2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-
The agent according to the above (11), which comprises 5-yl] isoindoline hydrochloride, (15) (R) -5,6-dimethoxy-2- [2,2,4,6,7-pentamethyl-3 −
The agent according to the above (11), comprising (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] isoindoline, (16) a group wherein W is represented by the formula (Wb) The agent according to the above (1), wherein (17) R ¹ and R
² is a methyl group, R ³ is a phenyl group which may have 1 to 3 substituents selected from fluorine, methyl and isopropyl, and the C ring further has C _1-6 alkyl and C _1-6 alkoxy. A benzene ring which may have 1 to 3 substituents selected from: Y is an oxygen atom, and R ⁴ has 1 to 3 substituents selected from fluorine, methoxy and methylenedioxy, respectively. (18) The agent according to the above (16), wherein R ⁵ is a hydrogen atom or a methyl group, which may be a benzyl or phenethyl group.
(1) N- (4-fluorobenzyl) -2,2,4
6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine, (2) N-benzyl-3- (4-isopropylphenyl) -2,2,4
6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, (3) 3- (4-isopropylphenyl) -N- (4-methoxybenzyl) -N, 2,
2,4,6,7-hexamethyl-2,3-dihydro-1
-Benzofuran-5-amine, (4) 3- (4-isopropylphenyl) -N- [2- (4-methoxyphenyl) ethyl] -2,2,4,6,7-pentamethyl-
2,3-dihydro-1-benzofuran-5-amine,
(5) N- (4-fluorobenzyl) -3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, (6) N- (1,3-benzodioxol-5-ylmethyl) -3- (4-isopropylphenyl) -2,
2,4,6,7-pentamethyl-2,3-dihydro-1
-Benzofuran-5-amine, (7) N- (4-fluorobenzyl) -3- (4-fluorophenyl) -2,
2,4,6,7-pentamethyl-2,3-dihydro-1
-Benzofuran-5-amine, (8) N- (4-methoxybenzyl) -2,2,4,6,7-pentamethyl-3
-(4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine, (9) N- (4-fluorobenzyl) -2,2,4,6,7-pentamethyl-3-
(4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine, (10) 3- (4-isopropylphenyl) -N- (4-methoxybenzyl) -2,4,
6,7-tetramethyl-1-benzofuran-5-amine, (11) N- (4-fluorobenzyl) -3- (4-
(Isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine, (12) N- (4-
Fluorobenzyl) -3- (4-fluorophenyl)-
2,4,6,7-tetramethyl-1-benzofuran-5
-Amine, (13) N- (4-fluorobenzyl) -3-
(4-Isopropylphenyl) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4′-
Piperidine] -5-amine or (14) (R) -N-
(4-fluorobenzyl) -3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3
The agent according to the above (16), which comprises -dihydro-1-benzofuran-5-amine hydrochloride;
The agent according to the above (1), which is a group represented by c), (20)
formula:

Embedded image [Wherein, R ¹ and R ² are each a C _1-6 alkyl _optionally having a 6-membered saturated cyclic amino substituted with phenyl, or R ¹ and R ² together with an adjacent carbon atom , _{C 1-6} alkyl or _{C 7-16} form piperidine substituted aralkyl; ^{R 3} is (i) hydrogen atom or (ii) _{(1) C 1-6} alkyl, (2) di -C
Phenyl ^optionally having 1 to 3 substituents selected from _1-6 alkylamino and (3) 6-membered saturated cyclic amino optionally having C _1-6 alkyl; R ^4c is (i) Phenyl optionally having 1 to 3 substituents selected from nitro and C _1-6 alkyl-carboxamide, (ii) C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-carbonyl, C _1-6 has alkylsulfonyl and C _1-6 alkylsulfinyl, 1 to substituents selected from the Le may have three each phenyl, quinolyl or pyridyl 1 to 3, respectively, phenyl as substituent, carboxy or _{C 1-6} alkoxy - optionally _{C 1 -6} alkyl optionally having carbonyl respectively or _{C 2-6} alkenyl or, (Iii) formula ^{- (C = O) -R 5} ' acyl represented ^by' wherein, R ^{5 ''} is a phenyl substituted with _{C 1-6} alkoxy]; and C ^'rings, further A benzene ring optionally having 1 to 3 C _1-6 alkyl], a salt thereof or a prodrug thereof, the agent according to the above (19),
3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran, 3- (4-methylphenyl) -2,4 , 6,7-tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3- (4-
(Isopropylphenyl) -2,4,6,7-tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,4,6,7 -Tetramethylbenzofuran, 3- (4-isopropylphenyl)-
5- (4-methoxybenzyloxy) -1 ′, 4,6
7-tetramethylspiro [benzofuran-2 (3H),
4′-piperidine] or a salt thereof in the presence of the agent according to the above (19), (22) the compound according to the above (1) or a salt thereof,
Or a method for culturing a stem cell, a neural progenitor cell and / or a neural cell, which comprises culturing a neural cell;
3) The culture method according to the above (22), wherein the stem cells are embryonic stem cells or neural stem cells, (24) the culture method according to the above (22) for preparing cells for transplantation therapy, and (25) the culture method according to the above (22). A cell obtained by the method, (26) an agent for promoting proliferation / differentiation in culture of a stem cell, a neural progenitor cell and / or a neural cell for transplantation, comprising the compound of the above-mentioned 1 or a salt thereof, and (27) a cognitive disorder. Alternatively, the agent according to the above (1), which is a therapeutic agent for a memory disorder. (28) The agent according to the above (1), which is a therapeutic agent for mild cognitive impairment or mild memory impairment, and (29) in the neural stem cell and / or nerve cell transplantation of the compound according to the above (1) or a salt thereof or a prodrug thereof. Use for production of an engraftment / differentiation promoting agent, (30) Neural stem cells for transplantation and / or a compound of the above (1) or a salt thereof or a prodrug thereof.
Or use for producing a nerve cell growth / differentiation promoter,
(31) Use of the compound of the above (1) or a salt thereof or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for a central nervous system disease, (32) the compound of the above (1) or a salt thereof or a prodrug thereof And (33) administering the compound according to (1) or a salt thereof or a prodrug thereof to a mammal in need thereof. And a method for preventing and treating central nervous system diseases in mammals.

[0006]

DETAILED DESCRIPTION OF THE INVENTION In the above formula, - - - indicates a single bond or a double bond. - - - is a single bond. In the above formula, R ¹ and R ² are the same or different and each represent a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent; ¹ and R ² may form a 3- to 8-membered homo- or heterocyclic ring which may have a substituent together with adjacent carbon atoms. In the above formula, - - - is when indicating a double bond, R ² is absent. That is, in the above formula,
(I) - - - is when represents a single bond, the partial structure:

Embedded image Is

Embedded image Are shown, (ii) - - - When the show a double bond, the partial structure:

Embedded image Is

Embedded image In the present specification, for convenience, (i) and (i)
i) put together the formula:

Embedded image May be represented by

[0007] R¹Or R²Having a substituent
The "hydrocarbon group" of the "hydrocarbon group which may be
For example, a chain or cyclic hydrocarbon group (eg, alkyl,
Lucenyl, alkynyl, cycloalkyl, aryl, etc.)
And the like. Among them, a chain having 1 to 16 carbon atoms
And a cyclic or cyclic hydrocarbon group. "Alkyl"
For example, C_1-6Alkyl (eg, methyl, ethi
, Propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, pentyl, hexyl, etc.)
preferable. “Alkenyl” includes, for example, C_2-6A
Lucenyl (eg, vinyl, allyl, isopropenyl, bute
, Isobutenyl, sec-butenyl, etc.) and the like.
“Alkynyl” includes, for example, C_2-6Alkynyl
(Eg, ethynyl, propargyl, butynyl, 1-hexyl
And the like are preferred. As “cycloalkyl”,
For example, C_3-6Cycloalkyl (eg, cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, etc.)
Is preferred. “Aryl” includes, for example, C_6-14
Aryl (eg, phenyl, 1-naphthyl, 2-naphthyl)
, Biphenylyl, 2-anthryl and the like).
R¹Or R²Represented by the `` may have a substituent
Examples of the “substituent” of the “hydrocarbon group” include (1) halogen
(Eg, fluorine, chlorine, bromine, iodine, etc.), (2) C
_1-3Alkylenedioxy (eg, methylenedioxy, d
(3) nitro, (4) cyano, (5) halo
C which may be genated_1-6Alkyl, (6) halogen
C which may be_2-6Alkenyl, (7) halogen
C which may be_2-6Alkynyl, (8) halogen
C which may be_3-6Cycloalkyl, (9) C
_6-14Aryl (eg, phenyl, 1-naphthyl, 2-
Naphthyl, biphenylyl, 2-anthryl, etc.), (10) c
C which may be formed into a log _1-6Alkoxy, (11) c
C which may be formed into a log_1-6Alkylthio or
Mercapto, (12) hydroxy, (13) amino, (14) mono-
C_1-6Alkylamino (eg, methylamino, ethyl
Mino, etc.), (15) Mono-C_6-14Arylamino (eg,
Phenylamino, 1-naphthylamino, 2-naphthylua
Mino, etc.), (16) Di-C_1-6Alkylamino (eg,
Tylamino, diethylamino, etc.), (17) di-C_6-14
Arylamino (eg, diphenylamino, etc.), (18)
, (19) acylamino, (20) acyloxy, (21) substituent
5 to 7-membered saturated cyclic amino optionally having (22)
5- to 10-membered aromatic heterocyclic group (eg, 2- or 3-thio)
Enyl, 2-, 3- or 4-pyridyl, 2-, 3-,
4-, 5- or 8-quinolyl, 1-, 3-, 4- or
Is 5-isoquinolyl, 1-, 2- or 3-indolini
2-benzothiazolyl, 2-benzo [b] thieni
Benzo [b] furanyl, etc.), (23) sulfo, (24) C
_6-14Aryloxy (eg, phenyloxy, naphthy
And the like). The "hydrocarbon group" is an example
For example, 1 to 5 substituents are preferably substituted at substitutable positions.
Preferably, it may have 1 to 3 substituents, and the number of substituents is 2
In the case of two or more, each substituent may be the same or different
No.

The above-mentioned “optionally halogenated C”
Examples of the “ _1-6 alkyl” include C _1-6 alkyl (eg, fluorine, chlorine, bromine, iodine, etc.) which may have 1 to 5, preferably 1 to 3, halogen atoms (eg, Methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.). As a specific example,
Methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl , 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like No. Examples of the “optionally halogenated C _2-6 alkenyl” include 1 to 5, preferably 1 to 3 halogen atoms (eg,
C which may have fluorine, chlorine, bromine, iodine, etc.)
_2-6 alkenyl (eg, vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.) and the like. Specific examples include vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, 3,
3,3-trifluoro-1-propenyl, 4,4,4-
Trifluoro-1-butenyl and the like. Examples of the “optionally halogenated C _2-6 alkynyl” include, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). And C _2-6 alkynyl (eg, ethynyl, propargyl, butynyl, 1-hexynyl, etc.) and the like. Specific examples include ethynyl, propargyl, butynyl, 1-hexynyl, 3,3,3-trifluoro-1
-Propynyl, 4,4,4-trifluoro-1-butynyl and the like. Examples of the “optionally halogenated C _3-6 cycloalkyl” include, for example, 1 to 5
, Preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
_3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, and the like. The “optionally halogenated C _1-6 alkoxy” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). C _1-6 alkoxy (eg,
Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.). Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,
4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like. As the “optionally halogenated C _1-6 alkylthio”, for example, 1 to 5, preferably 1
Or 3 halogen atoms (eg, fluorine, chlorine, bromine,
And C _1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) which may have iodine. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio,
Ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.

[0009] Examples of the "acyl" such as formyl, carboxy, _{carbamoyl, C 1 -6} alkyl - carbonyl (e.g., acetyl, propionyl, _{etc.), C 3-6}
Cycloalkyl-carbonyl (eg, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C _1-6 alkoxy-carbonyl (eg,
Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C
_6-14 aryl-carbonyl (eg, benzoyl, 1-
Naphthoyl, 2-naphthoyl, etc.), C _7-16 aralkyl-carbonyl (eg, phenylacetyl, phenylpropionyl, etc.), C _6-14 aryloxy-carbonyl (eg, phenoxycarbonyl, etc.), C _7-16 aralkyloxy-carbonyl (Eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.) 5- or 6-membered heterocyclic carbonyl (eg, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-
Furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl, etc.), mono-C _1-6 alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.),
Di-C _1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C _6-14 aryl-carbamoyl (eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), thio Carbamoyl, 5- or 6-membered heterocyclic carbamoyl (eg, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C _1-6 alkylsulfonyl (eg, methylsulfonyl) , Ethylsulfonyl, etc.), C
_6-14 arylsulfonyl (eg, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, etc.), C _6-14 arylsulfinyl (eg, phenyl Sulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like). Examples of the “acylamino” include formylamino, C _1-6 alkyl-carbonylamino (eg, acetylamino, etc.), C _6-14 aryl-carbonylamino (eg, phenylcarbonylamino, naphthylcarbonylamino, etc.), C _{1 -6} alkoxy-carbokinylamino (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarnylamino, butoxycarbonylamino, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _6-14 arylsulfonylamino (eg, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.) and the like. As the “acyloxy”, for example, C
_1-6 alkyl-carbonyloxy (eg, acetoxy,
Propionyloxy, etc.), C _6-14 aryl-carbonyloxy (eg, benzoyloxy, naphthylcarbonyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyl) Oxy), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C _6-14 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy and the like. Examples of the “5- to 7-membered saturated cyclic amino” of the “5- to 7-membered saturated cyclic amino optionally having substituent (s)” include, for example, morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidine-1- And the like. Examples of the “substituent” of the “optionally substituted 5- to 7-membered saturated cyclic amino” include C _1-6 alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, tert
-Butyl, pentyl, hexyl, etc.), C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.), 5- to 10-membered aromatic heterocyclic group (eg, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5- or 8-
Quinolyl, 1-, 3-, 4- or 5-isoquinolyl,
1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl and the like;

[0010] The "heterocyclic group" of the "heterocyclic group optionally having substituent (s)" for R ¹ or R ² is a heterocyclic group selected from nitrogen, sulfur and oxygen in addition to carbon. 5- to 14-membered heterocyclic groups containing 1 to 4 atoms (aromatic heterocyclic groups, saturated or unsaturated non-aromatic heterocyclic groups) and the like. The “aromatic heterocyclic group” is, for example, a 5- to 14-membered, preferably 5- to 14-membered group containing one or more (eg, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom. And a 10-membered aromatic heterocyclic group. In particular,
Thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, furan, isoindolizine, xanthrene, phenoxathiin, pyrrole, imidazole, pyrazole, pyridine, Pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole , Isothiazole, phenothiazine, oxazole, isoxazole, furazane, aromatic heterocyclic ring such as phenoxazine,
Alternatively, an arbitrary hydrogen atom can be removed from a ring formed by condensing one or more (preferably one or two) of these rings with one or more (preferably one or two) aromatic rings (eg, a benzene ring or the like). And a monovalent group. Preferred examples of the "aromatic heterocyclic group" include a 5- or 6-membered aromatic heterocyclic group which may be condensed with one benzene ring. Specific examples include 2-, 3- or 4-pyridyl, 2-, 3-
3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4
-Or 5-isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl, 2- or 3-thienyl and the like. More preferably, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3
-Quinolyl, 1-isoquinolyl, 1- or 2-indolyl, 2-benzothiazolyl and the like. As the "non-aromatic heterocyclic group", for example, oxiranyl, azetidinyl,
3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) non-aromatics such as oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like And a heterocyclic group (aliphatic heterocyclic group). Represented by R ¹ or R ² of the "optionally substituted heterocyclic group" as "substituent", the may have a "substituent represented by R ¹ or R ² carbide The same number as the “substituent” of the “hydrogen group” is used. Examples of the “3- to 8-membered homocycle” of the “optionally substituted 3- to 8-membered homocycle” formed by R ¹ and R ² include, for example, cyclopropane, cyclobutane, cyclopentane, _C3-8 cycloalkane such as cyclohexane and the like can be mentioned. R ¹ and R ²
And "optionally substituted 3 to 8"
Examples of the "3- to 8-membered heterocyclic ring" of the "membered heterocyclic ring" include, for example, nitrogen other than carbon atoms such as And a 3- to 8-membered heterocyclic ring containing 1 to 4 hetero atoms selected from atoms, sulfur atoms and oxygen atoms. As the “substituent” of the “optionally substituted 3- to 8-membered homo- or heterocyclic ring” formed by R ¹ and R ² , the “substituent” represented by the aforementioned R ¹ or R ² And the same number as the “substituent” of the “hydrocarbon group optionally having”. As the “hydrocarbon group optionally having substituent (s)” and “heterocyclic group optionally having substituent (s)” for R ³ , the “substituent for R ¹ or R ² ” The same as the "hydrocarbon group which may have" and the "heterocyclic group which may have a substituent" are used.

In the above formula, W is the formula (i):

Embedded image Wherein, in the formula, ring A represents a benzene ring which may have a substituent, and ring B represents a 5- to 7-membered nitrogen-containing heterocyclic ring which may have a substituent. (Ii) Formula:

Embedded image [In the formula, R ⁴ is (1) an aliphatic hydrocarbon group optionally substituted with an aromatic group, and further optionally having a substituent or (2) a substituent. An acyl group containing an aromatic group which may be substituted, R ⁵ represents a hydrogen atom,
A C _1-6 alkyl or acyl group] or a group represented by the formula (iii):

Embedded image [Wherein, R ^4c represents an aromatic group which may have a substituent,
X represents an aliphatic hydrocarbon group or an acyl which may have a substituent, and X represents an oxidized atom or a sulfur atom which may be oxidized]. When W is Wa,
In the above formula, R ³ is preferably a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent (hereinafter, may be referred to as R ^3a in some cases).

In the above formula, ring A represents a benzene ring which may have a substituent. The “substituent” of the “optionally substituted benzene ring” represented by ring A includes the aforementioned R
¹ or represented by R ² in the "optionally substituted hydrocarbon group" of the same "substituent", 1 to 4 at substitutable positions (preferably 1 or 2) Yes When the number of substituents is two or more, each substituent may be the same or different. In the above formula, the ring B represents a 5- to 7-membered nitrogen-containing heterocyclic ring which may have a substituent. Examples of the “5- to 7-membered nitrogen-containing heterocycle” represented by Ring B include pyrrole (eg, 1H-pyrrole), dihydropyrrole (eg, 2,5-dihydro-1H-pyrrole, etc.), dihydropyridine (eg, 1,2-dihydropyridine and the like),
Tetrahydropyridine (eg, 1,2,3,4-tetrahydropyridine etc.), azepine (eg, 1H-azepine etc.), dihydroazepine (eg, 2,3-dihydro-1H)
-Azepine, 2,5-dihydro-1H-azepine, 2,
5- to 7-members such as 7-dihydro-1H-azepine), tetrahydroazepine (eg, 2,3,6,7-tetrahydro-1H-azepine, 2,3,4,7-tetrahydro-1H-azepine, etc.) And nitrogen-containing heterocycles. B
As the “substituent” of the “optionally substituted 5- to 7-membered nitrogen-containing heterocycle” represented by the ring, the “optionally substituted substituent” represented by the above R ¹ or R ² The same number as those of the “substituent” of the “hydrocarbon group” can be used. An oxo group or the like is also used as a substituent on ring B.

Formula:

Embedded image Wherein each symbol is as defined above. More specifically, the group represented by the formula:

Embedded image [Wherein, R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a halogen, or a hydrocarbon group which may have a substituent, and ring A has the same meaning as described above. And a group represented by the formula:

Embedded image Wherein each symbol is as defined above. And more preferably a group represented by the formula:

Embedded image Wherein each symbol is as defined above. And a group represented by the formula:

Embedded image Wherein each symbol is as defined above. And the like are particularly preferred. Examples of the “halogen” or “optionally substituted hydrocarbon group” represented by R ⁶ and R ⁷ include “halogen” or “having a substituent” as the “substituent” of the ring B. The same hydrocarbon groups as those described above may be used.

In the above formula, ring C represents a benzene ring which may have a substituent in addition to the group represented by formula W.
The ring C may have 1 to 3 (preferably 1) at a position capable of substituting the group represented by the formula W. When the number of substituents is 2 or more, each substituent may be the same or different. You may. As the “substituent” which the ring C may further have, the same as the “substituent” of the “optionally substituted hydrocarbon group” for R ¹ or R ² can be mentioned. No. “C _1-6 alkyl” as the “substituent” of ring C is “C 4-6 which may be substituted with hydroxy or the like.
Or an 8-membered lactone (eg, 3-hydroxy-δ-valerolactone) ”or the like. The ring C may have 1 to 3 (preferably 3) at positions where these substituents can be substituted, and when the number of substituents is 2 or more, each substituent may be the same or different. . The C ring is preferably a benzene ring substituted with three C _1-6 alkyl such as methyl. When W is Wa, in the above formula, the ring C is a group represented by the formula:

Embedded image Wherein each symbol is as defined above. In addition to the group represented by the above, further has a substituent selected from halogen, lower alkyl which may be halogenated, lower alkoxy which may be halogenated, and lower alkylthio which may be halogenated. benzene ring which may be (hereinafter, may be referred to as ring C ¹⁾ is preferable.

The C ¹ ring has the formula:

Embedded image May have 1 to 3 (preferably 1) at a substitutable position, and when the number of substituents is 2 or more, each substituent may be the same or different. C ¹ may be ring further have a "halogen" as "substituent", for example, fluorine, chlorine, bromine, and iodine. As the “optionally halogenated lower alkyl”, for example, C ₁ which may have 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) _{- 6} alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl etc.) and the like, and specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl Methyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-
Trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like. As the "optionally halogenated lower alkoxy", for example, C ₁ which may have 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) _-6 alkoxy (eg,
Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.). Specific examples include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,
4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like. "Optionally halogenated lower alkylthio"
Is, for example, 1 to 5, preferably 1 to 3
C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) which may have one halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) ) And the like. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,
4,4,4-trifluorobutylthio, pentylthio,
Hexylthio and the like. The ring C ¹ may have 1 to 3 (preferably 3) of these substituents at substitutable positions. When the number of substituents is 2 or more, each substituent may be the same or different. Good.

When W represents Wb, in the above formula, R ³ is preferably a C _6-14 aryl group which may have a substituent (hereinafter sometimes referred to as R ^3b ). Represented by R ^3b of the "optionally substituted _{C 6-14} aryl" as the _{"C 6 -14} aryl", for example, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, such as anthryl _{C 6 -14} aryl group and the like. The “substituent” of the “optionally substituted C _6-14 aryl” includes the “optionally substituted hydrocarbon group” of the above R ¹ or R ^2. Substituents ''
The same number is used.

In the above formula, R ⁴ is (1) an aliphatic hydrocarbon group optionally substituted with an aromatic group which may be further substituted and (2) a substituted or unsubstituted aliphatic hydrocarbon group. It shows an acyl group containing an aromatic group which may have a group. R
^And "having an aromatic group which may have a substituent, and further having a substituent" as a substituent of the "aliphatic hydrocarbon group which may further have a substituent" As the "aromatic group" of the "aromatic group which may be", an aromatic hydrocarbon group,
And an aromatic heterocyclic group. Examples of the "aromatic hydrocarbon group" include a monocyclic or condensed polycyclic (bicyclic or tricyclic) aromatic hydrocarbon group having 6 to 14 carbon atoms. Specific examples thereof include phenyl, 1
And C _6-14 aryl such as -naphthyl, 2-naphthyl, biphenylyl and anthryl, and preferably C _6-10 aryl such as phenyl, 1-naphthyl and 2-naphthyl. As the "aromatic heterocyclic group", for example, one or more hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (for example, 1 to 4
And a 5- to 10-membered, preferably 5- to 10-membered, aromatic heterocyclic group. Specifically, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene,
Furan, isoindolizine, xanthrene, phenoxatiin, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole,
Isoindole, 1H-indazole, purine, 4H-
Quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,
Carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole,
Aromatic heterocycles such as phenothiazine, oxazole, isoxazole, furazane, phenoxazine, or an aromatic ring having one or more (preferably one or two) aromatic rings (preferably one or two) (eg, benzene ring, etc.) 1) by removing any hydrogen atom from the ring formed by condensation with
And a valence group. Preferred examples of the "aromatic heterocyclic group" include a 5- or 6-membered aromatic heterocyclic group which may be condensed with one benzene ring. Specific examples include 2-, 3- or 4-pyridyl, 2-, 3-, 4
-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl,
2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl, 2- or 3-thienyl and the like. More preferably, 2- or 3-thienyl,
2-, 3- or 4-pyridyl, 2- or 3-quinolyl, 1-isoquinolyl, 1- or 2-indolyl, 2
-Benzothiazolyl and the like. As the “substituent” of the “aromatic group optionally having substituent (s)”, the “substituent” of the “hydrocarbon group optionally having substituent (s)” for R ¹ or R ² is referred to. Are used in the same number.

R⁴Represented by `` may have a substituent
Having an aromatic group and may further have a substituent.
Aliphatic hydrocarbon group "as" aliphatic hydrocarbon group "
Is, for example, alkyl, alkenyl, alkynyl, cyclo
Alkyl and the like. Above all, C<sub>1-10</sub>Archi
Le, C<sub>2-10</sub>Alkenyl, C<sub>2-10</sub>Alkynyl, C
<sub>3 -10</sub>Cycloalkyl and the like are preferred. "Alkyl"
For example, C<sub>1-6</sub>Alkyl (eg, methyl, ethi
, Propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, pentyl, hexyl, etc.)
preferable. “Alkenyl” includes, for example, C<sub>2-6</sub>A
Lucenyl (eg, vinyl, allyl, isopropenyl, bute
, Isobutenyl, sec-butenyl, etc.) and the like.
“Alkynyl” includes, for example, C<sub>2-6</sub>Alkynyl
(Eg, ethynyl, propargyl, butynyl, 1-hexyl
And the like are preferred. As “cycloalkyl”,
For example, C<sub>3-6</sub>Cycloalkyl (eg, cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, etc.)
Is preferred. Above all, C<sub>1-6</sub>Alkyl is preferred. The
“Aliphatic hydrocarbon group” refers to “optionally having a substituent”
Having one to three aromatic groups at substitutable positions.
When the number of substituents is 2 or more, each substituent is the same
Or they may be different. The “aliphatic hydrocarbon group”
The “substituent” which may further have
R<sup>1</sup>Or R<sup>2</sup>Represented by the `` may have a substituent
The same number of "substituents" as in "hydrocarbon group"
It is. R⁴Represented by the "optionally substituted fragrance"
As the "acyl group" of the "acyl group containing an aromatic group",
Note R¹Or R²Represented by `` may have a substituent
Same as “acyl group” as “substituent” of “hydrocarbon group”
Is used. R<sup>4</sup>Having a substituent
Substituents of an acyl group containing an optionally substituted aromatic group "
The aromatic group which may have the above-mentioned R.<sup>4</sup>Indicated by
Having an aromatic group which may have a substituent,
Aliphatic hydrocarbon group which may further have a substituent "
The same as the "optionally substituted aromatic group"
Is used. R<sup>4</sup>`` Even if it has a substituent
Specific examples of the `` acyl group containing a good aromatic group '' include:
C_6-14Aryl-carbonyl (eg, benzoyl, 1
-Naphthoyl, 2-naphthoyl, etc.), C_7-16Aral
Kill-carbonyl (eg, phenylacetyl, phenyl
Lopionyl, etc.), C_6-14Aryloxy-carboni
(Eg, phenoxycarbonyl, etc.), C_7-16Aral
Killoxy-carbonyl (eg, benzyloxy carbonyl)
, Phenethyloxycarbonyl, etc.)
Ring carbonyl (eg, nicotinoyl, isonicotinoy
2-thenoyl, 3-thenoyl, 2-furoyl, 3-
Floyl, morpholinocarbonyl, thiomorpholinocar
Bonyl, piperidinocarbonyl, 1-pyrrolidinylcar
Bonyl), C_6-14Aryl-carbamoyl (eg,
Phenylcarbamoyl, 1-naphthylcarbamoyl, 2
-Naphthylcarbamoyl and the like) 5- or 6-membered heterocyclic car
Bamoyl (eg, 2-pyridylcarbamoyl, 3-pyridi
Rucarbamoyl, 4-pyridylcarbamoyl, 2-thier
Nylcarbamoyl, 3-thienylcarbamoyl, etc.), C
_6-14Arylsulfonyl (eg, phenylsulfonyl
1-naphthylsulfonyl, 2-naphthylsulfonyl
Etc.), C_6-14Arylsulfinyl (eg, phenyl
Sulfinyl, 1-naphthylsulfinyl, 2-naphthyl
And the like are preferred.

In the above formula, R ⁵ represents a hydrogen atom, a C _1-6 alkyl group or an acyl group. C _{1-6 represented} by R ⁵
Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, hexyl and the like. R
As "acyl group" represented by ^5, wherein R ¹ or R
"Hydrocarbon group which may have a substituent" represented by ²
The same ones as the "acyl group" as the "substituent" of are used.

When W is Wb, in the above formula, the ring C is a group represented by the formula -N
A benzene ring which may have a substituent in addition to the group represented by R ⁴ (R ⁵ ) is shown (hereinafter sometimes referred to as C ² ring). The ring C ² may have 1 to 3 groups at a substitutable position of a group represented by the formula —NR ⁴ (R ⁵ ),
When the number of substituents is two or more, each substituent may be the same or different. As the “substituent” that the C ² ring may further have in addition to the group represented by the formula —NR ⁴ (R ⁵ ), for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _2-6 alkenyl, Optionally halogenated C _2-6 alkynyl, optionally halogenated C _3-6 cycloalkyl, C _6-14 aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl) etc.), optionally halogenated _{C 1-6} alkoxy optionally, hydroxy, amino, _{mono--C 1-6} alkylamino (e.g., methylamino, ethylamino, etc.), _{mono--C 6- 4} arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di _{-C 1-6} alkylamino (e.g., dimethylamino, diethylamino, etc.), di _{-C 6-14} arylamino (e.g., Diphenylamino, etc.), acyl, acylamino, optionally substituted 5- to 7-membered saturated cyclic amino, 5- to 10-membered aromatic heterocyclic group (eg, 2- or 3-thienyl, 2-, 3- Or 4-pyridyl, 2-,
3-, 4-, 5- or 8-quinolyl, 1-, 3-, 4
-Or 5-isoquinolyl, 1-, 2- or 3-indolyl, 2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl, etc.), sulfo and the like. The “optionally halogenated C _1-6 alkyl”, the “optionally halogenated C _2-6 alkenyl”, the “optionally halogenated C _2-6 alkynyl”, the “optionally halogenated C _2-6 alkynyl” Optionally substituted C _3-6 cycloalkyl ”,“ optionally halogenated C _1-6 alkoxy ”,“ acyl ”,“ acylamino ”and“ optionally substituted 5- to 7-membered saturated ” Cyclic amino ''
Are the same as those described in detail as the “substituent” of the “optionally substituted hydrocarbon group” represented by R ¹ or R ² .

R ^4c represents an aromatic group which may have a substituent, an aliphatic hydrocarbon group which may have a substituent or an acyl group. Examples of the “aromatic group” of the “aromatic group optionally having substituent (s)” for R ^4c include an aromatic hydrocarbon group and an aromatic heterocyclic group. Examples of the "aromatic hydrocarbon group" include a monocyclic or condensed polycyclic (bi- or tricyclic) aromatic hydrocarbon group having 6 to 14 carbon atoms. Specific examples thereof include C _6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl and anthryl. The “aromatic heterocyclic group” is, for example, a 5- to 14-membered member containing one or more (eg, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom, preferably a 5-membered atom. And a 10-membered aromatic heterocyclic group. Specifically, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, furan, isoindolizine, xanthrene, phenoxatiin, pyrrole, imidazole , Pyrazole, pyridine, pyrazine,
Pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine,
Isoquinoline, quinoline, phthalazine, naphthyridine,
Quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine,
Aromatic aromatic rings such as phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazane, phenoxazine, or aromatics having one or more (preferably one or two) of these rings (preferably monocyclic) Examples include a monovalent group formed by removing an arbitrary hydrogen atom from a ring formed by condensing with a ring (eg, a benzene ring or the like). Preferred examples of the "aromatic heterocyclic group" include a 5- or 6-membered aromatic heterocyclic group which may be condensed with one benzene ring. Specific examples include 2-, 3- or 4-pyridyl, 2-, 3-, 4
-, 5- or 8-quinolyl, 1-, 3-, 4- or 5-isoquinolyl, 1-, 2- or 3-indolyl,
2-benzothiazolyl, 2-benzo [b] thienyl, benzo [b] furanyl, 2- or 3-thienyl and the like. More preferred are 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 3-quinolyl, 1-isoquinolyl, 1- or 2-indolyl, 2-benzothiazolyl and the like.

Said "aromatic group optionally having substituent (s)"
Examples of the “substituent” include a halogen atom (eg, fluorine)
Element, chlorine, bromine, iodine, etc.), C_1-3Alkylenedi
Oxy (eg, methylenedioxy, ethylenedioxy
), Nitro, cyano, optionally halogenated C
_1-6Alkyl, optionally halogenated C_2-6
Alkenyl, optionally halogenated C_2-6Al
Quinyl, optionally halogenated C_3-6Cycloa
Alkyl, optionally halogenated C_1-6Alkoki
C, optionally halogenated C_1-6Alkyl
E, hydroxy, amino, mono-C_1-6Alkylam
No (eg, methylamino, ethylamino, propylamino
, Isopropylamino, butylamino, etc.), di-C
_1-6Alkylamino (eg, dimethylamino, diethyl
Amino, dipropylamino, dibutylamino, ethylmethyl
5 to 5 which may have a substituent
7-membered saturated cyclic amino, acyl, acylamino, acylo
Xy, sulfo, C_6-14Aryl (eg, phenyl, 1
-Naphthyl, 2-naphthyl, etc.), C_6-14Aryl
Oxy (eg, phenyloxy, naphthyloxy, etc.)
And so on. The above-mentioned “optionally halogenated C
_1-6Alkyl ”,“ optionally halogenated C ”
_2-6Alkenyl "," optionally halogenated C
_2-6Alkynyl "," optionally halogenated C
_3-6Cycloalkyl "," may be halogenated
C_1-6Alkoxy "," may be halogenated
C _1-6Alkylthio "," may have a substituent "
5 to 7-membered saturated cyclic amino "," acyl "," ashi
Ruamino "and" acyloxy "include the aforementioned R ¹
Or R²Represented by the "optionally substituted carbonized
The same ones as those described in detail in “Substituent” of “Hydrogen”
I can do it. The "aromatic group" is, for example,
May have 1 to 3 substituents at the interchangeable positions,
When the number is two or more, each substituent is the same or different
You may. This "aromatic group which may have a substituent"
Is preferably a halogen atom, C_1-3Alkylene
Dioxy, nitro, cyano, halogenated
C_1-6Alkyl, optionally halogenated C
_2-6Alkenyl, optionally halogenated C
_2-6Alkynyl, optionally halogenated C
_3-6Cycloalkyl, optionally halogenated C
_1-6Alkoxy, optionally halogenated C
_1-6Alkylthio, hydroxy, amino, mono-C
_1-6Alkylamino, di-C_1-6Alkylamino,
5- to 7-membered saturated cyclic amine which may have a substituent
No, acyl, acylamino, acyloxy, sulfo, C
_{6 -14}Aryl, C_6-14Selected from aryloxy
Each of which may be substituted with 1 to 3 substituents
Phenyl, 2-, 3- or 4-pyridyl, 2- or
Is 3-quinolyl, 1-isoquinolyl and the like.

R^4c`` Even if it has a substituent
As "aliphatic hydrocarbon group" of "good aliphatic hydrocarbon group"
Is, for example, alkyl, alkenyl, alkynyl, cyclo
Alkyl and the like. Of these, C<sub>1-10</sub>Al
Kill, C<sub>2-10</sub>Alkenyl, C<sub>2-10</sub>Alkynyl,
C<sub>3-10</sub>Cycloalkyl and the like are preferred. "Arki
For example, C<sub>1-6</sub>Alkyl (eg, meth
, Ethyl, propyl, isopropyl, butyl, isobu
Tyl, sec-butyl, tert-butyl, pentyl, hexyl
Are preferred. For example, "alkenyl"
If C<sub>2-6</sub>Alkenyl (eg, vinyl, allyl, iso
Propenyl, butenyl, isobutenyl, sec-butenyl
Are preferred. As “alkynyl”, for example,
C<sub>2-6</sub>Alkynyl (eg, ethynyl, propargy;
, Butynyl, 1-hexynyl and the like).
“Cycloalkyl” includes, for example, C<sub>3-6</sub>Cycloa
Alkyl (eg, cyclopropyl, cyclobutyl, cycloalkyl)
Lopentyl, cyclohexyl, etc.) are preferred. What
Anyway, C<sub>1-6</sub>Alkyl is preferred. The "aliphatic carbonization
As the "substituent" which the "hydrogen group" may have,
The R <sup>1</sup>Or R<sup>2</sup>`` Even if it has a substituent
Same as "Substituent" in "Good hydrocarbon group"
Can be. This “substituent” is preferably an acyl
(Eg, carboxy, C_1-6Alkyl-carbonyl, C
_1-6Alkoxy-carbonyl, C_6-14Aryl-
Carbonyl and the like). R^4cIndicated by
As the “acyl group”, for example, the aforementioned R¹Or R²so
Of the "hydrocarbon group which may have a substituent"
The same as “acyl group” as “substituent” is used.
It is.

[0024] As "sulfur atom which may be oxidized" for X or Y, S, SO, SO ₂ and the like. "Imino optionally having substituent (s)" for Y
Examples of the "substituent" include a hydrocarbon group which may have a substituent, an acyl group, and the like. As the “hydrocarbon group optionally having substituent (s)”, for example, the same as the “hydrocarbon group optionally having substituent (s)” represented by R ¹ or R ² can be mentioned. The "acyl"
Examples thereof include the same as those described for “acyl” described in detail in “substituent” of “hydrocarbon group optionally having substituent (s)” for R ¹ or R ² . Preferably the "imino which may have a substituent" represented by Y, _{imino, C 1-6} alkylimino (e.g., methylimino, etc. _{ethylimino), C 6-1 4} arylimino (e.g., phenylimino, 1-naphthylimino, 2-naphthylimino, etc., C _7-16 aralkyl imino (eg,
Benzylimino, etc.). X and Y are preferably oxygen atoms.

Thus, the compound (I) of the present invention comprises
formula:

Embedded image [Wherein each symbol is as defined above], a compound (Ia) represented by the formula:

Embedded image Wherein each symbol is as defined above, and a compound represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described above], are included.

In the above compound (Ia), R¹And R²
As, for example, the same or different, a hydrogen atom or
Is an optionally substituted C_1-6Alkyl group
And C such as methyl_1-3Alkyl group), or
R¹And R²Has a substituent with adjacent carbon atoms
Forming a 3- to 8-membered homo- or heterocyclic ring
And the like, and among them, R¹And R²Is C
_1-6An alkyl group is more preferred. Ma
Was--- Is a double bond, R²Does not exist and R
¹Represents an optionally substituted C_1-6Archi
And the like, and particularly, C such as methyl_1-3Archi
Preferred is a thiol group. R³Has, for example, a substituent
May be C_6-14Aryl groups and the like are preferred. A ring
Are, for example, halogen, C_1-6Alkyl, C
_1-6Alkoxy and C_1-6Alkylenedioxy
Ben which may have 1 to 3 substituents selected from
A zen ring and the like are preferred. As the ring B, for example, 1 to
Two C_1-65 which may be substituted with alkyl
And a 7-membered nitrogen-containing heterocycle or the like is preferred. C¹As a ring,
One to three C_1-6Alkyl and C_1-6A
May be substituted with a substituent selected from alkoxy.
Preferred are benzene rings and the like. formula:

Embedded image (Wherein each symbol has the same meaning as described above), a group represented by the formula:

Embedded image (Wherein each symbol has the same meaning as described above), and the like are preferable. Particularly, R ⁶ and R ⁷ are preferably a hydrogen atom, and the ring A may have 1 to 3 substituents selected from halogen, C _1-6 alkoxy and C _1-6 alkylenedioxy. Good benzene rings are preferred. formula:

Embedded image (Wherein each symbol is as defined according to claim 1) substitution position on ring C ¹ of a group represented by or when a 5-position of the benzofuran ring or dihydrobenzofuran ring.

Particularly, as the compound (Ia), R¹And
And R²Is a hydrogen atom or C _1-6Alkyl group
(Especially, C such as methyl_1-3Alkyl group)^3a
Is a hydrogen atom or C_1-6Alkyl (especially methyl,
C such as chill, propyl, isopropyl, etc._1-3Archi
) And halogen atoms (especially fluorine)
A phenyl group optionally having 1 to 3 substituents,
A ring is halogen, C_{1- 6}Alkyl (especially methyl
C_1-3Alkyl), C_1-6Alkoxy (especially
C such as Toxic_1-3Alkoxy) and C_1-6Al
Killenedioxy (especially C such as methylenedioxy)
_1-3One substituent selected from alkylenedioxy)
A benzene ring which may have 3 rings and no 1 ring B
Two C_{1- 6}5 which may be substituted with alkyl
A 7-membered nitrogen-containing heterocyclic ring,¹1 to 3 more rings
C_1-6Alkyl (especially C such as methyl_1-3Al
Kill) and C_1-6Alkoxy (especially methoxy, etc.)
C_1-3Having a substituent selected from (alkoxy)
And a benzene ring, wherein Y is an oxygen atom.
More particularly, the formula:

Embedded image [Wherein each symbol has the same meaning as described above], the group represented by the formula:

Embedded image [In the formula, the ring A 1 represents a benzene ring which may have 1 to 3 substituents selected from halogen, C 1-6 alkoxy and C 1-6 alkylenedioxy] Are preferred. Further, - - - if a shows a double bond, R 2 is not present, the R 1, C 1-
6 alkyl groups and the like are preferable.
1-3 alkyl groups are preferred. As the other symbols, the same as those described above are preferable, and among them, R 3a represents 1 to 3 C 1-6 alkyl (particularly, C 1-3 alkyl such as methyl, ethyl, propyl, and isopropyl). A phenyl group optionally having 1 to 3 C atoms
In 1-6 alkoxy (especially methoxy) benzene ring which may be substituted with, in ring B 5 to 7-membered nitrogen-containing heterocyclic ring, to no further 1 C 1 ring three C 1-6 alkyl (in particular, A benzene ring which may be substituted with C 1-3 alkyl such as methyl (especially three C
(1-6 alkyl-substituted benzene ring) wherein Y is an oxygen atom. In particular, the formula:

Embedded image [Wherein each symbol has the same meaning as described above], the group represented by the formula:

Embedded image Compounds which are groups represented by are preferred.

As specific examples of the compound (Ia), the compounds produced in Synthesis Examples 1a to 22a to be described later or salts thereof are preferable, and among them, 2- [2,2,4,6,7- Pentamethyl-3- (4
-Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] isoindoline (Synthesis Example 4a) or a salt thereof, 5,6-dimethoxy-2- [2,2,4,6,7-pentamethyl -3- (4-Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] isoindoline (Synthesis Example 6a) or a salt thereof, 5,6-dimethoxy-2- [3- (4-isopropyl) Phenyl) -2,2,4,6,7-pentamethyl-2,
3-dihydro-1-benzofuran-5-yl] isoindoline (Synthesis Example 11a) or a salt thereof, 6- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -6,7-dihydro-5H-
[1,3] dioxolo [4,5-f] isoindole (Synthesis Example 12a) or a salt thereof, 6- [2,2,4,6,7-pentamethyl-3- (4
-Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -6H- [1,3] dioxolo [4,
5-f] isoindole (Synthesis Example 14a) or a salt thereof, 6- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -6 , 7-dihydro-5H- [1,3] dioxolo [4,5-f] isoindole (Synthesis Example 16a) or a salt thereof, (R) -5,6-dimethoxy-2- [2,2,4,
6,7-pentamethyl-3- (4-methylphenyl)-
2,3-dihydro-1-benzofuran-5-yl] isoindoline (Synthesis Example 17a), (R) -5,6-dimethoxy-2- [2,2,4,
6,7-pentamethyl-3- (4-methylphenyl)-
2,3-dihydro-1-benzofuran-5-yl] isoindoline hydrochloride (Synthesis Example 19a), 5,6-dimethoxy-2- [2,2,4,6,7-pentamethyl-3- (4- Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -2H-isoindole (Synthesis Example 23a) or other salts are preferred, and in particular, 5,6-dimethoxy-2- [2,2 , 4,6,7-Pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] isoindoline (Synthesis Example 6a), 6- [3- (4-isopropylphenyl) ) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -6,7-dihydro-5H-
[1,3] dioxolo [4,5-f] isoindole (Synthesis Example 12a), (R) -5,6-dimethoxy-2- [2,2,4,
6,7-pentamethyl-3- (4-methylphenyl)-
2,3-dihydro-1-benzofuran-5-yl] isoindoline (Synthesis Example 17a), (R) -5,6-dimethoxy-2- [2,2,4,
6,7-pentamethyl-3- (4-methylphenyl)-
2,3-dihydro-1-benzofuran-5-yl] isoindoline hydrochloride (Synthesis Example 19a), 5,6-dimethoxy-2- [2,2,4,6,7-pentamethyl-3- (4- Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -2H-isoindole (Synthesis Example 23a) and the like are preferable.

[0029] In the compound (Ib), ^{R 1} and ^{R 2}
Are the same or different and may be a hydrogen atom or a C _1-6 alkyl group which may have a substituent (particularly, a C _1-3 alkyl group such as methyl), or a carbon atom in which R ¹ and R ² are adjacent to each other. It is preferable to form a 3- to 8-membered homocyclic ring (C _3-8 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane or the like) which may have a substituent together with the atom, and the like or different. , A hydrogen atom or a C _1-6 alkyl group (particularly, a C _1-3 alkyl group such as methyl), or a case where R ¹ and R ² together with an adjacent carbon atom form a 3- to 8-membered homocyclic ring. preferable. Among them, a case where R ¹ and R ² are each a C _1-6 alkyl group is more preferable,
It is particularly preferable that each is a methyl group. R ^3b
Are, for example, halogen (particularly fluorine) and C
_A phenyl group which may have 1 to 3 substituent (s) selected from _1-6 alkyl (particularly, C _1-3 alkyl such as methyl, ethyl, propyl, isopropyl, etc.) is preferable. An optionally substituted phenyl group and the like are more preferred. As R ⁴ , for example, 1 is a substituent selected from halogen, C _1-6 alkoxy and C _1-3 alkylenedioxy.
To 3 which may have an aromatic group (particularly, C _6-14 aryl group or a thienyl, a nitrogen atom in addition to carbon atoms, such as pyridyl, such as phenyl, an oxygen atom, to 1 selected from sulfur atom and the like three A C _1-6 alkyl group substituted with a 5- or 6-membered aromatic heterocyclic group containing a hetero atom of formula (1) or (2) halogen, C _1-6 alkoxy and C _1-3 alkylenedioxy group 1 to 3 which may have an aromatic group (particularly, C _6-14 aryl group such as phenyl) acyl group containing preferably, (1) halogen (especially, fluorine, chlorine), C
C ₆ which may each have 1 to 3 substituents selected from _1-6 alkoxy (particularly, C _1-3 alkoxy such as methoxy) and C _1-3 alkylenedioxy (particularly, methylenedioxy). C substituted with _-14 aryl (especially phenyl), thienyl or pyridyl
_1-6 alkyl groups (particularly, _{C 1-3} alkyl group such as methyl) or (2) a halogen (in particular, fluorine, chlorine),
C _1-6 alkoxy (particularly, _{C 1-3} alkoxy such as methoxy) and _{C 1-3} alkylenedioxy (particularly,
C _6-14 aryl-carbonyl group (particularly, phenylcarbonyl group) and C _7-16 aralkyl-carbonyl group (particularly, benzylcarbonyl group) each having 1 to 3 substituents selected from methylenedioxy) Group), a _C6-14 aryl-sulfonyl group (particularly, a phenylsulfonyl group), a nicotinoyl group, a thenoyl group, and the like. Among them, a benzyl group or a phenethyl group which may have 1 to 3 substituents selected from fluorine, methoxy and methylenedioxy is particularly preferable. As R ⁵ , for example, a hydrogen atom, C
_{A 1-6} alkyl group (particularly, a C _1-3 alkyl group such as methyl) or a C _1-6 alkyl-carbonyl group (particularly,
(C _1-3 alkyl-carbonyl group such as acetyl) and the like are preferable, and a hydrogen atom and a methyl group are more preferable. As the C ² ring, a benzene ring which may be further substituted with 1 to 3 C _1-6 alkyl (particularly, C _1-3 alkyl such as methyl) is preferable, and further substituted with 3 methyl. Particularly preferred are benzene rings and the like. In particular, as the compound (Ib), R ¹ and R ² are the same or different and each is a hydrogen atom or a C _1-6 alkyl group (particularly, a C _1-3 alkyl group such as methyl), or R ¹ and R ² Forms a 3- to 8-membered homocyclic ring with adjacent carbon atoms; R ^3b is halogen (especially fluorine) and C _1-6 alkyl (especially methyl, ethyl, propyl,
A phenyl group optionally having 1 to 3 substituent (s) selected from C _1-3 alkyl) such as isopropyl; R ⁴
Is (1) a substituent selected from halogen (especially fluorine, chlorine), C _1-6 alkoxy (especially a C _1-3 alkoxy group such as methoxy) and C _1-3 alkylenedioxy (especially methylenedioxy) based on 1 to 3 each have unprotected _{C 6-14} aryl (particularly, phenyl), substituted thienyl or pyridyl the _{C 1-6} alkyl group (particularly, _{C 1-3} alkyl group such as methyl) Or (2) halogen (particularly, fluorine or chlorine), C _1-6
Alkoxy (especially _{C 1-3} alkoxy group such as methoxy) and _{C 1-3} alkylenedioxy (particularly, methylenedioxy), 1 to substituents selected from optionally having three respective _{C 6- 14} Aryl-carbonyl group (particularly phenylcarbonyl group), C _7-16 aralkyl-carbonyl group (particularly benzylcarbonyl group),
_6-14 aryl-sulfonyl group (especially phenylsulfonyl group), nicotinoyl group or thenoyl group; R ⁵ is a hydrogen atom, C _1-6 alkyl group (especially C
_1-3 alkyl group) or _{C 1-6} alkyl - group (in particular, _{C 1-3} alkyl such as acetyl - carbonyl group); Y is oxygen atom; no further 1 and ^{C 2} rings to three _{C 1- 6} alkyl (particularly, C _1-3 such as methyl
A benzene ring substituted with alkyl), R ¹ and R ² are each a methyl group; R ^3b is a phenyl group optionally substituted with fluorine, methyl or isopropyl; R ⁴ is fluorine, methoxy or methylene optionally substituted benzyl group or a phenethyl group dioxy; R ⁵ is a hydrogen atom or a methyl group; - - - is a single bond; Y is an oxygen atom; and ring C ² is further substituted with 3 methyl Particularly preferred are compounds having a benzene ring.

Also,--- Is a double bond, R²
Does not exist and R¹As C_{1- 6}Such as an alkyl group
Preferred, especially C such as methyl_1-3Alkyl groups are preferred
New Other symbols are preferably the same as described above.
But among them, R^3bAre halogen (especially fluorine) and
And C_1-6Alkyl (especially methyl, ethyl, propyl
C such as isopropyl and isopropyl_1-3Alkyl)
A phenyl group optionally having 1 to 3 substituents;
R⁴Is (1) halogen (particularly fluorine) and C _1-6
Alkoxy (especially C such as methoxy)_1-3Alkoxy
Group) may have 1 to 3 substituents selected from
C_6-14Substituted with aryl (especially phenyl)
C_1-6Alkyl group (especially C such as methyl_1-3Al
A kill group) or (2) a halogen (especially fluorine) and
C_1-6Alkoxy (especially C such as methoxy)_1-3A
1 to 3 substituents selected from
C that may have_6-14Aryl-carbonyl group
(Especially a phenylcarbonyl group) or C_7-16Ara
Alkyl-carbonyl group (particularly, benzylcarbonyl
Group); R⁵Is a hydrogen atom; Y is an oxygen atom; and C²Ring
1 to 3 more C_{1 -6}Alkyl (especially methyl
Etc. C_1-3Benzene ring substituted with alkyl)
And three Cs such as methyl_1-6Alkyl substituted
The compound which is a benzene ring) is preferable.

As specific examples of the compound (Ib), the compounds produced in Synthesis Examples 1b to 67b to be described later are preferable, and among them, (1) N- (4-fluorobenzyl) -2,2,2 4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (Synthesis Example 4b) or a salt thereof, (2) N-benzyl-3
-(4-isopropylphenyl) -2,2,4,6,7
-Pentamethyl-2,3-dihydro-1-benzofuran-5-amine (Synthesis Example 6b) or a salt thereof, (3) 3-
(4-isopropylphenyl) -N- (4-methoxybenzyl) -N, 2,2,4,6,7-hexamethyl-
2,3-dihydro-1-benzofuran-5-amine (Synthesis example 9b) or a salt thereof, (4) 3- (4-isopropylphenyl) -N- [2- (4-methoxyphenyl) ethyl] -2, 2,4,6,7-pentamethyl-2,3-
Dihydro-1-benzofuran-5-amine (Synthesis Example 11
b) or a salt thereof, (5) N- (4-fluorobenzyl) -3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (Synthesis Example 19b) or a salt thereof, (6) N- (1,3-benzodioxol-5-ylmethyl)- 3- (4-isopropylphenyl) -2,
2,4,6,7-pentamethyl-2,3-dihydro-1
-Benzofuran-5-amine (Synthesis Example 23b) or a salt thereof, (7) N- (4-fluorobenzyl) -3- (4
-Fluorophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (Synthesis Example 31b) or a salt thereof, (8) N- (4-methoxybenzyl) -2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1
-Benzofuran-5-amine (Synthesis Example 33b) or a salt thereof, (9) N- (4-fluorobenzyl) -2,2,
4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine (Synthesis Example 35b) or a salt thereof, (10) 3- (4-isopropylphenyl) -N- (4-methoxybenzyl)
-2,4,6,7-tetramethyl-1-benzofuran-
5-amine (Synthesis Example 45b) or a salt thereof, (11) N-
(4-fluorobenzyl) -3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine (Synthesis Example 47b) or a salt thereof,
(12) N- (4-fluorobenzyl) -3- (4-fluorophenyl) -2,4,6,7-tetramethyl-1-
Benzofuran-5-amine (Synthesis Example 51b) or a salt thereof, (13) N- (4-fluorobenzyl) -3- (4-
Isopropylphenyl) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4′-piperidin] -5-amine (Synthesis Example 55b) or a salt thereof,
(14) (R) -N- (4-fluorobenzyl) -3-
(4-isopropylphenyl) -2,2,4,6,7-
Pentamethyl-2,3-dihydro-1-benzofuran-
5-amine, its hydrochloride (Synthesis Example 61b) or other salts are preferred, and N- (4-fluorobenzyl) -3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl is particularly preferred. −
2,3-dihydro-1-benzofuran-5-amine (Synthesis Example 19b), N- (4-fluorobenzyl) -3- (4-isopropylphenyl) -1 ′, 4,6,7-tetramethylspiro [ Benzofuran-2 (3H), 4'-piperidine]-
5-amine (Synthesis Example 55b), (R) -N- (4-fluorobenzyl) -3- (4-
(Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride (Synthesis Example 61b) and the like are preferable.

The group represented by the formula -XR ^4c is preferably substituted at the 5-position of the basic skeleton as follows.

Embedded imageAs the compound (Ic), preferably, R¹And R²But,
Each (1) C_{6- 14}Aryl, (2) C_1-6Al
Koxy, (3) C_1-6Alkylthio, (4) hydroxy
(5) amino, (6) mono-C_1-6Alkylam
No, (7) Mono-C_6-14Arylamino, (8) di-
C_1-6Alkylamino, (9) di-C_{6 -14}Ally
Ruamino, (10) carboxy, (11) C_1-6Alkyl
Sulfonyl, (12) C_6-14Arylsulfonyl,
(13) C_1-6Alkylsulfinyl, (14) C
_6-14Arylsulfinyl and (15) C_1-6A
Luquil, C_{6 -14}Aryl and 5- to 10-membered aromatic
May have 1 to 3 substituents selected from the group consisting of
A substituent selected from 5- to 7-membered saturated cyclic amino
Or C which may have 3_1-6Is alkyl
Or R¹And R²Together with adjacent carbon atoms
_1-6Alkyl, C_6-14Aryl, C_7-16Ara
Selected from alkyl and 5- to 10-membered aromatic heterocyclic groups
3 to 8 members optionally having 1 to 3 substituents
Forming a homo- or heterocyclic ring; R³Is (1) a halogen atom,
(2) C_1-6Alkyl, (3) C_1-6Alkoxy,
(4) amino, (5) mono-C_1-6Alkylamino,
(6) Di-C_1-6Alkylamino and (7) C_1-6
Alkyl, C_6-14Aryl and 5-10 member Yoshi
Even if it has 1 to 3 substituents selected from aromatic groups
Substituents selected from good 5- to 7-membered saturated cyclic amino
1- to 3-phenyl which may each have 1-,
Naphthyl, 2-naphthyl, 2-tiniel, 3-thienyl
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-
Quinolyl, 3-quinolyl, 1-isoquinolyl, 1-yne
Drill, 2-indolyl or 2-benzothiazolyl;
R^4cIs (i) (1) halogen atom, (2) C_1-6Al
Kill, (3) C_1-6Alkoxy, (4) hydroxy,
(5) amino, (6) mono-C_1-6Alkylamino,
(7) Di-C_1-6Alkylamino, (8) carboxy and
And (9) C_1-6Alkyl, C_6-14Aryl and
And there is no substituent selected from 5- to 10-membered aromatic groups
A 5- to 7-membered saturated cyclic amino which may have 3
Having 1 to 3 substituents selected from
Good phenyl, 1-naphthyl, 2-naphthyl, 2-thier
Nil, 3-thienyl, 2-pyridyl, 3-pyridyl, 4
-Pyridyl, 2-quinolyl, 3-quinolyl, 1-isoquinoyl
Noryl, 1-indolyl, 2-indolyl or 2-
Having azothiazolyl, and additionally carboxy or C
_1-6C optionally having alkoxy-carbonyl
_1-6Alkyl or (ii) (1) halogen atom, (2)
C_1-6Alkyl, (3) C_1-6Alkoxy, (4)
Droxy, (5) amino, (6) mono-C_1-6Alkyl
Amino, (7) di-C_1-6Alkylamino and (8)
1 to 3 substituents selected from carboxy
C that you may have_1-6Alkyl-carbonyl, C
_3-6Cycloalkyl-carbonyl, C_6-14Ally
Le-carbonyl or C_7-16Aralkyl-Carboni
X is an oxygen atom; Y is an oxygen atom; C³Ring
Rogen atom, optionally halogenated C_1-6Al
Killed, optionally halogenated C_1-6Alkoki
Si, amino, mono-C_1-6Alkylamino and di-
C_1-61 to 3 substituents selected from alkylamino
It is a compound which is a benzene ring which may have three.
More preferably, R¹And R²Are C
_6-14Aryl, C_{1 -6}Alkoxy, C_1-6Al
Kirthio, hydroxy, amino, mono-C_1-6Archi
Ruamino, mono-C_6-14Arylamino, di-C
_1-6Alkylamino, di-C_6-14Arylami
No, carboxy, C_1-6Alkylsulfonyl, C
_6-14Arylsulfonyl, C_1-6Alkylsulf
Inyl and C_{6- 14}Selected from arylsulfinyl
Which may have 1 to 3 substituents_1-6A
Luquil or R¹And R²Is adjacent to the carbon source
With the child, C_1-6Alkyl, C_6-14Aryl and
And C_7-161 to 4 substituents selected from aralkyl
Forming an optionally substituted piperidine; R³Is haloge
Atom, C_1-6Alkyl, C_1-6Alkoxy, Ami
No, Mono-C_1-6Alkylamino and di-C_1-6
Having 1 to 3 substituents selected from alkylamino
Optionally substituted phenyl; R⁴Is (i) a halogen atom, C
_1-6Alkyl, C_1-6Alkoxy, hydroxy, a
Mino, Mono-C_1-6Alkylamino, di-C_1-6A
1 substituents selected from alkylamino and carboxy
Or three or more phenyl or pi
C with lysyl_1-6Alkyl, or (ii) a formula-
(C = O) -R^{5 '} [Wherein, R^{5 '}Is a halogen atom, C
_1-6Alkyl, C_1-6Alkoxy, hydroxy, a
Mino, Mono-C_1-6Alkylamino, di-C_1-6A
1 substituents selected from alkylamino and carboxy
Or three or more phenyl or phenyl groups each having
Enyl-C_1-6An acyl group represented by the formula:
X is an oxygen atom; Y is an oxygen atom; C³Rings are more halogenated
Atom, C which may be halogenated_1-6Archi
, Optionally halogenated C_1-6Alkoxy,
Amino, mono-C_1-6Alkylamino and di-C
_1-61 to 3 substituents selected from alkylamino
The compound is a benzene ring which may have one or more benzene rings.

Also, the formula:

Embedded image [Wherein, R ¹ and R ² are each a C _1-6 alkyl _optionally having a 6-membered saturated cyclic amino substituted with phenyl, or R ¹ and R ² together with an adjacent carbon atom , _{C 1-6} alkyl or _{C 7-16} form piperidine substituted aralkyl; ^{R 3} is (i) hydrogen atom or (ii) _{(1) C 1-6} alkyl, (2) di -C
Phenyl ^optionally having 1 to 3 substituents selected from _1-6 alkylamino and (3) 6-membered saturated cyclic amino optionally having C _1-6 alkyl; R ^4c is (i) Phenyl optionally having 1 to 3 substituents selected from nitro and C _1-6 alkyl-carboxamide, (ii) C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-carbonyl, C _1-6 has alkylsulfonyl and C _1-6 alkylsulfinyl, 1 to substituents selected from the Le may have three each phenyl, quinolyl or pyridyl 1 to 3, respectively, phenyl as substituent, carboxy or _{C 1-6} alkoxy - optionally _{C 1 -6} alkyl optionally having carbonyl respectively or _{C 2-6} alkenyl or, (Iii) formula ^{- (C = O) -R 5} ' acyl represented ^by' wherein, R ^{5 ''} is a phenyl substituted with _{C 1-6} alkoxy]; and C ^'rings, further A benzene ring which may have 1 to 3 C _1-6 alkyl (particularly, a benzene ring substituted with three C _1-6 alkyl such as methyl) is also preferable.

As specific examples of the compound (Ic), the compounds prepared in Synthesis Examples 1c to 33c described below are preferable, and among them, 3- (4-isopropylphenyl) -5- (4-methoxybenzyl) is preferable. Oxy) -2,2
4,6,7-pentamethyl-2,3-dihydrobenzofuran, 3- (4-methylphenyl) -2,4,6,7-
Tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3- (4-isopropylphenyl) -2,
4,6,7-tetramethylbenzofuran-5-yl 4
-Methoxybenzoate, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,
4,6,7-tetramethylbenzofuran, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4 '-Piperidine], 3- (4
-Isopropylphenyl) -5- (3-pyridylmethyl) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran and salts thereof. Of these, preferred is 3- (4-isopropylphenyl)
-5- (4-methoxybenzyloxy) -2,2,4
6,7-pentamethyl-2,3-dihydrobenzofuran, 3- (4-methylphenyl) -2,4,6,7-tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3- (4-isopropylphenyl) −2,
4,6,7-tetramethylbenzofuran-5-yl 4
-Methoxybenzoate, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,
4,6,7-tetramethylbenzofuran, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4 '-Piperidine] and their salts.

Examples of the salt of the compound include a metal salt, an ammonium salt, a salt with an organic base or the like when it has an acidic group such as —COOH, and an inorganic salt when it has a basic group such as —NH _2. Other internal salts such as salts with acids, organic acids, basic or acidic amino acids and the like may be used. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-
And salts with dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like. Preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group,
Alkali metal salts (eg, sodium salt, potassium salt, etc.),
Inorganic salts such as salts with alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.), ammonium salts, etc., and when the compound has a basic functional group, hydrochloride, sulfate, Phosphate, inorganic salts such as hydrobromide, or acetate, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate,
Organic salts such as citrate and tartrate are exemplified.

Compound (I) (compounds (Ia) and (Ib)
And (Ic)) are known per se, for example,
WO 98/55454, WO 00/36262, WO
95/29907, JP-A-5-194466,
USP 4,881,967, USP 4,212,865 and Tetrahedron Letters,
37, No. 51, pages 9183-9186, 1996 and the like, or a method analogous thereto.

The prodrug of the compound (I) is a compound which is converted into the compound (I) by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, a compound which is enzymatically oxidized, reduced, hydrolyzed, etc. Compound (I) which is converted to (I), which is hydrolyzed by gastric acid or the like to cause compound (I)
May be a compound that changes to As a prodrug of compound (I), the amino group of compound (I) is acylated,
Alkylated and phosphorylated compounds (eg, compound (I)
Is eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,
3-dioxolen-4-yl) methoxycarbonylation,
Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (eg, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound) The hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated,
Alanylated, dimethylaminomethylcarbonylated compounds, etc.); the carboxyl group of compound (I) is esterified, the carboxyl group of the amidated compound is ethylesterified, phenylesterified, carboxymethylesterified, dimethylaminomethyl Esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl Esterified, methylamidated compounds, etc.). These compounds can be produced from compound (I) by a method known per se. Further, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, pages 163 to 198, Molecular Design. It may be.

Compound (I) or a salt thereof or a prodrug thereof (hereinafter sometimes abbreviated simply as compound (I)) has, for example, a promoting effect on neural stem cell self-renewal, a promoting effect on neural progenitor cell differentiation, and a neurotrophic factor. It has excellent medicinal effects, such as a potentiating action, a neurotrophic factor activity enhancing action, a neurodegeneration suppressing action, a nerve regeneration promoting action, an antioxidant action or an inhibitory action on nerve cell death by β-amyloid, and has low toxicity and side effects. It also has excellent properties such as small amount and is useful as a pharmaceutical. Compound (I) is a mammal (eg, mouse,
Rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, etc.) as stem cell (eg, embryonic stem cells, neural stem cells, etc.) As a trophic factor-like substance, a neurotrophic factor activity enhancer, and a neurodegenerative inhibitor, it suppresses nerve cell death and promotes regeneration of nerve tissue and function through neurogenesis and nerve axon development. It is also useful for preparing neural stem cells / neural cells (including neural progenitor cells) from fetal brain / patient brain tissue and embryonic stem cells, which are used for transplantation therapy. Promotes cell engraftment / differentiation and functional expression. Therefore, a stem cell and / or neural progenitor cell proliferation and / or differentiation promoting agent comprising the compound (I) can be used, for example, for neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis ( ALS), Huntington's disease, spinocerebellar degeneration, etc.), neuropsychiatric disorders (eg, schizophrenia, etc.), head trauma, spinal cord injury, cerebrovascular disorder, cerebrovascular dementia, etc. It is used as a prophylactic / therapeutic agent for central nervous system diseases. Compound (I) has a low toxicity and is a pharmaceutical composition in which a pharmacologically acceptable carrier is mixed as it is or according to a means known per se, for example, tablets (including sugar-coated tablets, film-coated tablets, orally disintegrating tablets and the like) ), Powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, patches, etc., and orally or parenterally (eg, topical, rectal, intravenous) Administration etc.) can be safely administered. The content of compound (I) in the preparation of the present invention is about 0.01 to about 100% by weight of the whole preparation. The dose varies depending on the administration subject, administration route, disease and the like.For example, when administered as an oral agent to an adult as a therapeutic agent for Alzheimer's disease, the compound of the present invention is used as an active ingredient in an amount of about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg
kg body weight, more preferably about 0.5 to about 10 mg / kg
The body weight can be administered once or several times a day. Furthermore, other active ingredients (eg, cholinesterase inhibitors (eg, Aricept (donepezil), etc.), β-secretase inhibitors, β-amyloid production / deposition inhibitors, brain function activators (eg, idebenone, vinpocetine, etc.), Parkinson's disease Even when used in combination with a therapeutic agent (eg, L-dopa, deprenyl, bromocriptene, talipexole, prasipexole, adamantadine, etc.), a therapeutic agent for amyotrophic lateral sclerosis (eg, riluzole, etc.), neurotrophic factor, etc. Good. The other active ingredient and the compound of the present invention or a salt thereof are mixed according to a method known per se, and one pharmaceutical composition (eg, tablet, powder, granule, capsule (including soft capsule), liquid, injection) is prepared. Suppositories, sustained-release preparations, etc.) and may be used together, or may be separately formulated and administered to the same subject at the same time or with a time interval. When transplanting neural stem cells, neural progenitor cells or fetal neural tissue prepared from embryonic stem cells and neural tissue,
Further, it may be used together with an agent such as an immunosuppressant after transplantation.

The pharmacologically acceptable carriers that may be used in the preparation of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials, such as excipients and lubricants in solid preparations. Solvents, binders, disintegrants; solvents in liquid formulations, solubilizers, suspending agents, tonicity agents,
Buffers, soothing agents and the like can be mentioned. If necessary, conventional additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like. As a lubricant, for example, magnesium stearate, calcium stearate, talc,
Colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate,
Examples include ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, Examples include hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate.
Examples of the soothing agent include benzyl alcohol and the like. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

[0040]

The present invention will be described in more detail with reference to the following Reference Examples, Synthesis Examples, Formulation Examples and Experimental Examples, which are merely examples and do not limit the present invention. Changes may be made without departing from the scope of the present invention. "Room temperature" in the following Reference Examples and Synthesis Examples usually indicates about 10 to about 35 ° C. % Indicates weight percent unless otherwise specified. Abbreviations used in other texts have the following meanings. s: singlet d: doublet (doublet) dd: doublet of doublets (doublet of doublet)
s) dt: doublet of tripl
ets) t: triplet (triplet) q: quartet (quartet) septet: septet m: multiplet (multiplet) br: broad (broad) J: coupling constant (coupling constant) Hz: Hertz (Hertz) CDCl _3: deuterated chloroform DMSO-d ₆ : Deuterated dimethyl sulfoxide ¹ H-NMR: Proton nuclear magnetic resonance

[Compound (Ia)] Reference Example 1a 3- (4-isopropylphenyl) -2-methyl-2-
Ethyl propenoate sodium hydride (60% liquid paraffin dispersion, 5.
To a suspension of N, N-dimethylformamide (92 g, 148 mmol) in N, N-dimethylformamide (150 mL) was added triethyl 2-phosphonopropionate (35.0 g, 148 mmol) at 0 ° C., followed by stirring at the same temperature for 10 minutes. 4-Isopropylbenzaldehyde (20.0 g, 135 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure.
30.1 g (96% yield) of the oily target product was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7.0 Hz), 1.35
(3H, t, J = 7.0 Hz), 2.13 (3H, s), 2.92 (1H, septe
t, J = 7.0 Hz), 4.27 (2H, q, J = 7.0 Hz), 7.21-7.3
8 (4H, m), 7.67 (1H, s). Reference Example 2a Ethyl 2-methyl-3- (4-methylphenyl) -2-propenoate Sodium hydride (60% liquid paraffin dispersion, 1
To a suspension of 5.0 g (375 mmol) of N, N-dimethylformamide (160 mL) at 0 ° C. was added a solution of triethyl 2-phosphonopropionate (87.7 g, 368 mmol) in N, N-dimethylformamide (10 mL). And stirred at the same temperature for 1 hour. N, N- of 4-methylbenzaldehyde (43.3 g, 361 mmol) was added to the reaction solution.
A dimethylformamide (10 mL) solution was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. Wash the combined extracts with water, dry over magnesium sulfate, and concentrate under reduced pressure to give the oily target product.
66.7 g (91% yield) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.0 Hz), 2.12
(3H, d, J = 1.4 Hz), 2.37 (3H, s), 4.26 (2H, q, J
= 7.0 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.31 (2H, d,
J = 8.4 Hz), 7.66 (1H, s).

Reference Example 3a Ethyl 3- (4-fluorophenyl) -2-methyl-2-propenoate The desired product was synthesized according to Reference Example 1a using 4-fluorobenzaldehyde. Yield 97%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, t, J = 7.0 Hz), 2.10
(3H, d, J = 1.2 Hz), 4.28 (2H, q, J = 7.0 Hz), 7.0
8 (2H, t, J = 8.8 Hz), 7.32-7.43 (2H, m), 7.65 (1
H, s). Reference Example 4a Ethyl (E) -3- (4-isopropylphenyl) -2-propenoate Sodium hydride (60% liquid paraffin dispersion, 1
To a suspension of 0.4 g (260 mmol) in N, N-dimethylformamide (200 mL) was added triethyl phosphonoacetate (58.2 g, 236 mmol) at 0 ° C., and the mixture was stirred at the same temperature for 10 minutes. 4-Isopropylbenzaldehyde (35.0 g, 260 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. Wash the combined extracts with water,
After drying over magnesium sulfate, the mixture was concentrated under reduced pressure to obtain 47.5 g (yield 92%) of the target product as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7.0 Hz), 1.33
(3H, t, J = 7.0 Hz), 2.92 (1H, septet, J = 7.0 H
z), 4.26 (2H, q, J = 7.0 Hz), 6.40 (1H, d, J = 15.8
Hz), 7.24 (2H, d, J = 8.2 Hz), 7.46 (2H, d, J =
8.2 Hz), 7.67 (1H, d, J = 15.8 Hz).

Reference Example 5a Ethyl (E) -3- (4-fluorophenyl) -2-propenoate The desired product was synthesized according to Reference Example 4a using 4-fluorobenzaldehyde. Yield 88%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.0 Hz), 4.26
(2H, q, J = 7.0 Hz), 6.31 (1H, d, J = 15.8 Hz), 7.
00-7.11 (2H, m), 7.43-7.58 (2H, m), 7.67 (1H, d, J
= 15.8 Hz). Reference Example 6a 3- (4-isopropylphenyl) -2-methyl-2-
Propen-1-ol 3- (4-isopropylphenyl) -2-methyl-2-
Lithium aluminum hydride (1.47 g, 38.7 mmol) was added to a suspension of ethyl propenoate (9.00 g, 38.7 mmol) and cerium chloride (1.00 g, 4.06 mmol) in tetrahydrofuran (50 mL) at -40 ° C.
l) was added in four portions over 30 minutes and stirred at the same temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (hexane-ethyl acetate 8: 1).
Then, 6.30 g (yield 86%) of an oily target product was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7.0 Hz), 1.91
(3H, d, J = 1.4 Hz), 2.90 (1H, septet, J = 7.0 H
z), 4.17 (2H, d, J = 0.8 Hz), 6.49 (1H, dd, J = 2.
6, 1.4 Hz), 7.15-7.25 (4H, m), 1H Not confirmed.

Reference Example 7a Ethyl 2-methyl-3- (4-methylphenyl) -2-propen-1-ol 2-methyl-3- (4-methylphenyl) -2-propenoate (26.31 g, 128 .8 mmol) and a suspension of cerium chloride (10.32 g, 41.89 mmol) in tetrahydrofuran (120 mL) at -40 ° C at lithium aluminum hydride (4.89 g, 129 mmol).
l) was added in four portions over 30 minutes and stirred at the same temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 8.87 g of the desired product as an oil.
(42% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.87 (3H, s), 2.32 (3H, s), 4.1
3 (2H, s), 6.46 (1H, s), 7.08-7.22 (4H, m), 1H Not confirmed. Reference Example 8a Using 3- (4-fluorophenyl) -2-methyl-2-propenoic acid ethyl according to Reference Example 6a, using 3- (4-fluorophenyl) -2-methyl-2-propen-1-ol ethyl Was synthesized. Yield 95%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, d, J = 1.6 Hz), 4.11
(2H, s), 6.58 (1H, s), 7.01 (2H, t, J = 8.8 Hz), 7.
18-7.28 (2H, m), 1H Not confirmed.

Reference Example 9a Reference Example was carried out using ethyl (E) -3- (4-isopropylphenyl) -2-propen-1-ol (E) -3- (4-isopropylphenyl) -2-propenoate. The target compound was synthesized according to 6a. Yield 65%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7.0 Hz), 2.79-
3.00 (2H, m), 4.30 (2H, d, J = 5.6 Hz), 6.35 (1H,
dt, J = 15.8, 5.6 Hz), 6.59 (1H, d, J = 15.8Hz),
7.10-7.39 (4H, m). Reference Example 10a Using (E) -3- (4-fluorophenyl) -2-propen-1-ol ethyl (E) -3- (4-fluorophenyl) -2-propenoate according to Reference Example 6a, Was synthesized. Yield 84%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 4.31 (2H, d, J = 5.6 Hz), 6.28
(1H, dt, J = 15.8, 5.6Hz), 6.59 (1H, d, J = 15.8H
z), 6.90-7.40 (4H, m), 1H Not confirmed. Reference Example 11a 1- (3-bromo-2-methyl-1-propenyl) -4
-Isopropylbenzene 3- (4-isopropylphenyl) -2-methyl-2-
Propen-1-ol (6.30 g, 33.1 mmol
Phosphorus tribromide (5.98 g, 22.1 mmol) was added to a solution of 1) in isopropyl ether (50 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was extracted with isopropyl ether. The organic layer was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 7.63 g of the desired product as an oil.
(91% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7.0 Hz), 2.03
(3H, d, J = 1.4 Hz), 2.90 (1H, septet, J = 7.0 H
z), 4.15 (2H, d, J = 0.8 Hz), 6.62 (1H, s), 7.14-
7.26 (4H, m).

Reference Example 12a Using 1- (3-bromo-2-methyl-1-propenyl) benzene 2-methyl-3-phenyl-2-propen-1-ol, the desired product was synthesized according to Reference Example 11a. . Yield 89%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, d, J = 1.4 Hz), 4.13
(2H, d, J = 0.8 Hz), 6.64 (1H, s), 7.19-7.44 (5H,
m). Reference Example 13a 1- (3-bromo-2-methyl-1-propenyl) -4
-Methylbenzene 2-methyl-3- (4-methylphenyl) -2-propen-1-ol (11.40 g, 70.27 mmol)
Phosphorus tribromide (12.83 g, 47.38 mmol) was added to a solution of isopropyl ether (100 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Add water to the reaction solution,
Extracted with isopropyl ether. The organic layer was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the desired product as an oil.
1 g (80% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, s), 2.34 (3H, s), 4.1
3 (2H, s), 6.60 (1H, s), 7.09-7.22 (4H, m). Reference Example 14a 1- (3-bromo-2-methyl-1-propenyl) -4
-Fluorobenzene Using 3- (4-fluorophenyl) -2-methyl-2-propen-1-ol, the target compound was synthesized according to Reference Example 11a. Yield 79%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.87 (3H, s), 4.17 (2H, s), 6.4
8 (1H, s), 7.01 (2H, t, J = 8.8 Hz), 7.18-7.27 (2
H, m).

Reference Example 15a 1-[(E) -3-bromo-1-propenyl] -4-isopropylbenzene Using (E) -3- (4-isopropylphenyl) -2-propen-1-ol, The target compound was synthesized according to Reference Example 11a. Yield 72%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7.0 Hz), 2.89
(1H, septet, J = 7.0 Hz), 4.16 (2H, dd, J = 7.8,
0.8 Hz), 6.35 (1H, dt, J = 15.4, 7.8 Hz), 6.63 (1
H, d, J = 15.4 Hz), 7.14-7.35 (4H, m). Reference Example 16a 1-[(E) -3-bromo-1-propenyl] -4-fluorobenzene Reference Example 11a using (E) -3- (4-fluorophenyl) -2-propen-1-ol The desired product was synthesized according to Yield 61%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 4.15 (2H, d, J = 7.6 Hz), 6.30
(1H, dt, J = 15.4, 7.6Hz), 6.61 (1H, d, J = 15.4 H
z), 6.83-7.08 (2H, m), 7.31-7.45 (2H, m). Reference Example 17a N- [4-[[3- (4-isopropylphenyl) -2
-Methyl-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide N, N of N- (4-hydroxy-2,3,6-trimethylphenyl) formamide (3.00 g, 16.7 mmol) To a solution of -dimethylformamide (30 mL) was added sodium hydride (60% liquid paraffin dispersion, 0.74 g, 18.4 mmol) at 0 ° C under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 10 minutes. 1- (3-bromo-2) was added to the reaction solution.
-Methyl-1-propenyl) -4-isopropylbenzene (4.66 g, 18.4 mmol) was added, and the mixture was added at room temperature for 3 hours.
Stirred for 0 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue is crystallized from ethyl acetate-hexane to give the desired product 3.7
0 g (63% yield) was obtained. 153-155 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7.0 Hz), 2.00
(3H, s), 2.07-2.34 (9H, m), 2.91 (1H, septet, J =
7.0 Hz), 4.54 (2H, d, J = 5.4 Hz), 6.59-6.84 (3H,
m), 7.17-7.36 (4H, m), 7.98 (0.5H, d, J = 12.0 H
z), 8.41 (0.5H, s).

Reference Example 18a N- [2,3,6-trimethyl-4-[(2-methyl-
3-phenyl-2-propenyl) oxy] phenyl] formamide N- (4-hydroxy-2,3,6-trimethylphenyl) formamide and 1- (3-bromo-2-methyl-1
The target compound was synthesized using -propenyl) benzene according to Reference Example 17a. Yield 41%. Melting point 152-15
4 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, d, J = 1.6 Hz), 2.10-
2.32 (9H, m), 4.54 (2H, d, J = 5.2 Hz), 6.65 (1H,
s), 6.67 (1H, s), 6.69-6.90 (1H, m), 7.11-7.41 (5
H, m), 7.98 (0.5H, d, J = 12.0 Hz), 8.41 (0.5H, d,
J = 1.4 Hz). Reference Example 19a N- [2,3,6-trimethyl-4-[[2-methyl-
3- (4-Methylphenyl) -2-propenyl] oxy] phenyl] formamide N, N-dimethyl of N- (4-hydroxy-2,3,6-trimethylphenyl) formamide (9.31 g, 52.0 mmol) Sodium hydride (60% liquid paraffin dispersion, 2.11 g, 52.8 mmol) was added to a formamide (120 mL) solution at 0 ° C. under a nitrogen atmosphere,
The mixture was stirred at the same temperature for 10 minutes. 1- (3-bromo-
A solution of 2-methyl-1-propenyl) -4-methylbenzene (12.48 g, 55.44 mmol) in N, N-dimethylformamide (20 mL) was added, and the mixture was added at room temperature for 30 minutes.
Stirred for minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-isopropyl ether to obtain 7.34 g of the desired product (44% yield). Melting point 167-
169 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, s), 2.07-2.38 (9H,
m), 2.35 (3H, s), 4.53 (2H, d, J = 6.6 Hz), 6.61
(1H, s), 6.66 (1H, d, J = 2.4 Hz), 6.82-7.09 (1H,
m), 7.11-7.31 (4H, m), 7.98 (0.5H, d, J = 12.2 H
z), 8.38 (0.5H, s).

Reference Example 20a N- [4-[[3- (4-fluorophenyl) -2-methyl-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide N- (4-hydroxy- 2,3,6-trimethylphenyl) formamide and 1- (3-bromo-2-methyl-1)
The target compound was synthesized using -propenyl) -4-fluorobenzene according to Reference Example 17a. Yield 52%. 164-165 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.96 (3H, s), 2.12-2.32 (9H,
m), 4.53 (2H, d, J = 5.2Hz), 6.60 (1H, s), 6.66 (1
H, s), 6.71-6.95 (1H, m), 7.04 (2H, t, J = 8.8 H
z), 7.22-7.33 (2H, m), 8.04 (0.5H, d, J = 12.0 H
z), 8.40 (0.5H, d, J = 1.4 Hz). Reference Example 21a N- [4-[[(E) -3- (4-isopropylphenyl) -2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide N- (4-hydroxy-2,3 The target compound was synthesized according to Reference Example 17a using (6,6-trimethylphenyl) formamide and 1-[(E) -3-bromo-1-propenyl] -4-isopropylbenzene. Yield 59%. 165-167 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 6.8 Hz), 2.13-
2.27 (9H, m), 2.90 (1H, septet, J = 6.8 Hz), 4.66
(2H, t, J = 5.8 Hz), 6.37 (1H, dt, J = 15.8,5.8 H
z), 6.65-6.88 (3H, m), 7.16-7.26 (2H, m), 7.35 (2
H, d, J = 8.0 Hz), 7.98 (0.5H, d, J = 12.0 Hz), 8.
40 (0.5H, d, J = 1.4 Hz).

Reference Example 22a N- [2,3,6-trimethyl-4-[[(E) -3-
Phenyl-2-propenyl] oxy] phenyl] formamide Using N- (4-hydroxy-2,3,6-trimethylphenyl) formamide and cinnamyl chloride, the target compound was synthesized according to Reference Example 17a. Yield 44%. 197-199 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 2.05-2.18 (9H, m), 4.62-4.72 (2
H, m), 6.35-6.50 (1H, m), 6.62-7.00 (3H, m), 7.24-
7.52 (5H, m), 8.00 (0.5H, d, J = 12.0 Hz), 8.39
(0.5H, d, J = 1.6 Hz). Reference Example 23a N- [4-[[(E) -3- (4-fluorophenyl)
-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide N- (4-hydroxy-2,3,6-trimethylphenyl) formamide and 1-[(E) -3-bromo-1-propenyl Reference Example 1 using 4-fluorobenzene
The target compound was synthesized according to 7a. Yield 52%. Melting point 1
96-198 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 2.10-2.32 (9H, m), 4.67 (2H, t,
J = 5.0 Hz), 6.37 (1H, dt, J = 15.6, 5.0 Hz), 6.5
9-6.89 (3H, m), 6.92-7.09 (2H, m), 7.32-7.43 (2H, m
m), 7.99 (0.5H, d, J = 12.0 Hz), 8.42 (0.5H, d, J
= 1.4 Hz).

Reference Example 24a N- [4-hydroxy-3- [1- (4-isopropylphenyl) -2-propenyl] -2,5,6-trimethylphenyl] formamide N- [4-[[(E) -3- (4-Isopropylphenyl) -2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide (5.80 g, 17.2 m
mol) of N, N-dimethylaniline (50 mL) was stirred at 215 ° C. for 6 hours under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 2N hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 3.50 g of the desired product (yield
60%). 170-171 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.40 (6H, m), 2.11-2.27 (9
H, m), 2.77-3.00 (1H, m), 5.00-5.22 (2H, m), 5.30-
5.42 (1H, m), 6.30-6.85 (2H, m), 7.10-7.37 (5H,
m), 7.97 (0.5H, d, J = 12.2 Hz), 8.43 (0.5H, d, J
= 1.4 Hz). Reference Example 25a N- [4-hydroxy-3- (1-phenyl-2-propenyl) -2,5,6-trimethylphenyl] formamide N- [2,3,6-trimethyl-4-[[(E) -3-
Using phenyl-2-propenyl] oxy] phenyl] formamide, the target compound was synthesized according to Reference Example 24a. Yield 78%. 144-145 ° C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 2.08-2.27 (9H, m), 5.02-5.41 (3
H, m), 6.32-6.52 (1H, m), 6.61-7.03 (2H, m), 7.18-
7.42 (5H, m), 7.95 (0.5H, d, J = 12.0 Hz), 8.42
(0.5H, d, J = 1.8 Hz).

Reference Example 26a N- [4-hydroxy-3- [1- (4-fluorophenyl) -2-propenyl] -2,5,6-trimethylphenyl] formamide N- [4-[[(E) -3- (4-fluorophenyl)
Using [-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide, the target compound was synthesized according to Reference Example 24a. Yield 66%. Melting point 168-17
0 ° C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 2.10-2.29 (9H, m), 5.02-5.22
(1.5H, m), 5.33-5.50 (1.5H, m), 6.35-6.55 (1H, m),
6.72-7.08 (4H, m), 7.18-7.30 (2H, m), 7.96 (0.5H,
d, J = 12.2 Hz), 8.42 (0.5H, d, J = 1.4 Hz). Reference Example 27a 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine N- [4-[[3- (4-isopropylphenyl) -2
-Methyl-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide (3.70 g, 10.
5 mmol) N, N-dimethylaniline (20 mL)
The solution was stirred at 215 ° C. for 6 hours under an argon atmosphere. After cooling the reaction mixture, it was diluted with ethyl acetate, 2N hydrochloric acid,
After washing with water, drying over magnesium sulfate, concentration under reduced pressure,
N- [4-hydroxy-3- [1- (4-isopropylphenyl) -2-methyl-2-propenyl] -2,5
A crude product of [6-trimethylphenyl] formamide was obtained. A mixture of this compound (2.98 g, 8.47 mmol) in concentrated hydrochloric acid (20 mL) -methanol (60 mL) was heated to reflux under a nitrogen atmosphere for 2 hours. The solvent was concentrated under reduced pressure,
The obtained residue was neutralized with an 8 N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was crystallized from isopropyl ether-hexane to obtain 2.23 g (yield 66%) of the desired product. 130-132 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.21 (6H, d, J =
6.6 Hz), 1.47 (3H, s), 1.78 (3H, s), 2.12 (3H, s),
2.19 (3H, s), 2.40-2.60 (3H, m), 4.08 (1H, s), 6.72
-7.00 (2H, m), 7.07 (2H, d, J = 8.0 Hz).

Reference Example 28a 2,2,4,6,7-pentamethyl-3-phenyl-
2,3-dihydro-1-benzofuran-5-amine N- [2,3,6-trimethyl-4-[(2-methyl-
Using 3-phenyl-2-propenyl) oxy] phenyl] formamide, the target compound was synthesized according to Reference Example 27a. Yield 67%. 129-131 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.48 (3H, s), 1.7
7 (3H, s), 2.13 (3H, s), 2.19 (3H, s), 3.20 (2H, b
rs), 4.12 (1H, s), 6.70-7.30 (5H, m). Reference Example 29a 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
-Amine N- [2,3,6-trimethyl-4-[[2-methyl-
3- (4-methylphenyl) -2-propenyl] oxy] phenyl] formamide (5.43 g, 16.8 m
mol) of N, N-dimethylaniline (60 mL) was stirred at 210 ° C. for 6 hours under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 2N hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was heated and refluxed with hydrochloric acid-methanol reagent (40 mL) under a nitrogen atmosphere for 2 hours. The solvent was concentrated under reduced pressure, and the obtained residue was neutralized with an 8 N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue is crystallized from hexane to obtain the desired product 2.81
g (57% yield). 114-115 ° C.
(Petroleum ether) ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.47 (3H, s), 1.7
7 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 2.30 (3H, s)
s), 3.23 (2H, br s), 4.08 (1H, s), 6.60-7.23 (4H,
m).

Reference Example 30a 3- (4-Fluorophenyl) -2,2,4,6,7-
Pentamethyl-2,3-dihydro-1-benzofuran-
5-Amine Using N- [4-[[3- (4-fluorophenyl) -2-methyl-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide according to Reference Example 27a, Was synthesized. Yield 78%. Melting point 125-
127 ° C. (Petroleum ether) ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.47 (3H, s), 1.7
7 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 3.10 (2H, b
rs), 4.09 (1H, s), 6.62-7.20 (4H, m). Reference Example 31a 3- (4-isopropylphenyl) -2,4,6,7-
Tetramethyl-1-benzofuran-5-amine hydrochloride N- [4-hydroxy-3- [1- (4-isopropylphenyl) -2-propenyl] -2,5,6-trimethylphenyl] formamide (3.50 g) , 10.4mm
ol) and calcium carbonate (1.35 g, 13.5 mmo)
l) A suspension of tetrahydrofuran (15 mL) -methanol (15 mL) in benzyltrimethylammonium iodo dichloride (3.90 g, 11.4 mmol).
Was slowly added. The reaction was stirred at room temperature for 30 minutes. After filtering off the insoluble matter, the solvent was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with a 10% aqueous sodium hydrate sulfite solution, water, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, concentrated under reduced pressure, and 4.08 g of N- [2-iodomethyl-3. -(4-isopropylphenyl) -4,6,7
-Trimethyl-2,3-dihydro-1-benzofuran-
5-yl] formamide was obtained. This compound (4.08
g, 8.81 mmol) and 1,8-diazabicyclo [5,4,0] -7-undecene (6.58 mL, 4
(4.0 mmol) in toluene (30 mL) was stirred at 100 ° C. for 3 hours under an argon atmosphere. Water was added to the reaction solution, which was extracted twice with ethyl acetate. The extract was washed with 2N hydrochloric acid and water, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 20: 1) to give 2.40 g of N-
[3- (4-isopropylphenyl) -2,4,6,7
-Tetramethyl-1-benzofuran-5-yl] formamide. This compound (2.40 g, 7.18 mm
ol) concentrated hydrochloric acid (20 mL) -methanol (60 mL)
The mixture was heated at reflux under a nitrogen atmosphere for 2 hours. The solvent was concentrated under reduced pressure, and the obtained residue was neutralized with an 8 N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 1.80 g of an oily free base. This free base (0.50 g, 1.63 mmol) was added to hydrochloric acid-
Dissolve in a methanol solution, concentrate the solvent under reduced pressure, crystallize the resulting residue with methanol, and obtain 0.41 g of the desired product
(Yield 41%) was obtained. 194-197 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J = 7.0 Hz), 2.30
(6H, s), 2.41 (3H, s), 2.60 (3H, s), 2.94 (1H, se
ptet, J = 7.0 Hz), 7.13-7.26 (4H, m), 10.1 (2H, br
s), 1H Not confirmed.

Reference Example 32a 2,4,6,7-Tetramethyl-3-phenyl-1-benzofuran-5-amine hydrochloride N- [4-hydroxy-3- (1-phenyl-2-propenyl) -2 Using 5,5,6-trimethylphenyl] formamide, the target compound was synthesized according to Reference Example 31a. Yield 26%. 189-192 ° C. (Ethanol-hexane) ¹ H-NMR (CDCl ₃ ) δ: 2.30 (6H, s), 2.42 (3H, s), 2.
60 (3H, s), 7.21-7.37 (5H, m), 10.2 (2H, br s), 1H
unconfirmed. Reference Example 33a 3- (4-fluorophenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine hydrochloride N- [4-hydroxy-3- [1- (4-fluorophenyl) Using 2--2-propenyl] -2,5,6-trimethylphenyl] formamide, the target compound was synthesized according to Reference Example 31a. Yield 87%. Melting point 208-210
° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 2.29 (6H, s), 2.42 (3H, s), 2.
60 (3H, s), 7.03-7.28 (4H, m), 10.2 (2H, br s), 1H
unconfirmed. Reference Example 34a 5,6-dichloro-2- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) -1H-isoindole-1, 3
(2H) -dione Tetrahydrofuran of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.56 mmol) under an argon atmosphere (30 mL) solution, 4,5-dichlorophthalic anhydride (850.6 mg, 3.92 mmol)
Was added and the mixture was refluxed for 13 hours. The reaction mixture was cooled to room temperature and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) hydrochloride (760.0 m
g, 3.96 mmol) and 1-hydroxy-1H-benzotriazole (HOBt) monohydrate (602.6 m
g, 3.93 mmol). The mixture was heated under reflux for 3 hours and then cooled to room temperature. Water and an 8 N aqueous sodium hydroxide solution were added to the reaction mixture, and the product was extracted twice with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 1.16 g (yield 68%) of the desired product. Melting point
178-181 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.56 (3H, s), 1.
61 (3H, s), 2.01 (3H, s), 2.20 (3H, s), 4.21 (1H,
s), 6.8-7.4 (5H, m), 7.99 (1H, s), 8.03 (1H, s).

Reference Example 35a 2- [2,2,4,6,7-pentamethyl-3- (4-
Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -1H-isoindole-1,3 (2
H) -Dione A solution of phthalic anhydride (566.4 mg, 3.82 mmol) in tetrahydrofuran (5 mL) was added to 2,2,4,4.
6,7-pentamethyl-3- (4-methylphenyl)-
2,3-dihydro-1-benzofuran-5-amine (9
(87.3 mg, 3.38 mmol) in tetrahydrofuran (10 mL) was added and the mixture was heated to reflux for 11 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. Sodium acetate (314.6 mg, 3.84) was added to the residue.
mmol) and acetic anhydride (20 mL).
Stirred at 0 ° C. for 2 hours. After cooling the reaction mixture to room temperature, an 8 N aqueous sodium hydroxide solution was added until the mixture became basic, and the product was extracted twice with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 1.16 g of the desired product (yield 8).
1%). 222-224 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.55 (3H, s), 1.
64 (3H, s), 2.05 (3H, s), 2.20 (3H, s), 2.30 (3H,
s), 4.19 (1H, s), 6.6-7.1 (4H, m), 7.76-7.82 (2H,
m), 7.88-7.97 (2H, m). Reference Example 36a 5,6-dichloro-2- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -1H- Isoindole-1,3 (2H) -dione 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
-The desired product was synthesized according to Reference Example 34a using an amine. Yield 62%. 157-159 [deg.] C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.54 (3H, s), 1.
61 (3H, s), 2.01 (3H, s), 2.19 (3H, s), 2.30 (3H,
s), 4.18 (1H, s), 6.8-7.1 (4H, m), 7.99 (1H, s), 8.
03 (1H, s).

Reference Example 37a 2- [3- (4-fluorophenyl) -2,2,4
6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -1H-isoindole-1,3
(2H) -dione 3- (4-fluorophenyl) -2,2,4,6,7-
Pentamethyl-2,3-dihydro-1-benzofuran-
The target compound was synthesized according to Reference Example 35a using 5-amine. Yield 72%. Melting point 209-211 ° C (ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.55 (3H, s), 1.
61 (3H, s), 2.05 (3H, s), 2.20 (3H, s), 4.21 (1H,
s), 6.9-7.1 (4H, m), 7.76-7.83 (2H, m), 7.90-7.97
(2H, m). Reference Example 38a 5,6-Dichloro-2- [3- (4-fluorophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -1H- Isoindole-1,3 (2H) -dione 3- (4-fluorophenyl) -2,2,4,6,7-
Pentamethyl-2,3-dihydro-1-benzofuran-
The target compound was synthesized according to Reference Example 34a using 5-amine. Yield 62%. 232-233 ° C (ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.54 (3H, s), 1.
61 (3H, s), 2.01 (3H, s), 2.19 (3H, s), 4.19 (1H,
s), 6.8-7.1 (4H, m), 8.00 (1H, s), 8.03 (1H, s). Reference Example 39a 2- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -1H-isoindole-1,
3 (2H) -dione 3- (4-isopropylphenyl) -2,2,4,6
The target compound was synthesized according to Reference Example 35a using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 97%. 180-181 ° C.
(Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.55 (3H, s), 1.64 (3H, s), 2.05 (3H, s)
s), 2.20 (3H, s), 2.85 (1H, septet, J = 7.0 Hz),
4.20 (1H, s), 6.7-7.2 (4H, m), 7.75-7.82 (2H, m),
7.87-7.97 (2H, m).

Reference Example 40a 5,6-Dichloro-2- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-
Dihydro-1-benzofuran-5-yl] -1H-isoindole-1,3 (2H) -dione 3- (4-isopropylphenyl) -2,2,4,6
The target compound was synthesized according to Reference Example 34a using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine. Yield 31%. 237-239 ° C.
(Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.21 (6H, d, J
= 6.6 Hz), 1.54 (3H, s), 1.62 (3H, s), 2.01 (3H,
s), 2.19 (3H, s), 2.85 (1H, septet, J = 6.6 Hz),
4.18 (1H, s), 6.8-7.2 (4H, m), 7.99 (1H, s), 8.03
(1H, s). Reference Example 41a 2- [3- (4-isopropylphenyl) -2,4,
6,7-tetramethyl-1-benzofuran-5-yl]
-1H-isoindole-1,3 (2H) -dione 3- (4-isopropylphenyl) -2,4,6,7-
The target compound was synthesized using tetramethyl-1-benzofuran-5-amine according to Reference Example 35a. Yield 7
1%. 232-234 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 7.0 Hz), 1.85
(3H, s), 2.14 (3H, s), 2.33 (3H, s), 2.48 (3H, s),
2.94 (1H, septet, J = 7.0 Hz), 7.24 (4H, s), 7.72-
7.83 (2H, m), 7.90-8.03 (2H, m). Reference Example 42a 2- [2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -1H-isoindole-1,3 (2H) -dione 2,2 Reference Example 34 using 4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine
The desired product was synthesized according to a. Yield 77%. Melting point 16
6-168 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.49 (6H, s), 1.95 (3H, s), 1.9
9 (3H, s), 2.12 (3H, s), 2.97 (2H, s), 7.66-7.83
(2H, m), 7.91-8.01 (2H, m).

Reference Example 43a 4-methoxy-2,3,6-trimethylaniline N- (4-hydroxy-2,3,6-trimethylphenyl) formamide (30.0 g, 167 mmol) was added to 4
It was dissolved in a mixed solvent of a normal aqueous potassium hydroxide solution (100 mL) and methanol (300 mL), and dimethyl sulfate (42.0 g, 334 mmol) was added to the solution at room temperature, followed by heating under reflux for 14 hours. After cooling, the precipitated crystals were collected by filtration to obtain a crude product of N- (4-methoxy-2,3,6-trimethylphenyl) formamide. Concentrated hydrochloric acid (5 mL) was added to a suspension of this compound in methanol (200 mL).
0 mL) and heated to reflux for 3 hours. After the reaction mixture was cooled to room temperature, it was neutralized with an 8 N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate, and the combined extracts were 10% aqueous sodium hydrosulfite,
After washing with water, it was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from isopropyl ether to obtain 21.0 g of the desired product (yield: 76%). Melting point 70-72
° C. ¹ H-NMR (CDCl ₃ ) δ: 2.11 (3H, s), 2.16 (3H, s), 2.1
8 (3H, s), 3.16 (1H, br s), 3.74 (3H, s), 6.54 (1
H, s). Reference Example 44a tert-butyl 4-methoxy-2,3,6-trimethylphenylcarbamate 4-methoxy-2,3,6-trimethylaniline (2
1.0 g, 127 mmol) and triethylamine (2
1.0 mL, 152 mmol) in tetrahydrofuran (150 mL) at room temperature.
(2 mL, 140 mmol) and heated under reflux for 14 hours. The solvent was concentrated under reduced pressure, water was poured into the residue, and extracted twice with ethyl acetate. The combined organic layer was washed with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 25.2 g of the desired product (yield: 75%). 104-106 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.12 (3H, s), 2.1
7 (3H, s), 2.24 (3H, s), 3.78 (3H, s), 5.81 (1H, b
rs), 6.58 (1H, s).

Reference Example 45a tert-butyl 3-bromo-4-methoxy-2,5,6
-Trimethylphenylcarbamate tert-butyl 4-methoxy-2,3,6-trimethylphenylcarbamate (12.7 g, 47.9 mmol
l), sodium acetate (4.72 g, 57.5 mmol)
l) in acetic acid (50 mL) at room temperature in bromine (8.42).
g, 52.7 mmol) and stirred at the same temperature for 1 hour. Water (80 mL) was poured into the reaction mixture, and the precipitated crystals were collected by filtration and dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from methanol to obtain 15.0 g of the desired product (yield: 91%). Melting point 159-161 [deg.] C. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.15 (3H, s), 2.2
4 (3H, s), 2.35 (3H, s), 3.74 (3H, s), 5.92 (1H, b
rs). Reference Example 46a 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
-Amine tert-butyl 3-bromo-4-methoxy-2,5,6
-Trimethylphenyl carbamate (27.8 g, 8
0.8 mmol) of tetrahydrofuran (150 mL)
The solution was added at −78 ° C. with n-butyllithium (1.6 M,
110 mL, 176 mmol) and stirred at the same temperature for 20 minutes. 2-Methyl-1- (4-methylphenyl) propan-1-one (13.1 g, 80.7 mm) was added to the reaction solution.
ol) and stirred at room temperature for 1 hour. Water (150 mL) was poured into the reaction mixture, extracted three times with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate, and then dried.
25. Filter and concentrate under reduced pressure to give a crude product of tert-butyl 3- [1-hydroxy-2-methyl-1- (4-methylphenyl) propyl] -4-methoxy-2,5,6-trimethylphenylcarbamate. 0 g was obtained. A mixture of this compound and 47% hydrobromic acid (100 mL) was heated under reflux for 4 hours under an argon atmosphere. After the reaction mixture was cooled to room temperature, it was neutralized with an 8 N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate, and the combined extracts were washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to give the desired product 1.
4.8 g (62% yield) were obtained. Melting point 114-115
° C. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.47 (3H, s), 1.7
8 (3H, s), 2.12 (3H, s), 2.17 (3H, s), 2.30 (3H,
s), 2.80 (2H, br s), 4.08 (1H, s), 6.60-7.10 (4H,
m).

Reference Example 47a (+)-2,2,4,6,7-pentamethyl-3- (4
-Methylphenyl) -2,3-dihydro-1-benzofuran-5-amine 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
-High performance liquid chromatography of amines (Equipment: Wat
ers semi-preparative system, column: CHIRALCEL
OD (20 (i, d) x 250 mm, manufactured by Daicel Chemical Industries, Ltd.), moving bed: hexane: isopropyl alcohol = 95: 5, flow rate: 5 mL / min, column temperature: 30 ° C., injection amount: 40 mg) And the one with the shorter retention time was sampled. 87-89 ° C. [Α] D = +
4.7 ° (c = 0.495, methanol) Reference Example 48a (−)-2,2,4,6,7-pentamethyl-3- (4
-Methylphenyl) -2,3-dihydro-1-benzofuran-5-amine 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
-High performance liquid chromatography of amines (Equipment: Wat
ers semi-preparative system, column: CHIRALCEL
OD (20 (i, d) x 250 mm, manufactured by Daicel Chemical Industries, Ltd.), moving bed: hexane: isopropyl alcohol = 95: 5, flow rate: 5 mL / min, column temperature: 30 ° C., injection amount: 40 mg) The longer holding time was separated. 88-90 ° C. [Α] D = −
4.3 ° (c = 0.499, methanol)

Synthesis Example 1a 2- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)
Isoindoline 2,2,4,6,7-pentamethyl-3-phenyl-
2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.55 mmol) and 1,2-bis (bromomethyl) benzene (1.03 g, 3.91 mmol)
l) and potassium carbonate (540 mg, 3.91 mmol)
Of N, N-dimethylformamide (20 mL) was stirred at room temperature for 1 hour. Water (30 mL) was poured into the reaction solution, and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10: 1) to give the desired product 2
08 mg (15% yield) was obtained. Melting point 164-166
° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.52 (3H, s), 1.
76 (3H, s), 2.18 (6H, s), 4.13 (1H, s), 4.52 (4H,
s), 6.70-7.41 (9H, m).

Synthesis Example 2a 5,6-Dichloro-2- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) isoindoline Aluminum chloride ( To a solution of 1.01 g (7.59 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (276.5 mg, 7.29 mmol), and the mixture was stirred for 10 minutes. 5,6-dichloro-2-
(2,2,4,6,7-pentamethyl-3-phenyl-
2,3-dihydro-1-benzofuran-5-yl) -1
H-isoindole-1,3 (2H) -dione (90
(7.4 mg, 1.89 mmol) in tetrahydrofuran (10 mL) was added and the mixture was heated to reflux for 2 hours. After cooling the reaction mixture to room temperature, water was added and the product was extracted twice with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give 153 mg of the desired product (yield
18%). 194-196 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.52 (3H, s), 1.
74 (3H, s), 2.16 (6H, s), 4.12 (1H, s), 4.45 (4H,
s), 6.8-7.4 (7H, m).

Synthesis Example 3a 5,6-Dimethoxy-2- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) isoindoline 2,2 , 4,6,7-pentamethyl-3-phenyl-
To a solution of 2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.56 mmol) in tetrahydrofuran (30 mL) was added 1,2-bis (chloromethyl).
-4,5-dimethoxybenzene (889.1 mg, 3.
78 mmol), sodium carbonate (1.15 g, 10.
85 mmol) and tetrabutylammonium iodide (701.4 mg, 1.90 mmol) were added and the mixture was heated at reflux for 21 hours. After cooling the reaction mixture to room temperature, it was poured into ice water and the product was extracted twice with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10: 1) to obtain 403.0 mg of the desired product.
(26% yield). Melting point 154-157 [deg.] C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.53 (3H, s), 1.
76 (3H, s), 2.18 (6H, s), 3.87 (6H, s), 4.13 (1H,
s), 4.46 (4H, s), 6.7-7.4 (7H, m).

Synthesis Example 4a 2- [2,2,4,6,7-pentamethyl-3- (4-
Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] isoindoline 2- [2,2,4,6,7-pentamethyl-3- (4-
Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -1H-isoindole-1,3 (2
The target compound was synthesized using H) -dione according to Synthesis Example 2a. Yield 46%. 141-143 ° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.51 (3H, s), 1.
77 (3H, s), 2.17-2.18 (6H, m), 2.31 (3H, s), 4.10
(1H, s), 4.52 (4H, s), 6.8-7.1 (4H, m), 7.24 (4H,
s).

Synthesis Example 5a 5,6-Dichloro-2- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] Isoindoline 5,6-dichloro-2- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -1H-iso The target compound was synthesized using indole-1,3 (2H) -dione according to Synthesis Example 2a. Yield 25%. Melting point 201-
203 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.50 (3H, s), 1.
74 (3H, s), 2.16 (6H, s), 2.31 (3H, s), 4.08 (1H,
s), 4.45 (4H, s), 6.6-7.1 (4H, m), 7.31 (2H, s).

Synthesis Example 6a 5,6-Dimethoxy-2- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] Isoindoline 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
To a solution of -amine (806.1 mg, 2.76 mmol) in tetrahydrofuran (30 mL) was added 1,2-bis (chloromethyl) -4,5-dimethoxybenzene (686.
6 mg, 2.92 mmol), sodium carbonate (87
8.5 mg, 8.29 mmol) and tetrabutylammonium iodide (543.6 mg, 1.47 mmol).
l) was added and the mixture was heated at reflux for 11 hours. After cooling the reaction mixture to room temperature, it was poured into ice water and the product was extracted twice with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered,
It was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give 199.6 mg of the desired product (yield 16).
%). 156-159 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.51 (3H, s), 1.
76 (3H, s), 2.17 (6H, s), 2.31 (3H, s), 3.88 (6H,
s), 4.10 (1H, s), 4.45 (4H, s), 6.7-7.2 (6H, m).

Synthesis Example 7a 2- [3- (4-Fluorophenyl) -2,2,4
6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] isoindoline 2- [3- (4-fluorophenyl) -2,2,4
6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -1H-isoindole-1,3
Using (2H) -dione, the target product was synthesized according to Synthesis Example 2a. 55% yield. 204-205 ° C.
(Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.51 (3H, s), 1.
76 (3H, s), 2.17 (3H, s), 2.18 (3H, s), 4.11 (1H,
s), 4.52 (4H, s), 6.7-7.1 (4H, m), 7.25 (4H, s).

Synthesis Example 8a 5,6-Dichloro-2- [3- (4-fluorophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] Isoindoline 5,6-dichloro-2- [3- (4-fluorophenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -1H-iso Synthesis Example 2 Using Indole-1,3 (2H) -dione
The desired product was synthesized according to a. Yield 25%. Melting point 23
3-238 ° C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.50 (3H, s), 1.
60 (3H, s), 1.74 (3H, s), 2.15 (3H, s), 4.09 (1H,
s), 4.45 (4H, s), 6.8-7.1 (4H, m), 7.32 (2H, s).

Synthesis Example 9a 2- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] isoindoline 2- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -1H-isoindole-1,
Using 3 (2H) -dione, the target product was synthesized according to Synthesis Example 2a. Yield 57%. 113-114 ° C.
(Hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.51 (3H, s), 1.77 (3H, s), 2.17 (3H,
s), 2.18 (3H, s), 2.86 (1H, septet, J = 7.0 Hz),
4.11 (1H, s), 4.53 (4H, s), 6.7-7.2 (4H, m), 7.24
(4H, s).

Synthesis Example 10a 5,6-Dichloro-2- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-
Dihydro-1-benzofuran-5-yl] isoindoline 5,6-dichloro-2- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-
Using dihydro-1-benzofuran-5-yl] -1H-isoindole-1,3 (2H) -dione, the desired product was synthesized according to Synthesis Example 2a. Yield 16%. Melting point 1
48-150 ° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.01-1.06 (3H, m), 1.22 (6H,
d, J = 7.0 Hz), 1.50-1.54 (3H, m), 1.74-1.78 (3H,
m), 2.16-2.20 (6H, m), 2.86 (1H, septet, J = 7.0 H
z), 4.09-4.13 (1H, m), 4.46 (4H, s), 6.7-8.0 (6H,
m).

Synthesis Example 11a 5,6-Dimethoxy-2- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3
-Dihydro-1-benzofuran-5-yl] isoindoline 3- (4-isopropylphenyl) -2,2,4,6
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, the target compound was synthesized according to Synthesis Example 3a. Yield 68%. 153-155 ° C. (Isopropyl ether-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.01-1.05 (3H, m), 1.22 (6H,
d, J = 7.0 Hz), 1.48-1.55 (3H, m), 1.77-1.83 (3H,
m), 2.17-2.19 (6H, m), 2.86 (1H, septet, J = 7.0 H
z), 3.87-3.91 (7H, m), 4.10-4.14 (1H, m), 4.48 (3
H, s), 6.77 (2H, s), 6.8-7.0 (2H, m), 7.07-7.11 (2
H, m).

Synthesis Example 12a 6- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -6,7-dihydro-5H-
[1,3] dioxolo [4,5-f] isoindole 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (835.5 mg, 2.58 mmol)
In a tetrahydrofuran (20 mL) solution of 5,6-bis (chloromethyl) -1,3-benzodioxazole (574.5 mg, 2.62 mmol), sodium carbonate (832.8 mg, 7.88 mmol) and tetrabutylammonium Iodide (481.6 mg, 1.3
0 mmol) was added and the mixture was heated at reflux for 23 hours.
After cooling the reaction mixture to room temperature, it was poured into ice water and the product was extracted twice with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from isopropyl ether to give 395.0 mg of the desired product
(33% yield). 175-177 ° C. _{^{1 H-NMR (CDCl 3)}} δ: 1.00 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.50 (3H, s), 1.76 (3H, s), 2.17 (6H,
s), 2.86 (1H, septet, J = 7.0 Hz), 4.10 (1H, s),
4.42 (4H, s), 5.94 (2H, s), 6.89 (2H, s), 6.80-7.1
1 (4H, m).

Synthesis Example 13a 2- [3- (4-isopropylphenyl) -2,4
6,7-tetramethyl-1-benzofuran-5-yl]
Isoindoline 2- [3- (4-isopropylphenyl) -2,4
6,7-tetramethyl-1-benzofuran-5-yl]
Using -1H-isoindole-1,3 (2H) -dione, the desired product was synthesized according to Synthesis Example 2a. Yield 7
0%. 126-129 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 7.0 Hz), 1.97
(3H, s), 2.27 (3H, s), 2.31 (3H, s), 2.44 (3H, s),
2.95 (1H, septet, J = 7.0 Hz), 4.57 (4H, s), 7.25
(8H, s).

Synthesis Example 14a 6- [2,2,4,6,7-pentamethyl-3- (4-
Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -6H- [1,3] dioxolo [4,5
-F] isoindole 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
To a solution of -amine (799.8 mg, 2.73 mmol) in tetrahydrofuran (30 mL) was added 5,6-bis (chloromethyl) -1,3-benzodioxazole (60
3.8 mg, 2.76 mmol), sodium carbonate (8
77.8 mg, 8.28 mmol) and tetrabutylammonium iodide (506.8 mg, 1.37 mm)
ol) and the mixture was heated at reflux for 23 hours. After cooling the reaction mixture to room temperature, it was poured into ice water and the product was extracted twice with isopropyl ether. The extract was washed with saturated saline, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10: 1) to give the desired product 1
36.8 mg (11% yield) were obtained. Melting point 236-2
42 ° C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.06 (3H, s), 1.47 (3H, s), 1.5
4 (3H, s), 1.82 (3H, s), 2.19 (3H, s), 2.31 (3H, s)
s), 4.12 (1H, s), 5.85 (2H, s), 6.7-7.1 (8H, m).

Synthesis Example 15a 2- [2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] isoindoline 2- [2,2,4,6,7- Synthesis Example 2 using pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -1H-isoindole-1,3 (2H) -dione
The desired product was synthesized according to a. Yield 84%. Melting point 16
1-163 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.48 (6H, s), 2.08 (3H, s), 2.1
1 (3H, s), 2.14 (3H, s), 2.93 (2H, s), 4.56 (4H,
s), 7.27 (4H, s).

Synthesis Example 16a 6- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl)
-6,7-dihydro-5H- [1,3] dioxolo [4,5-f] isoindole 2,2,4,6,7-pentamethyl-3-phenyl-
To a solution of 2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.56 mmol) in tetrahydrofuran (30 mL) was added 5,6-bis (chloromethyl).
-1,3-benzodioxazole (604 mg, 2.7
6 mmol), sodium carbonate (1.17 g, 11.0
mmol) and tetrabutylammonium iodide (700 mg, 1.90 mmol).
The mixture was refluxed for 5 hours. After the reaction mixture was cooled to room temperature, it was poured into ice water, and the product was extracted twice with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 8: 1) to obtain 853 mg of the desired product (56% yield). Melting point 2
45-248 ° C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.52 (3H, s), 1.7
6 (3H, s), 2.17 (6H, s), 4.12 (1H, s), 4.43 (4H,
s), 5.94 (2H, s), 6.68 (2H, s), 6.8-7.3 (5H, m).

Synthesis Example 17a (+)-5,6-dimethoxy-2- [2,2,4,6
7-pentamethyl-3- (4-methylphenyl) -2,
3-Dihydro-1-benzofuran-5-yl] isoindoline Under an argon atmosphere, (+)-2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro- 1-benzofuran-5-amine (6.00 g,
20.3 mmol) in tetrahydrofuran (50 mL)
4,5-Dimethoxyphthalic anhydride (4.43) was added to the solution.
g, 21.3 mmol) and heated under reflux for 3 hours.
The reaction mixture was cooled to room temperature and 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide (WSC) hydrochloride (4.67 g, 24.4 mmol) and 1-hydroxy-1H-benzotriazole (HOBt) monohydrate (3.74 g, 24.4 mmol) were added. The mixture was heated at reflux for 14 hours and then cooled to room temperature. Water and an 8 N aqueous sodium hydroxide solution were added to the reaction mixture, and the product was extracted twice with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and dried over magnesium sulfate.
After filtration and concentration under reduced pressure, (+)-5,6-dimethoxy-2
-[2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -1H-isoindole-1,3 (2H)
8.40 g of crude product of -dione were obtained. Lithium aluminum hydride (3.87 g, 102 mmol) was added to a solution of aluminum chloride (13.6 g, 102 mmol) in tetrahydrofuran (60 mL), and the mixture was stirred for 10 minutes. The crude product tetrahydrofuran (3
0 mL) solution was added and the mixture was heated at reflux for 3 hours. After cooling the reaction mixture to room temperature, water was added and the product was extracted twice with ethyl acetate. The extract was washed with a 1N aqueous solution of sodium hydroxide, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 8: 1) to obtain 6.23 g (yield 68%) of the desired product. Melting point 157-1
59 ° C. (Ethanol) [α] D = + 62.3 ° (c =
0.488, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.51 (3H, s), 1.
76 (3H, s), 2.17 (3H, s), 2.18 (3H, s), 2.31 (3H,
s), 3.87 (6H, s), 4.10 (1H, s), 4.45 (4H, s), 6.70
-7.15 (6H, m).

Synthesis Example 18a (-)-5,6-dimethoxy-2- [2,2,4,6
7-pentamethyl-3- (4-methylphenyl) -2,
3-dihydro-1-benzofuran-5-yl] isoindoline (-)-2,2,4,6,7-pentamethyl-3- (4
-Methylphenyl) -2,3-dihydro-1-benzofuran-5-amine was used to synthesize the desired product according to Synthesis Example 17a. Yield 34%. 157-159 [deg.] C.
(Ethanol) [α] D = -61.5 ° (c = 0.50)
1, methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.51 (3H, s), 1.
76 (3H, s), 2.17 (6H, s), 2.31 (3H, s), 3.88 (6H,
s), 4.10 (1H, s), 4.45 (4H, s), 6.74-7.10 (6H,
m).

Synthesis Example 19a (+)-5,6-Dimethoxy-2- [2,2,4,6
7-pentamethyl-3- (4-methylphenyl) -2,
3-dihydro-1-benzofuran-5-yl] isoindoline hydrochloride (+)-5,6-dimethoxy-2- [2,2,4,6,
7-pentamethyl-3- (4-methylphenyl) -2,
3-Dihydro-1-benzofuran-5-yl] isoindoline (296 mg, 0.65 mmol) was dissolved in ethyl acetate (5.0 mL), and a 4N hydrogen chloride-ethyl acetate solution (0.38 mL) was added. After evaporating the solvent under reduced pressure,
It was diluted with ethyl acetate-diethyl ether (1: 5) for crystallization. The crystals were collected by filtration and washed with a cold ethyl acetate-diethyl ether (1: 5) solution to obtain 291 mg (yield: 87%) of the title compound as crystals. Melting point 170-17
1 ° C. [Α] D = + 44.9 ° (c = 0.495, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 1.05 (3H, s), 1.49 (3H, s), 2.
03 (3H, br), 2.18 (3H, s), 2.32 (3H, s), 2.45 (3H, b
r), 3.86 (6H, s), 4.06 (1H, s), 4.60 (2H, br), 5.7
0 (2H, br), 6.71 (2H, s), 6.80 (2H, br), 7.07 (2H,
brd, J = 6.0 Hz).

Synthesis Example 20a (-)-5,6-dimethoxy-2- [2,2,4,6
7-pentamethyl-3- (4-methylphenyl) -2,
3-dihydro-1-benzofuran-5-yl] isoindoline hydrochloride (-)-5,6-dimethoxy-2- [2,2,4,6,
7-pentamethyl-3- (4-methylphenyl) -2,
Using 3-dihydro-1-benzofuran-5-yl] isoindoline, the desired product was obtained according to Synthesis Example 19a.
Yield 61%. 173-175 [deg.] C. [Α] D = -4
4.4 ° (c = 0.501, chloroform) ¹ H-NMR (CDCl ₃ ) δ: 1.05 (3H, s), 1.49 (3H, s), 2.
05 (3H, br), 2.18 (3H, s), 2.31 (3H, s), 2.48 (3H, b
r), 3.86 (6H, s), 4.06 (1H, s), 4.55 (2H, br), 5.7
5 (2H, br), 6.71 (2H, s), 6.85 (2H, br), 7.07 (2H,
brd, J = 7.0 Hz).

Synthesis Example 21a (+)-5,6-dimethoxy-2- [2,2,4,6
7-pentamethyl-3- (4-methylphenyl) -2,
3-dihydro-1-benzofuran-5-yl] isoindoline hydrobromide (+)-5,6-dimethoxy-2- [2,2,4,6
7-pentamethyl-3- (4-methylphenyl) -2,
3-Dihydro-1-benzofuran-5-yl] isoindoline (150 mg, 0.327 mmol) was dissolved in a 25% hydrogen bromide acetic acid solution (10 mL) and concentrated under reduced pressure. The residue was crystallized from methanol to obtain 92 mg of the desired product (yield: 52%). 174-1 melting point
77 ° C. [Α] D = + 40.2 ° (c = 0.495, methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.51 (3H, s), 1.
76 (3H, s), 2.17 (3H, s), 2.18 (3H, s), 2.31 (3H,
s), 3.87 (6H, s), 4.10 (1H, s), 4.45 (4H, s), 6.70
-7.15 (6H, m).

Synthesis Example 22a (-)-5,6-dimethoxy-2- [2,2,4,6
7-pentamethyl-3- (4-methylphenyl) -2,
3-dihydro-1-benzofuran-5-yl] isoindoline hydrobromide (-)-5,6-dimethoxy-2- [2,2,4,6,
7-pentamethyl-3- (4-methylphenyl) -2,
Using 3-dihydro-1-benzofuran-5-yl] isoindoline, the target compound was synthesized according to Synthesis Example 21a. Yield 46%. Melting point 171-174 [deg.] C. [Α] D =
-40.1 ° (c = 0.498, methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.51 (3H, s), 1.
76 (3H, s), 2.17 (6H, s), 2.31 (3H, s), 3.88 (6H,
s), 4.10 (1H, s), 4.45 (4H, s), 6.74-7.10 (6H,
m). Synthetic Example 23a 5,6-Dimethoxy-2- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -2H
-Isoindole 5,6-dimethoxy-2- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -2H
-Isoindole (1.83 g, 4 mmol) in toluene (50 mL)
To the solution was added 10% -palladium carbon (containing 50% water, 1.83 g), and the mixture was stirred at 100 ° C for 20 minutes under a nitrogen stream. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the residue was crystallized from hexane-ethyl acetate (6: 1) to obtain 1.37 g of the desired product (yield: 75%). [Α] D = + 92.9 ° (c = 0.498 chloroform). 146-147 ° C. _{^{1 H-NMR (CDCl 3)}} δ: 1.06 (3H, s), 1.48 (3H, s), 1.5
5 (3H, s), 1.82 (3H, s), 2.20 (3H, s), 2.32 (3H,
s), 3.90 (3H, s), 3.91 (3H, s), 4.13 (1H, s), 6.82
(2H, s), 6.84 (2H, brs), 6.90 (2H, br), 7.07 (2H,
brd, J = 7.8Hz). The chemical structural formula of the compound obtained in the above synthesis example is shown below.

[0084]

[Table 1]

[0085]

[Table 2]

Formulation Example 1a (1) Compound obtained in Synthesis Example 14a 50 mg (2) Lactose 34 mg (3) Maize starch 10.6 mg (4) Maize starch (paste-like) 5 mg (5) Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg The above (1) to (6) are mixed according to a conventional method, and the mixture is tableted with a tableting machine to produce tablets.

[Compound (Ib)] Reference Example 1b 3- (4-isopropylphenyl) -2-methyl-2-
Ethyl propenoate sodium hydride (60% liquid paraffin dispersion, 5.
To a suspension of N, N-dimethylformamide (92 g, 148 mmol) in N, N-dimethylformamide (150 mL) was added triethyl 2-phosphonopropionate (35.0 g, 148 mmol) at 0 ° C., followed by stirring at the same temperature for 10 minutes. 4-Isopropylbenzaldehyde (20.0 g, 135 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure.
30.1 g (96% yield) of the oily target product was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7.0 Hz), 1.35
(3H, t, J = 7.0 Hz), 2.13 (3H, s), 2.92 (1H, septe
t, J = 7.0 Hz), 4.27 (2H, q, J = 7.0 Hz), 7.21-7.3
8 (4H, m), 7.67 (1H, s). Reference Example 2b Ethyl 2-methyl-3- (4-methylphenyl) -2-propenoate The desired product was synthesized according to Reference Example 1b using 4-methylbenzaldehyde. Yield 94%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.0 Hz), 2.12
(3H, d, J = 1.4 Hz), 2.37 (3H, s), 4.26 (2H, q, J
= 7.0 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.31 (2H, d,
J = 8.4 Hz), 7.66 (1H, s). Reference Example 3b Ethyl 3- (4-fluorophenyl) -2-methyl-2-propenoate The desired product was synthesized according to Reference Example 1b using 4-fluorobenzaldehyde. Yield 97%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, t, J = 7.0 Hz), 2.10
(3H, d, J = 1.2 Hz), 4.28 (2H, q, J = 7.0 Hz), 7.0
8 (2H, t, J = 8.8 Hz), 7.32-7.43 (2H, m), 7.65 (1
H, s).

Reference Example 4b Ethyl (E) -3- (4-isopropylphenyl) -2-propenoate Sodium hydride (60% liquid paraffin dispersion, 1
To a suspension of 0.4 g (260 mmol) in N, N-dimethylformamide (200 mL) was added triethyl phosphonoacetate (58.2 g, 236 mmol) at 0 ° C., and the mixture was stirred at the same temperature for 10 minutes. 4-Isopropylbenzaldehyde (35.0 g, 260 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. Wash the combined extracts with water,
After drying over magnesium sulfate, the mixture was concentrated under reduced pressure to obtain 47.5 g (yield 92%) of the target product as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7.0 Hz), 1.33
(3H, t, J = 7.0 Hz), 2.92 (1H, septet, J = 7.0 H
z), 4.26 (2H, q, J = 7.0 Hz), 6.40 (1H, d, J = 15.8
Hz), 7.24 (2H, d, J = 8.2 Hz), 7.46 (2H, d, J =
8.2 Hz), 7.67 (1H, d, J = 15.8 Hz). Reference Example 5b Ethyl (E) -3- (4-fluorophenyl) -2-propenoate The desired product was synthesized according to Reference Example 4b using 4-fluorobenzaldehyde. Yield 88%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.0 Hz), 4.26
(2H, q, J = 7.0 Hz), 6.31 (1H, d, J = 15.8 Hz), 7.
00-7.11 (2H, m), 7.43-7.58 (2H, m), 7.67 (1H, d, J
= 15.8 Hz).

Reference Example 6b 3- (4-isopropylphenyl) -2-methyl-2-
Propen-1-ol 3- (4-isopropylphenyl) -2-methyl-2-
Lithium aluminum hydride (1.47 g, 38.7 mmol) was added to a suspension of ethyl propenoate (9.00 g, 38.7 mmol) and cerium chloride (1.00 g, 4.06 mmol) in tetrahydrofuran (50 mL) at -40 ° C.
l) was added in four portions over 30 minutes and stirred at the same temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 8: 1) to give 6.30 g (yield 86%) of the desired product as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7.0 Hz), 1.91
(3H, d, J = 1.4 Hz), 2.90 (1H, septet, J = 7.0 H
z), 4.17 (2H, d, J = 0.8 Hz), 6.49 (1H, dd, J = 2.
6, 1.4 Hz), 7.15-7.25 (4H, m), 1H Not confirmed. Reference Example 7b 2-methyl-3- (4-methylphenyl) -2-propen-1-ol Using 2-ethyl-3- (4-methylphenyl) -2-propenoate ethyl according to Reference Example 6b. Was synthesized. Yield 98%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.87 (3H, s), 2.32 (3H, s), 4.
13 (2H, s), 6.46 (1H, s), 7.08-7.22 (4H, m), 1H Not confirmed. Reference Example 8b Using 3- (4-fluorophenyl) -2-methyl-2-propenoic acid ethyl according to Reference Example 6b, using ethyl 3- (4-fluorophenyl) -2-methyl-2-propenoate. Was synthesized. Yield 95%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, d, J = 1.6 Hz), 4.11
(2H, s), 6.58 (1H, s), 7.01 (2H, t, J = 8.8 Hz),
7.18-7.28 (2H, m), 1H Not confirmed.

Reference Example 9b (E) -3- (4-isopropylphenyl) -2-pro
Pen-1-ol (E) -3- (4-isopropylphenyl) -2-pro
Tet of ethyl penate (20.0 g, 91.6 mmol)
Hydrogen at −40 ° C. in a suspension of lahydrofuran (200 mL)
Lithium aluminum chloride (2.61 g, 68.7 mmo
l) is added 4 times in 30 minutes and stirred at the same temperature for 30 minutes
did. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate.
Issued. Wash the combined extracts with water and extract magnesium sulfate.
After drying on a buffer, the mixture was concentrated under reduced pressure. Residue is silica gel column
Chromatography (hexane-ethyl acetate 8: 1)
This gave 10.5 g (yield: 65%) of the target product as an oil. ¹ H-NMR (CDCl _Three ) δ: 1.24 (6H, d, J = 7.0 Hz), 2.79-
3.00 (2H, m), 4.30 (2H, d, J = 5.6 Hz), 6.35 (1H,
dt, J = 15.8, 5.6 Hz), 6.59 (1H, d, J = 15.8Hz),
7.10-7.39 (4H, m). Reference Example 10b (E) -3- (4-Fluorophenyl) -2-propene
-1-ol (E) -3- (4-fluorophenyl) -2-propene
Using ethyl acetate, the target compound was synthesized according to Reference Example 6b.
Was. Yield 84%. Oil. ¹ H-NMR (CDCl _Three ) δ: 4.31 (2H, d, J = 5.6 Hz), 6.28
(1H, dt, J = 15.8, 5.6 Hz), 6.59 (1H, d, J = 15.8
Hz), 6.90-7.40 (4H, m), 1H Not confirmed.

Reference Example 11b 1- (3-bromo-2-methyl-1-propenyl) -4
-Isopropylbenzene 3- (4-isopropylphenyl) -2-methyl-2-
Propen-1-ol (6.30 g, 33.1 mmol
Phosphorus tribromide (5.98 g, 22.1 mmol) was added to a solution of 1) in isopropyl ether (50 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was extracted with isopropyl ether. The organic layer was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 7.63 g of the desired product as an oil.
(91% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 7.0 Hz), 2.03
(3H, d, J = 1.4 Hz), 2.90 (1H, septet, J = 7.0 H
z), 4.15 (2H, d, J = 0.8 Hz), 6.62 (1H, s), 7.14-
7.26 (4H, m). Reference Example 12b 1- (3-Bromo-2-methyl-1-propenyl) benzene The intended product was synthesized according to Reference Example 11b using 2-methyl-3-phenyl-2-propen-1-ol. Yield 89%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, d, J = 1.4 Hz), 4.13
(2H, d, J = 0.8 Hz), 6.64 (1H, s), 7.19-7.44 (5H,
m). Reference Example 13b 1- (3-bromo-2-methyl-1-propenyl) -4
-Methylbenzene Using 2-methyl-3- (4-methylphenyl) -2-propen-1-ol, the target product was synthesized according to Reference Example 11b. Yield 77%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, s), 2.34 (3H, s), 4.
13 (2H, s), 6.60 (1H, s), 7.09-7.22 (4H, m). Reference Example 14b 1- (3-bromo-2-methyl-1-propenyl) -4
-Fluorobenzene Using 3- (4-fluorophenyl) -2-methyl-2-propen-1-ol, the target compound was synthesized according to Reference Example 11b. Yield 79%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.87 (3H, s), 4.17 (2H, s), 6.
48 (1H, s), 7.01 (2H, t, J = 8.8 Hz), 7.18-7.27 (2
H, m).

Reference Example 15b 1-[(E) -3-bromo-1-propenyl] -4-isopropylbenzene (E) -3- (4-isopropylphenyl) -2-propen-1-ol (10.5 g) , 59.6 mmol) in isopropyl ether (100 mL) was added phosphorus tribromide (10.7 g, 39.7 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was extracted with isopropyl ether. The organic layer was washed with water and a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 10.2 g of an oily target substance.
(72% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.24 (6H, d, J = 7.0 Hz), 2.89
(1H, septet, J = 7.0 Hz), 4.16 (2H, dd, J = 7.8,
0.8 Hz), 6.35 (1H, dt, J = 15.4, 7.8 Hz), 6.63 (1
H, d, J = 15.4 Hz), 7.14-7.35 (4H, m). Reference Example 16b Reference Example 11b using 1-[(E) -3-bromo-1-propenyl] -4-fluorobenzene (E) -3- (4-fluorophenyl) -2-propen-1-ol Was synthesized according to the procedure. Yield 61%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 4.15 (2H, d, J = 7.6 Hz), 6.30
(1H, dt, J = 15.4, 7.6 Hz), 6.61 (1H, d, J = 15.4
Hz), 6.83-7.08 (2H, m), 7.31-7.45 (2H, m). Reference Example 17b N- [4-[[3- (4-isopropylphenyl) -2]
-Methyl-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide N, N of N- (4-hydroxy-2,3,6-trimethylphenyl) formamide (3.00 g, 16.7 mmol) To a solution of -dimethylformamide (30 mL) was added sodium hydride (60% liquid paraffin dispersion, 0.74 g, 18.4 mmol) at 0 ° C under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 10 minutes. 1- (3-bromo-2) was added to the reaction solution.
-Methyl-1-propenyl) -4-isopropylbenzene (4.66 g, 18.4 mmol) was added, and the mixture was added at room temperature for 3 hours.
Stirred for 0 minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue is crystallized from ethyl acetate-hexane to give the desired product 3.7
0 g (63% yield) was obtained. 153-155 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7.0 Hz), 2.00
(3H, s), 2.07-2.34 (9H, m), 2.91 (1H, septet, J =
7.0 Hz), 4.54 (2H, d, J = 5.4 Hz), 6.59-6.84 (3H,
m), 7.17-7.36 (4H, m), 7.98 (0.5H, d, J = 12.0 H
z), 8.41 (0.5H, s).

Reference Example 18b N- [2,3,6-trimethyl-4-[(2-methyl-
3-phenyl-2-propenyl) oxy] phenyl] formamide N- (4-hydroxy-2,3,6-trimethylphenyl) formamide and 1- (3-bromo-2-methyl-1
Using (-propenyl) benzene, the target product was synthesized according to Reference Example 17b. Yield 41%. Melting point 152-15
4 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, d, J = 1.6 Hz), 2.10
-2.32 (9H, m), 4.54 (2H, d, J = 5.2 Hz), 6.65 (1H,
s), 6.67 (1H, s), 6.69-6.90 (1H, m), 7.11-7.41 (5
H, m), 7.98 (0.5H, d, J = 12.0 Hz), 8.41 (0.5H, d,
J = 1.4 Hz). Reference Example 19b N- [2,3,6-trimethyl-4-[[2-methyl-
3- (4-methylphenyl) -2-propenyl] oxy] phenyl] formamide N- (4-hydroxy-2,3,6-trimethylphenyl) formamide and 1- (3-bromo-2-methyl-1
The target compound was synthesized using -propenyl) -4-methylbenzene according to Reference Example 17b. Yield 57%. Melting point
167-169 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.98 (3H, s), 2.07-2.38 (9H,
m), 2.35 (3H, s), 4.53 (2H, d, J = 6.6 Hz), 6.61 (1
H, s), 6.66 (1H, d, J = 2.4 Hz), 6.82-7.09 (1H,
m), 7.11-7.31 (4H, m), 7.98 (0.5H, d, J = 12.2 H
z), 8.38 (0.5H, s). Reference Example 20b N- [4-[[3- (4-fluorophenyl) -2-methyl-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide N- (4-hydroxy-2,3 , 6-Trimethylphenyl) formamide and 1- (3-bromo-2-methyl-1)
The target compound was synthesized using -propenyl) -4-fluorobenzene according to Reference Example 17b. Yield 52%. 164-165 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.96 (3H, s), 2.12-2.32 (9H,
m), 4.53 (2H, d, J = 5.2 Hz), 6.60 (1H, s), 6.66
(1H, s), 6.71-6.95 (1H, m), 7.04 (2H, t, J = 8.8 H
z), 7.22-7.33 (2H, m), 8.04 (0.5H, d, J = 12.0 H
z), 8.40 (0.5H, d, J = 1.4 Hz).

Reference Example 21b N- [4-[[(E) -3- (4-isopropylphenyl) -2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide N- (4-hydroxy- To a solution of 2,3,6-trimethylphenyl) formamide (5.20 g, 29.0 mmol) in N, N-dimethylformamide (30 mL) at 0 ° C. under a nitrogen atmosphere at 0 ° C., sodium hydride (60% liquid paraffin dispersion, 1. 39 g, 34.8 mmol) and stirred at the same temperature for 10 minutes. 1-[(E) -3-Bromo-1-propenyl] -4-isopropylbenzene (9.00 g, 37.7 mmol) was added to the reaction solution, and the mixture was added at room temperature for 30 minutes.
Stirred for minutes. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue is crystallized from ethyl acetate-hexane to obtain the desired product 5.80
g (yield 59%) was obtained. 165-167 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (6H, d, J = 6.8 Hz), 2.13-
2.27 (9H, m), 2.90 (1H, septet, J = 6.8 Hz), 4.66
(2H, t, J = 5.8 Hz), 6.37 (1H, dt, J = 15.8,5.8 H
z), 6.65-6.88 (3H, m), 7.16-7.26 (2H, m), 7.35 (2
H, d, J = 8.0 Hz), 7.98 (0.5H, d, J = 12.0 Hz), 8.
40 (0.5H, d, J = 1.4 Hz). Reference Example 22b N- [2,3,6-trimethyl-4-[[(E) -3-
Phenyl-2-propenyl] oxy] phenyl] formamide Using N- (4-hydroxy-2,3,6-trimethylphenyl) formamide and cinnamyl chloride, the target compound was synthesized according to Reference Example 17b. Yield 44%. 197-199 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 2.05-2.18 (9H, m), 4.62-4.72
(2H, m), 6.35-6.50 (1H, m), 6.62-7.00 (3H, m), 7.24
-7.52 (5H, m), 8.00 (0.5H, d, J = 12.0 Hz), 8.39
(0.5H, d, J = 1.6 Hz).

Reference Example 23b N- [4-[[(E) -3- (4-fluorophenyl)
-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide N- (4-hydroxy-2,3,6-trimethylphenyl) formamide and 1-[(E) -3-bromo-1-propenyl Reference Example 1 using 4-fluorobenzene
The target compound was synthesized according to 7b. Yield 52%. Melting point 1
96-198 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 2.10-2.32 (9H, m), 4.67 (2H,
t, J = 5.0 Hz), 6.37 (1H, dt, J = 15.6, 5.0 Hz),
6.59-6.89 (3H, m), 6.92-7.09 (2H, m), 7.32-7.43 (2
H, m), 7.99 (0.5H, d, J = 12.0 Hz), 8.42 (0.5H, d,
J = 1.4 Hz). Reference Example 24b N- [4-hydroxy-3- [1- (4-isopropylphenyl) -2-propenyl] -2,5,6-trimethylphenyl] formamide N- [4-[[(E) -3- (4-Isopropylphenyl) -2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide (5.80 g, 17.2 m
mol) of N, N-dimethylaniline (50 mL) was stirred at 215 ° C. for 6 hours under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 2N hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give 3.50 g of the desired product (yield
60%). 170-171 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.40 (6H, m), 2.11-2.27
(9H, m), 2.77-3.00 (1H, m), 5.00-5.22 (2H, m), 5.30
-5.42 (1H, m), 6.30-6.85 (2H, m), 7.10-7.37 (5H,
m), 7.97 (0.5H, d, J = 12.2 Hz), 8.43 (0.5H, d, J
= 1.4 Hz).

Reference Example 25b N- [4-hydroxy- (1-phenyl-2-propenyl) -2,5,6-trimethylphenyl] formamide N- [2,3,6-trimethyl-4-[[(E ) -3-
Using phenyl-2-propenyl] oxy] phenyl] formamide, the target compound was synthesized according to Reference Example 24b. Yield 78%. 144-145 ° C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 2.08-2.27 (9H, m), 5.02-5.41
(3H, m), 6.32-6.52 (1H, m), 6.61-7.03 (2H, m), 7.18
-7.42 (5H, m), 7.95 (0.5H, d, J = 12.0 Hz), 8.42
(0.5H, d, J = 1.8 Hz). Reference Example 26b N- [4-hydroxy-3- [1- (4-fluorophenyl) -2-propenyl] -2,5,6-trimethylphenyl] formamide N- [4-[[(E) -3- (4-fluorophenyl)
Using [-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide, the target compound was synthesized according to Reference Example 24b. Yield 66%. Melting point 168-17
0 ° C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 2.10-2.29 (9H, m), 5.02-5.22
(1.5H, m), 5.33-5.50 (1.5H, m), 6.35-6.55 (1H, m),
6.72-7.08 (4H, m), 7.18-7.30 (2H, m), 7.96 (0.5H,
d, J = 12.2 Hz), 8.42 (0.5H, d, J = 1.4 Hz). Reference Example 27b 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine N- [4-[[3- (4-isopropylphenyl) -2
-Methyl-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide (3.70 g, 10.
5 mmol) N, N-dimethylaniline (20 mL)
The solution was stirred at 215 ° C. for 6 hours under an argon atmosphere. After cooling the reaction mixture, it was diluted with ethyl acetate, 2N hydrochloric acid,
After washing with water, drying over magnesium sulfate, concentration under reduced pressure,
N- [4-hydroxy-3- [1- (4-isopropylphenyl) -2-methyl-2-propenyl] -2,5
A crude product of [6-trimethylphenyl] formamide was obtained. A mixture of this compound (2.98 g, 8.47 mmol) in concentrated hydrochloric acid (20 mL) -methanol (60 mL) was heated to reflux under a nitrogen atmosphere for 2 hours. The solvent was concentrated under reduced pressure,
The obtained residue was neutralized with an 8 N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from isopropyl ether-hexane to obtain 2.23 g (yield 66%) of the desired product. 130-132 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.21 (6H, d, J =
6.6 Hz), 1.47 (3H, s), 1.78 (3H, s), 2.12 (3H, s),
2.19 (3H, s), 2.40-2.60 (3H, m), 4.08 (1H, s), 6.72
-7.00 (2H, m), 7.07 (2H, d, J = 8.0 Hz).

Reference Example 28b 2,2,4,6,7-pentamethyl-3-phenyl-
2,3-dihydro-1-benzofuran-5-amine N- [2,3,6-trimethyl-4-[(2-methyl-
Using 3-phenyl-2-propenyl) oxy] phenyl] formamide, the target compound was synthesized according to Reference Example 27b. Yield 67%. 129-131 ° C. (Petroleum ether) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.48 (3H, s), 1.7
7 (3H, s), 2.13 (3H, s), 2.19 (3H, s), 3.20 (2H, b
rs), 4.12 (1H, s), 6.70-7.30 (5H, m). Reference Example 29b 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
-Amine N- [2,3,6-trimethyl-4-[[2-methyl-
Using 3- (4-methylphenyl) -2-propenyl] oxy] phenyl] formamide, the target compound was synthesized according to Reference Example 27b. Yield 62%. Melting point 114-
115 ° C. (Petroleum ether) ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.47 (3H, s), 1.7
7 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 2.30 (3H, s)
s), 3.23 (2H, br s), 4.08 (1H, s), 6.60-7.23 (4H,
m). Reference Example 30b 3- (4-fluorophenyl) -2,2,4,6,7-
Pentamethyl-2,3-dihydro-1-benzofuran-
5-Amine Using N- [4-[[3- (4-fluorophenyl) -2-methyl-2-propenyl] oxy] -2,3,6-trimethylphenyl] formamide according to Reference Example 27b, Was synthesized. Yield 78%. Melting point 125-
127 ° C. (Petroleum ether) ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.47 (3H, s), 1.7
7 (3H, s), 2.12 (3H, s), 2.19 (3H, s), 3.10 (2H, b
rs), 4.09 (1H, s), 6.62-7.20 (4H, m).

Reference Example 31b 3- (4-isopropylphenyl) -2,4,6,7-
Tetramethyl-1-benzofuran-5-amine hydrochloride N- [4-hydroxy-3- [1- (4-isopropylphenyl) -2-propenyl] -2,5,6-trimethylphenyl] formamide (3.50 g) , 10.4mm
ol) and calcium carbonate (1.35 g, 13.5 mmo)
l) A suspension of tetrahydrofuran (15 mL) -methanol (15 mL) in benzyltrimethylammonium iodo dichloride (3.90 g, 11.4 mmol).
Was slowly added. The reaction was stirred at room temperature for 30 minutes. After filtering off the insoluble matter, the solvent was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with a 10% aqueous sodium hydrate sulfite solution, water, a saturated aqueous sodium bicarbonate solution and saturated saline, dried over magnesium sulfate, concentrated under reduced pressure, and 4.08 g of N- [2- (iodomethyl). -3- (4-isopropylphenyl) -4,
6,7-Trimethyl-2,3-dihydro-1-benzofuran-5-yl] formamide was obtained. This compound (4.08 g, 8.81 mmol) and 1,8-diazabicyclo [5,4,0] -7-undecene (6.58 m
L, 44.0 mmol) in toluene (30 mL) was stirred at 100 ° C. for 3 hours under an argon atmosphere. Water was added to the reaction solution, which was extracted twice with ethyl acetate. The extract was washed with 2N hydrochloric acid and water, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 20: 1) to give 2.40 g of N- [3- (4 -Isopropylphenyl) -2,4
6,7-tetramethyl-1-benzofuran-5-yl]
Formamide was obtained. This compound (2.40 g, 7.1)
8 mmol) concentrated hydrochloric acid (20 mL) -methanol (60
mL) the mixture was heated to reflux under a nitrogen atmosphere for 2 hours. The solvent was concentrated under reduced pressure, and the obtained residue was neutralized with an 8 N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 1.80 g of an oily free base. This free base (0.50 g, 1.63 mmol) was dissolved in a hydrochloric acid-methanol solution, the solvent was concentrated under reduced pressure, and the obtained residue was crystallized from methanol to obtain the target compound.
41 g (41% yield) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J = 7.0 Hz), 2.30
(6H, s), 2.41 (3H, s), 2.60 (3H, s), 2.94 (1H, se
ptet, J = 7.0 Hz), 7.13-7.26 (4H, m), 10.1 (2H, br
s), 1H Not confirmed.

Reference Example 32b 2,4,6,7-Tetramethyl-3-phenyl-1-benzofuran-5-amine hydrochloride N- [4-hydroxy- (1-phenyl-2-propenyl) -2,5 Using 6-trimethylphenyl] formamide, the target compound was synthesized according to Reference Example 31b. Yield 26%. 189-192 ° C. (Ethanol-hexane) ¹ H-NMR (CDCl ₃ ) δ: 2.30 (6H, s), 2.42 (3H, s), 2.
60 (3H, s), 7.21-7.37 (5H, m), 10.2 (2H, br s), 1H
unconfirmed. Reference Example 33b 3- (4-fluorophenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine hydrochloride N- [4-hydroxy-3- [1- (4-fluorophenyl) Using 2--2-propenyl] -2,5,6-trimethylphenyl] formamide, the target compound was synthesized according to Reference Example 31b. Yield 87%. Melting point 208-210
° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 2.29 (6H, s), 2.42 (3H, s), 2.
60 (3H, s), 7.03-7.28 (4H, m), 10.2 (2H, br s), 1H
unconfirmed. Reference Example 34b (1-Benzyl-4-piperidyl) (4-isopropylphenyl) (3,4,6-trimethyl-2-methoxyphenyl) methanol Under an argon atmosphere, 2-methoxy-3,4,6
-Trimethylbromobenzene (15.48 g, 67.5)
6 mmol) in tetrahydrofuran (200 mL) was cooled to −78 ° C., and a solution of n-butyllithium in hexane (1.59 mol / L, 42 mL, 66.
78 mmol) was added dropwise and stirred for 30 minutes. A solution of 1-benzyl-4- (4-isopropylbenzoyl) piperidine (19.81 g, 61.63 mmol) in tetrahydrofuran (50 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Water was added to the mixture and the product was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 23. The target compound is obtained by crystallizing the residue from ethyl acetate-hexane.
01 g (79% yield) was obtained. Melting point 154-156
° C. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (6H, d, J = 7.0 Hz), 1.40-
1.47 (2H, m), 1.85-1.96 (4H, m), 2.07 (3H, s), 2.1
7 (3H, s), 2.26 (1H, m), 2.39 (3H, s), 2.57-2.94
(6H, m), 3.48 (2H, s), 6.18 (1H, br), 6.72 (1H,
s), 7.08-7.12 (2H, d, J = 8.0 Hz), 7.12-7.34 (7H,
m).

Reference Example 35b 1'-benzyl-3- (4-isopropylphenyl)-
4,6,7-trimethylspiro [benzofuran-2 (3
H), 4'-piperidine] Under an argon atmosphere, (1-benzyl-4-piperidyl) (4-isopropylphenyl) (3,4,6-
Trimethyl-2-methoxyphenyl) methanol (5.
To a solution of 61 g (11.89 mmol) in acetic acid (40 mL) was added 47% hydrobromic acid (50 mL), and the resulting mixture was heated to reflux for 13 hours. After cooling the reaction mixture to room temperature, 8N aqueous sodium hydroxide solution was added to the mixture until the solution became basic, and the product was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain 4.44 g of the desired product (yield: 76%). 125-128 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.8 Hz), 1.36-
1.40 (2H, m), 1.72-1.95 (5H, m), 2.17 (3H, s), 2.2
3 (3H, s), 2.29-2.91 (5H, m), 3.52 (2H, s), 4.04 (1
H, s), 6.48 (1H, s), 6.6-7.2 (4H, m), 7.22-7.32 (5
H, m). Reference Example 36b 3- (4-isopropylphenyl) -4,6,7-trimethylspiro [benzofuran-2 (3H), 4′-piperidine] hydrochloride 1′-benzyl-3- (4-isopropylphenyl)-
4,6,7-trimethylspiro [benzofuran-2 (3
H), 4'-piperidine] (10.26 g, 23.34
mmol) in tetrahydrofuran (100 mL) was added to α-chloroethyl formate (3.76 g, 26.60 m).
mol) was added and the mixture was heated at reflux for 1 hour. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. Methanol (80 mL) was added to the obtained residue, and the mixture was heated under reflux for 1 hour. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The residue was crystallized from ethanol to obtain 7.32 g of the desired product (81% yield). Melting point> 2
60 ° C (decomposition). ¹ H-NMR (DMSO-d ₆ ) δ: 1.17 (6H, d, J = 7.0 Hz), 1.2
9-1.67 (2H, m), 1.77 (3H, s), 1.95-2.05 (2H, m),
2.11 (3H, s), 2.18 (3H, s), 2.78-3.28 (5H, m), 4.3
1 (1H, s), 6.50 (1H, s), 6.6-7.2 (4H, m), 2H Not confirmed.

Reference Example 37b 3- (4-isopropylphenyl) -1 ′, 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
4'-piperidine] 3- (4-isopropylphenyl) -4,6,7-trimethylspiro [benzofuran-2 (3H), 4'-piperidine] hydrochloride (389.6 mg, 1.01 mmol)
37% formalin (2.0 mL) was added to an acetonitrile (5 mL) suspension of, and cooled to 0 ° C. Sodium cyanoborohydride (101.8 mg, 1.6) was added to the mixture.
2 mmol) was added and the mixture was stirred at room temperature for 1 hour.
After the reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue. The product was extracted twice with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (Chromatorex NHDM1020 (trade name, manufactured by Fuji Silysia Chemical); hexane-ethyl acetate 1)
0: 1) to give 145.0 mg of the desired product (yield 40
%). 63-64 ° C. (Petroleum ether) ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 7.0 Hz), 1.34-
1.41 (2H, m), 1.84 (3H, s), 1.87-1.97 (2H, m), 2.0
4 (3H, s), 2.17 (3H, s), 2.30 (3H, s), 2.32-2.69
(4H, m), 2.85 (1H, septet, J = 7.0 Hz), 4.05 (1H,
s), 6.48 (1H, s), 6.6-7.2 (4H, m). Reference Example 38b 3- (4-isopropylphenyl) -1 ′, 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
4′-Piperidine] -5-amine Under an argon atmosphere, a solution of nitrosyl tetrafluoroborate (470.7 mg, 4.03 mmol) in acetonitrile (40 mL) was cooled to 0 ° C. A solution of 3- (4-isopropylphenyl) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4′-piperidine] (479.1 mg, 1.32 mmol) in acetonitrile (10 mL) was prepared. The mixture was stirred for 20 minutes. The reaction mixture was poured into ice water and made basic with an aqueous 8N sodium hydroxide solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in ethanol (20 mL), palladium-carbon (59.9 mg) was added, and the mixture was stirred under a hydrogen atmosphere at 60 ° C. for 18 hours.
After the reaction mixture was cooled to room temperature, insolubles were removed by filtration and concentrated under reduced pressure. The residue was subjected to column chromatography (Chromatorex NHDM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.); hexane-ethyl acetate 3:
The resulting product was subjected to 1) to obtain 402.0 mg of the desired product (83% yield). 123-124 ° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.38 (8H, m), 1.69-2.04 (5
H, m), 2.12 (3H, s), 2.22 (3H, s), 2.25-2.51 (7H,
m), 2.84 (1H, septet, J = 6.6 Hz), 3.23 (2H, br),
4.05 (1H, s), 6.6-7.1 (4H, m).

Reference Example 39b 4-Methoxy-2,3,6-trimethylaniline N- (4-hydroxy-2,3,6-trimethylphenyl) formamide (30.0 g, 167 mmol) was added to 4
It was dissolved in a mixed solvent of a normal aqueous potassium hydroxide solution (100 mL) and methanol (300 mL), and dimethyl sulfate (42.0 g, 334 mmol) was added to the solution at room temperature, followed by heating under reflux for 14 hours. After cooling, the precipitated crystals were collected by filtration to obtain a crude product of N- (4-methoxy-2,3,6-trimethylphenyl) formamide. Concentrated hydrochloric acid (5 mL) was added to a suspension of this compound in methanol (200 mL).
0 mL) and heated to reflux for 3 hours. After the reaction mixture was cooled to room temperature, it was neutralized with an 8 N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate, and the combined extracts were 10% aqueous sodium hydrosulfite,
After washing with water, it was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from isopropyl ether to obtain 21.0 g of the desired product (yield: 76%). Melting point 70-72
° C. ¹ H-NMR (CDCl ₃ ) δ: 2.11 (3H, s), 2.16 (3H, s), 2.1
8 (3H, s), 3.16 (1H, br s), 3.74 (3H, s), 6.54 (1
H, s). Reference Example 40b tert-butyl 4-methoxy-2,3,6-trimethylphenylcarbamate 4-methoxy-2,3,6-trimethylaniline (2
1.0 g, 127 mmol) and triethylamine (2
1.0 mL, 152 mmol) in tetrahydrofuran (150 mL) at room temperature.
(2 mL, 140 mmol) and heated under reflux for 14 hours. The solvent was concentrated under reduced pressure, water was poured into the residue, and extracted twice with ethyl acetate. The combined organic layer was washed with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 25.2 g of the desired product (yield: 75%). 104-106 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.12 (3H, s), 2.1
7 (3H, s), 2.24 (3H, s), 3.78 (3H, s), 5.81 (1H, b
rs), 6.58 (1H, s).

Reference Example 41b tert-butyl 3-bromo-4-methoxy-2,5,6
-Trimethylphenylcarbamate tert-butyl 4-methoxy-2,3,6-trimethylphenylcarbamate (12.7 g, 47.9 mmol
l), sodium acetate (4.72 g, 57.5 mmol)
l) in acetic acid (50 mL) at room temperature in bromine (8.42).
g, 52.7 mmol) and stirred at the same temperature for 1 hour. Water (80 mL) was poured into the reaction mixture, and the precipitated crystals were collected by filtration and dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from methanol to obtain 15.0 g of the desired product (yield: 91%). Melting point 159-161 [deg.] C. ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 2.15 (3H, s), 2.2
4 (3H, s), 2.35 (3H, s), 3.74 (3H, s), 5.92 (1H, b
rs). Reference Example 42b 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
-Amine tert-butyl 3-bromo-4-methoxy-2,5,6
-Trimethylphenyl carbamate (27.8 g, 8
0.8 mmol) of tetrahydrofuran (150 mL)
The solution was added at −78 ° C. with n-butyllithium (1.6 M,
110 mL, 176 mmol) and stirred at the same temperature for 20 minutes. 2-Methyl-1- (4-methylphenyl) propan-1-one (13.1 g, 80.7 mm) was added to the reaction solution.
ol) and stirred at room temperature for 1 hour. Water (150 mL) was poured into the reaction mixture, extracted three times with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate, and then dried.
25. Filter and concentrate under reduced pressure to give a crude product of tert-butyl 3- [1-hydroxy-2-methyl-1- (4-methylphenyl) propyl] -4-methoxy-2,5,6-trimethylphenylcarbamate. 0 g was obtained. A mixture of this compound and 47% hydrobromic acid (100 mL) was heated under reflux for 4 hours under an argon atmosphere. After the reaction mixture was cooled to room temperature, it was neutralized with an 8 N aqueous sodium hydroxide solution. The product was extracted twice with ethyl acetate, and the combined extracts were washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to give the desired product 1.
4.8 g (62% yield) were obtained. Melting point 114-115
° C. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.47 (3H, s), 1.7
8 (3H, s), 2.12 (3H, s), 2.17 (3H, s), 2.30 (3H,
s), 2.80 (2H, br s), 4.08 (1H, s), 6.60-7.10 (4H,
m).

Reference Example 43b (+)-3- (4-isopropylphenyl) -2,2
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine was subjected to high performance liquid chromatography (equipment:
Waters semi-preparative system, column: CHIRAL
CEL OD (20 (i, d) × 250 mm, manufactured by Daicel Chemical Industries, Ltd.), moving bed: hexane: isopropyl alcohol = 98: 2, flow rate: 6 mL / min, column temperature: 30 ° C., injection amount: 40 mg) The sample with the shorter retention time was sampled. 72-75 ° C. [Α] D =
+ 2.8 ° (c = 0.500, methanol) Reference Example 44b (−)-3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine was subjected to high performance liquid chromatography (equipment:
Waters semi-preparative system, column: CHIRAL
CEL OD (20 (i, d) × 250 mm, manufactured by Daicel Chemical Industries, Ltd.), moving bed: hexane: isopropyl alcohol = 98: 2, flow rate: 6 mL / min, column temperature: 30 ° C., injection amount: 40 mg) The sample with the longer retention time was sampled. 74-76 ° C. [Α] D =
-3.3 ° (c = 0.506, methanol)

Synthesis Example 1b 4-methoxy-N- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) benzamide 2,2,4 6,7-pentamethyl-3-phenyl-
To a solution of 2,3-dihydro-1-benzofuran-5-amine (1.60 g, 5.69 mmol) and 4-methoxybenzoyl chloride (1.16 g, 6.82 mmol) in chloroform (20 mL) at room temperature was added triethylamine (0. 87 mL, 6.26 mmol) and add 3 at room temperature.
Stirred for 0 minutes. The solvent was concentrated under reduced pressure, and water (30 m
L), and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure.
The residue was crystallized from methanol to give 1.70 g of the desired product
(72% yield). 190-192 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.53 (3H, s), 1.
80 (3H, s), 2.19 (6H, s), 3.86 (3H, s), 4.16 (1H,
s), 6.80-7.36 (8H, m), 7.86 (2H, d, J = 8.8Hz).

Synthesis Example 2b N- (4-methoxybenzyl) -2,2,4,6,7-
Pentamethyl-3-phenyl-2,3-dihydro-1-
Benzofuran-5-amine Lithium aluminum hydride (640 mg, 16.9 mm) was added to a suspension of aluminum chloride (2.25 g, 16.9 mmol) in tetrahydrofuran (20 mL) under ice cooling.
ol) was added little by little and stirred at the same temperature for 10 minutes. To this mixture was added 4-methoxy-N- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) benzamide (1.40 g,
(3.37 mmol) was added and the mixture was heated under reflux for 3 hours. The reaction mixture was added to ice water, neutralized with 8N aqueous sodium hydroxide solution, and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and reduced in pressure. Concentrated. The residue was crystallized from methanol to obtain 0.80 g of the desired product (yield 59%). Melting point 11
3-115 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.50 (3H, s), 1.
78 (3H, s), 1.98 (1H, br s), 2.18 (3H, s), 2.27 (3
H, s), 3.79 (3H, s), 3.85 (2H, s), 4.11 (1H, s), 6.
80-7.31 (9H, m).

Synthesis Example 3b 4-Fluoro-N- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) benzamide 2,2,4 6,7-pentamethyl-3-phenyl-
2,3-dihydro-1-benzofuran-5-amine and 4
Using -fluorobenzoyl chloride, the desired product was synthesized according to Synthesis Example 1b. Yield 92%. Melting point 156-
158 ° C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.53 (3H, s), 1.8
0 (3H, s), 2.19 (3H, s), 2.20 (3H, s), 4.17 (1H,
s), 6.62-7.35 (8H, m), 7.85-7.94 (2H, m).

Synthesis Example 4b N- (4-Fluorobenzyl) -2,2,4,6,7-
Pentamethyl-3-phenyl-2,3-dihydro-1-
Synthesis Example 2b using benzofuran-5-amine 4-fluoro-N- (2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl) benzamide The desired product was synthesized according to Yield 60%. Melting point 93-95
° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.52 (3H, s), 1.7
6 (3H, s), 2.18 (3H, s), 2.26 (3H, s), 2.61 (1H, b
rs), 3.88 (2H, s), 4.11 (1H, s), 6.62-7.40 (9H,
m).

Synthesis Example 5b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] benzamide 3- (4-isopropylphenyl) -2,2,4,6
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and benzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 90%. Melting point 2
18-220 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.52 (3H, s), 1.82 (3H, s), 2.19 (6H, s),
2.85 (1H, septet, J = 7.0 Hz), 4.14 (1H, s), 6.70-
7.13 (4H, m), 7.30 (1H, br s), 7.42-7.61 (3H, m),
7.85-7.92 (2H, m).

Synthesis Example 6b N-benzyl-3- (4-isopropylphenyl)-
2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride A suspension of aluminum chloride (1.18 g, 8.89 mmol) in tetrahydrofuran (20 mL) was ice-cooled. Lithium aluminum hydride below (337 mg, 8.89 mm
ol) was added little by little and stirred at the same temperature for 10 minutes. This mixture was added to N- [3- (4-isopropylphenyl)-
2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] benzamide (0.7
(6 g, 1.78 mmol) and heated under reflux for 3 hours.
After the reaction mixture was added to ice water and neutralized with 8N aqueous sodium hydroxide, the product was extracted twice with ethyl acetate.
The combined organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 0.52 g of an oily free base. This free base (0.52 g, 1.26 mmol) was dissolved in a hydrochloric acid-methanol solution, the solvent was concentrated under reduced pressure, and the obtained residue was crystallized from methanol to obtain the target compound.
47 g (59% yield) were obtained. 186-188
° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.94 (3H, s), 1.20 (6H, d, J
= 6.6 Hz), 1.41 (3H, s), 1.62 (3H, s), 2.10 (3H,
s), 2.26 (3H, s), 2.86 (1H, septet, J = 6.6 Hz),
4.14 (1H, s), 4.23-4.58 (2H, m), 6.40-7.42 (9H,
m), 10.4 (2H, br s).

Synthesis Example 7b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -4-methoxybenzamide 3- (4-isopropylphenyl) -2,2,4,6
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 4
2%. 202-205 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.21 (6H, d, J =
6.8 Hz), 1.49 (3H, s), 1.80 (3H, s), 2.18 (6H,
s), 2.85 (1H, septet, J = 6.8 Hz), 3.86 (3H, s),
4.13 (1H, s), 6.62-7.19 (6H, m), 7.23 (1H, s), 7.8
5 (2H, d, J = 9.2 Hz).

Synthesis Example 8b 3- (4-isopropylphenyl) -N- (4-methoxybenzyl) -2,2,4,6,7-pentamethyl-
2,3-dihydro-1-benzofuran-5-amine N- [3- (4-isopropylphenyl) -2,2,
The target product was synthesized according to Synthesis Example 2b using 4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -4-methoxybenzamide. yield
80%. 95-96 ° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.22 (6H, d, J =
6.8 Hz), 1.49 (3H, s), 1.6-1.7 (1H, br), 1.79 (3H,
s), 2.81 (3H, s), 2.27 (3H, s), 2.86 (1H, septet,
J = 6.8 Hz), 3.80 (3H, s), 3.86 (2H, s), 4.09 (1H,
s), 6.81-6.88 (4H, m), 7.06-7.11 (2H, m), 7.24-7.2
8 (2H, m).

Synthesis Example 9b 3- (4-Isopropylphenyl) -N- (4-methoxybenzyl) -N, 2,2,4,6,7-hexamethyl-2,3-dihydro-1-benzofuran-5- Amine Sodium hydride (60% liquid paraffin dispersion, 59
8.8 mg, 14.97 mmol) was washed twice with hexane, and then N, N-dimethylformamide (10 mL).
Was suspended. To this suspension was added 3- (4-isopropylphenyl) -N- (4-methoxybenzyl) -2,2,2.
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (998.9 mg, 2.25 m
mol) of N, N-dimethylformamide (30 mL)
After the solution was slowly added dropwise, the reaction mixture was heated at 60 ° C. for 30 minutes.
For a minute. Methyl iodide (2.19 g, 15.45 m
mol), and the mixture was further stirred at the same temperature for 30 minutes. After cooling the reaction solution to room temperature, water was added and the product was extracted using ethyl acetate. The extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 10: 1) to give the desired product (yield 69%) as a mixture of oily rotamers. ¹ H-NMR (CDCl ₃ ) δ: 0.97-1.00 (3H, m), 1.20-1.25 (6
H, m), 1.50 (3H, m), 1.83-1.88 (3H, m), 2.14-2.16
(3H, m), 2.27-2.28 (3H, m), 2.59-2.67 (3H, m), 2.8
0-2.94 (1H, m), 3.79-3.80 (3H, m), 4.03-4.06 (2H,
m), 4.08-4.10 (1H, m), 6.78-6.87 (4H, m), 7.06-7.3
0 (4H, m).

Synthesis Example 10b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -4-methoxyphenylacetamide 3- (4-isopropylphenyl) -2,2,4,6
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxyphenylacetyl chloride, the desired product was synthesized according to Synthesis Example 1b. Yield 74%. 171-173 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 1.20 (6H, d, J =
6.6 Hz), 1.46 (3H, s), 1.64 (3H, s), 2.03 (3H, s),
2.12 (3H, s), 2.84 (1H, septet, J = 6.6 Hz), 3.68
(2H, s), 3.80 (3H, s), 4.06 (1H, s), 6.45 (1H, b
r), 6.6-6.9 (2H, m), 6.89 (2H, d, J = 8.6 Hz), 7.05
(2H, d, J = 8.0 Hz), 7.26 (d, 2H, J = 8.6 Hz).

Synthesis Example 11b 3- (4-isopropylphenyl) -N- [2- (4-
Methoxyphenyl) ethyl] -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5
-Amine N- [3- (4-isopropylphenyl) -2,2,
Using 4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -4-methoxyphenylacetamide, the target compound was synthesized according to Synthesis Example 2b. Yield 66%. 63-65 ° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 1.21 (6H, d, J =
6.8 Hz), 1.46 (3H, s), 1.68 (3H, s), 1.8-1.9 (1H, b
r), 2.12 (3H, s), 2.14 (3H, s), 2.76-3.04 (5H, m),
3.78 (3H, s), 4.05 (1H, s), 6.6-7.0 (4H, m), 7.04
-7.08 (2H, m), 7.12-7.19 (2H, m).

Synthesis Example 12b 3- (4-isopropylphenyl) -N- [2- (4-
Methoxyphenyl) ethyl] -N, 2,2,4,6,7
-Hexamethyl-2,3-dihydro-1-benzofuran-5-amine 3- (4-isopropylphenyl) -N- [2- (4-
Methoxyphenyl) ethyl] -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5
-The target compound was synthesized according to Synthesis Example 9b using an amine. Yield 85%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.20-1.24 (6H,
m), 1.48-1.50 (3H, m), 1.77 (3H, s), 2.14-2.17 (6
H, m), 2.58-2.89 (6H, m), 3.1-3.2 (2H, m), 3.76-3.
77 (3H, m), 4.06-4.09 (1H, m), 6.74-6.90 (4H, m),
7.00-7.04 (4H, m).

Synthesis Example 13b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-Pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -N- [2- (4-methoxyphenyl) ethyl] acetamide sodium hydride (60% paraffin dispersion, 232.
(1 mg, 5.80 mmol) was washed twice with hexane, and then suspended in N, N-dimethylformamide (25 mL). Under an argon atmosphere,
(4-Isopropylphenyl) -N- [2- (4-methoxyphenyl) ethyl] -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (537.9 mg) , 1.18 mmol) and add 60
Stirred at 20 ° C. for 20 minutes. Acetyl chloride (0.5 mL,
7.03 mmol) and stirred at the same temperature for 1 hour.
After cooling the reaction mixture to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted twice with ethyl acetate. After washing the extract with water, drying over magnesium sulfate,
After filtration and concentration under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 3: 1),
The desired rotamer 1 (Rf = 0.38; hexane-ethyl acetate 3: 1) was obtained (46% yield). Melting point 13
4-136 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.54 (3H, s), 1.66 (3H, s), 1.72 (3H, s),
2.12 (3H, s), 2.18 (3H, s), 2.77-2.89 (3H, m), 3.59
-3.70 (2H, m), 3.77 (3H, s), 4.11 (1H, s), 6.77-7.
13 (8H, m).

Synthesis Example 14b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-Pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -N- [2- (4-methoxyphenyl) ethyl] acetamide The residue obtained in the same manner as in Synthesis Example 13b was subjected to silica gel column chromatography. Chromatography (hexane-ethyl acetate 3: 1)
To give the desired rotational isomer 2 (Rf = 0.25; hexane-ethyl acetate 3: 1) (yield 36%). Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.23 (6H, d, J =
6.8 Hz), 1.53 (3H, s), 1.73 (3H, s), 1.75 (3H, s),
2.12 (3H, s), 2.18 (3H, s), 2.67-2.75 (2H, m), 2.80
-2.94 (1H, septet, J = 6.8 Hz), 3.57-3.74 (2H, m),
3.77 (3H, s), 4.14 (1H, s), 6.77-7.13 (8H, m).

Synthesis Example 15b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -3- (4-methoxyphenyl) propionamide 3- (4-isopropylphenyl) -2,2,4,6
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 3- (4-methoxyphenyl) propionyl chloride, the desired product was synthesized according to Synthesis Example 1b. Yield 72%. 188-191 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 0.99-1.01 (3H, m), 1.19-1.26 (6
H, m), 1.48 (3H, s), 1.64-1.68 (3H, m), 1.99 (3H,
s), 2.05-2.13 (5H, m), 2.65-3.04 (3H, m), 3.72-3.7
7 (3H, m), 4.08 (1H, s), 6.47-7.19 (9H, m).

Synthesis Example 16b 3- (4-isopropylphenyl) -N- [3- (4-
Methoxyphenyl) propyl] -2,2,4,6,7-
Pentamethyl-2,3-dihydro-1-benzofuran-
5-amine N- [3- (4-isopropylphenyl) -2,2,
Using 4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -3- (4-methoxyphenyl) propionamide, the desired product was synthesized according to Synthesis Example 2b. Yield 99%. 62-65 ° C.
(Pentane) ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.21 (6H, d, J =
6.6 Hz), 1.48 (3H, s), 1.78-1.88 (6H, m), 2.15 (3H,
s), 2.20 (3H, s), 2.65 (2H, t, J = 7.6 Hz), 2.76
(3H, m), 3.78 (3H, s), 4.08 (1H, s), 6.6-6.8 (4H,
m), 7.05-7.12 (4H, m).

Synthesis Example 17b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -4-methoxybenzenesulfonamide 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (0.35 g, 1.08 mmol) and 4
-Methoxybenzenesulfonyl chloride (0.25 g,
1.19 mmol) in chloroform (5 mL) at room temperature in triethylamine (0.16 mL, 1.19 mmol).
l) was added and the mixture was stirred at room temperature for 14 hours. The solvent was concentrated under reduced pressure, water (20 mL) was poured into the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Concentrated. The residue was crystallized from ethyl acetate-hexane to obtain 0.18 g (yield 34%) of the desired product.
206-208 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.23 (6H, d, J =
6.8 Hz), 1.40 (3H, s), 1.47 (3H, s), 2.10 (3H,
s), 2.13 (3H, s), 2.87 (1H, septet, J = 6.8 Hz),
3.80 (3H, s), 3.90 (1H, s), 5.79 (1H, s), 6.70-7.1
5 (4H, m), 7.09 (2H, d, J = 8.4 Hz), 7.57 (2H, d,
J = 8.8 Hz).

Synthesis Example 18b 4-Fluoro-N- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] benzamide 3 -(4-isopropylphenyl) -2,2,4,6
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 6
5%. Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.21 (6H, d, J =
6.8 Hz), 1.41 (3H, s), 1.80 (3H, s), 2.17 (3H,
s), 2.19 (3H, s), 2.85 (1H, septet, J = 6.8 Hz),
4.13 (1H, s), 6.60-7.31 (7H, m), 7.89 (2H, dd, J =
8.8, 5.2 Hz).

Synthesis Example 19b N- (4-Fluorobenzyl) -3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-
Lithium aluminum hydride (340 mg, 9.00 mm) was added to a suspension of 2,3-dihydro-1-benzofuran-5-amine hydrochloride in aluminum chloride (1.20 g, 9.00 mmol) in tetrahydrofuran (25 mL) under ice-cooling.
ol) was added little by little and stirred at the same temperature for 10 minutes. To this mixture was added 4-fluoro-N- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,
[3-Dihydro-1-benzofuran-5-yl] benzamide (0.83 g, 1.86 mmol) was added and the mixture was heated under reflux for 3 hours. The reaction mixture was added to ice water, neutralized with 8N aqueous sodium hydroxide solution, and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and reduced in pressure. Concentration gave 0.51 g of an oily free base. The free base (0.51 g, 1.1
8 mmol) was dissolved in hydrochloric acid-methanol solution, the solvent was concentrated under reduced pressure, and the obtained residue was crystallized from methanol to obtain 0.49 g (yield: 56%) of the desired product. Melting point 2
01-204 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.92 (3H, s), 1.19 (6H, d, J
= 7.0 Hz), 1.40 (3H, s), 1.54 (3H, s), 2.10 (3H, s)
s), 2.31 (3H, s), 2.85 (1H, septet, J = 6.8 Hz),
4.13 (1H, s), 4.29 (1H, d, J = 12.8 Hz), 4.43 (1H,
d, J = 12.8 Hz), 6.20-7.40 (8H, m), 10.4 (2H, br
s).

Synthesis Example 20b 4-Chloro-N- [3- (4-isopropylphenyl)
-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] benzamide 3- (4-isopropylphenyl) -2,2,4,6
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-chlorobenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 71
%. 201-203 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.51 (3H, s), 1.80 (3H, s), 2.17 (3H,
s), 2.19 (3H, s), 2.85 (1H, septet, J = 6.8 Hz),
4.13 (1H, s), 6.62-7.13 (4H, m), 7.24 (1H, br s),
7.44 (2H, d, J = 8.8 Hz), 7.82 (2H, d, J = 8.8 H
z).

Synthesis Example 21b N- (4-chlorobenzyl) -3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,
3-dihydro-1-benzofuran-5-amine 4-chloro-N- [3- (4-isopropylphenyl)
Using 2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] benzamide, the target product was synthesized according to Synthesis Example 2b. Yield 37
%. 93-94 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.49 (3H, s), 1.58 (1H, br s), 1.74 (3H,
s), 2.18 (3H, s), 2.25 (3H, s), 2.86 (1H, septet,
J = 6.8 Hz), 3.89 (2H, s), 4.07 (1H, s), 6.63-7.1
2 (4H, m), 7.25 (4H, s).

Synthesis Example 22b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -1,3-benzodioxole-5-carboxamide 3- (4-isopropylphenyl) -2,2,4 , 6,
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 1,3-benzodioxole-5-carbonyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 67%. 165-167 ° C.
(Ethyl ether-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.51 (3H, s), 1.80 (3H, s), 2.17 (3H, s),
2.18 (3H, s), 2.85 (1H, septet, J = 7.0 Hz), 4.13
(1H, s), 6.03 (2H, s), 6.63-7.13 (5H, m), 7.17 (1
H, br s), 7.35-7.45 (2H, m).

Synthesis Example 23b N- (1,3-benzodioxol-5-ylmethyl)
-3- (4-Isopropylphenyl) -2,2,4
6,7-Pentamethyl-2,3-dihydro-1-benzofuran-5-amine Lithium aluminum hydride (240 mg, 6 mg) was added to a suspension of aluminum chloride (847 mg, 6.35 mmol) in tetrahydrofuran (10 mL) under ice cooling. .35mm
ol) was added little by little and stirred at the same temperature for 10 minutes. This mixture was added to N- [3- (4-isopropylphenyl)-
2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -1,3-benzodioxole-5-carboxamide (0.60 g, 1.2
7 mmol) and heated under reflux for 3 hours. The reaction mixture was added to ice water, neutralized with 8N aqueous sodium hydroxide solution, and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and reduced in pressure. Concentrated. The residue was crystallized from methanol to obtain 0.23 g of the desired product (yield: 40%). Melting point 100-1
02 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.49 (3H, s), 1.80 (3H, s), 1.86 (1H, br
s), 2.17 (3H, s), 2.26 (3H, s), 2.86 (1H, septet,
J = 7.0 Hz), 3.82 (2H, s), 4.08 (1H, s), 5.93 (2H,
s), 6.62-7.00 (5H, m), 7.08 (2H, d, J = 8.0 Hz).

Synthesis Example 24b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -2-thiophencarboxamide 3- (4-isopropylphenyl) -2,2,4,6
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 2-thiophenecarbonyl chloride, the target compound was synthesized according to Synthesis Example 1b. yield
66%. 222-224 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.51 (3H, s), 1.82 (3H, s), 2.19 (6H, s),
2.85 (1H, septet, J = 7.0 Hz), 4.13 (1H, s), 6.70-
7.20 (6H, m), 7.50 (1H, dd, J = 4.8, 1.2 Hz), 7.63
(1H, dd, J = 3.6, 1.2 Hz).

Synthesis Example 25b 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-N- (2-thienylmethyl) -2,
3-dihydro-1-benzofuran-5-amine N- [3- (4-isopropylphenyl) -2,2,
Using 4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -2-thiophencarboxamide, the target compound was synthesized according to Synthesis Example 2b.
Yield 61%. Melting point 101-103 <0> C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.49 (3H, s), 1.80 (3H, s), 3.00-2.40 (7H,
m), 2.86 (1H, septet, J = 7.0 Hz), 4.08 (1H, s),
4.11 (2H, s), 6.71-7.30 (7H, m).

Synthesis Example 26b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] nicotinamide 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (0.85 g, 2.63 mmol) and nicotinoyl chloride hydrochloride (516 mg, 2.90 mm)
ol) in chloroform (15 mL) was added at room temperature with triethylamine (0.80 mL, 5.80 mmol) and stirred at room temperature for 30 minutes. The solvent was concentrated under reduced pressure, water (30 mL) was poured into the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-
0.72 g (yield)
61%). 214-216 ° C. (Ethyl ether-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.52 (3H, s), 1.82 (3H, s), 2.19 (6H, s),
2.86 (1H, septet, J = 7.0 Hz), 4.14 (1H, s), 6.70-
7.13 (4H, m), 7.31 (1H, br s), 7.44 (1H, dd, J =
7.8, 4.8 Hz), 8.23 (1H, dt, J = 8.0, 2.2 Hz), 8.74
-8.79 (1H, m), 9.12 (1H, br s).

Synthesis Example 27b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] isonicotinamide hydrochloride 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (0.85 g, 2.63 mmol) and isonicotinoyl chloride hydrochloride (516 mg, 2.90)
(mmol) of chloroform (15 mL) at room temperature was added with triethylamine (0.80 mL, 5.80 mmol), and the mixture was stirred at room temperature for 30 minutes. The solvent was concentrated under reduced pressure, water (30 mL) was poured into the residue, and the mixture was extracted twice with ethyl acetate.
The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 5: 1) to obtain 0.9 g of an oily free base.
0 g was obtained. This free base (0.90 g, 2.10 mm
ol) was dissolved in hydrochloric acid-methanol solution, and the solvent was concentrated under reduced pressure to obtain 0.47 g (yield: 64%) of an amorphous target product. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.19 (6H, d, J =
6.8 Hz), 1.49 (3H, s), 1.80 (3H, s), 2.14 (6H, s),
2.83 (1H, septet, J = 6.8 Hz), 4.13 (1H, s), 6.70-
7.19 (5H, m), 8.20-9.20 (4H, m), 9.79 (1H, br s).

Synthesis Example 28b N- [3- (4-fluorophenyl) -2,2,4
6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -4-methoxybenzamide 3- (4-fluorophenyl) -2,2,4,6,7-
Pentamethyl-2,3-dihydro-1-benzofuran-
Using 5-amine and 4-methoxybenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 79
%. Melting point 191-194 [deg.] C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.51 (3H, s), 1.7
9 (3H, s), 2.17 (3H, s), 2.20 (3H, s), 3.86 (3H,
s), 4.14 (1H, s), 6.60-7.21 (7H, m), 7.85 (2H, d,
J = 8.8 Hz).

Synthesis Example 29b 3- (4-Fluorophenyl) -N- (4-methoxybenzyl) -2,2,4,6,7-pentamethyl-2,3
-Dihydro-1-benzofuran-5-amine N- [3- (4-fluorophenyl) -2,2,4
The target product was synthesized according to Synthesis Example 2b using 6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -4-methoxybenzamide. Yield 52
%. 114-115 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.49 (3H, s), 1.7
6 (3H, s), 2.18 (3H, s), 2.27 (3H, s), 2.80 (1H, b
rs), 3.79 (3H, s), 3.85 (2H, s), 4.08 (1H, s), 6.7
1-7.03 (6H, m), 7.20-7.27 (2H, m).

Synthesis Example 30b 4-Fluoro-N- [3- (4-fluorophenyl)-
2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] benzamide 3- (4-fluorophenyl) -2,2,4,6,7-
Pentamethyl-2,3-dihydro-1-benzofuran-
Using 5-amine and 4-fluorobenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 75
%. 140-142 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.52 (3H, s), 1.8
0 (3H, s), 2.19 (6H, s), 4.14 (1H, s), 6.75-7.25
(7H, m), 7.85-7.94 (2H, m).

Synthesis Example 31b N- (4-fluorobenzyl) -3- (4-fluorophenyl) -2,2,4,6,7-pentamethyl-2,3
-Dihydro-1-benzofuran-5-amine 4-fluoro-N- [3- (4-fluorophenyl)-
Using 2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] benzamide, the target compound was synthesized according to Synthesis Example 2b. Yield 66
%. 118-120 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.49 (3H, s), 1.7
7 (3H, s), 2.18 (3H, s), 2.26 (3H, s), 2.92 (1H, b
rs), 3.88 (2H, s), 4.08 (1H, s), 6.50-7.21 (6H,
m), 7.24-7.41 (2H, m).

Synthesis Example 32b 4-methoxy-N- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-
1-benzofuran-5-yl] benzamide 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
Using an amine and 4-methoxybenzoyl chloride,
The target compound was synthesized according to Synthesis Example 1b. 86% yield.
Melting point 161-163 <0> C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.51 (3H, s), 1.7
9 (3H, s), 2.18 (6H, s), 2.30 (3H, s), 3.86 (3H,
s), 4.12 (1H, s), 6.58-7.11 (6H, m), 7.20 (1H, br
s), 7.85 (2H, d, J = 8.8 Hz).

Synthesis Example 33b N- (4-methoxybenzyl) -2,2,4,6,7-
Pentamethyl-3- (4-methylphenyl) -2,3-
Dihydro-1-benzofuran-5-amine 4-methoxy-N- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-
1-benzofuran-5-yl] benzamide,
The target compound was synthesized according to Synthesis Example 2b. Yield 58%.
97-98 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.49 (3H, s), 1.7
8 (3H, s), 2.18 (3H, s), 2.26 (3H, s), 2.31 (3H, s)
s), 2.60 (1H, br s), 3.79 (3H, s), 3.85 (2H, s), 4.
08 (1H, s), 6.58-7.38 (8H, m).

Synthesis Example 34b 4-Fluoro-N- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-
1-benzofuran-5-yl] benzamide 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
Using an amine and 4-fluorobenzoyl chloride,
The target compound was synthesized according to Synthesis Example 1b. Yield 43%.
148-120 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.52 (3H, s), 1.8
0 (3H, s), 2.19 (6H, s), 2.30 (3H, s), 4.13 (1H,
s), 6.60-7.20 (7H, m), 7.85-7.94 (2H, m).

Synthesis Example 35b N- (4-Fluorobenzyl) -2,2,4,6,7-
Pentamethyl-3- (4-methylphenyl) -2,3-
Dihydro-1-benzofuran-5-amine 4-fluoro-N- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-
1-benzofuran-5-yl] benzamide,
The target compound was synthesized according to Synthesis Example 2b. Yield 39%.
92-94 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.49 (3H, s), 1.7
7 (3H, s), 2.18 (3H, s), 2.25 (3H, s), 2.31 (3H,
s), 2.82 (1H, br s), 3.87 (2H, s), 4.07 (1H, s), 6.
60-7.32 (8H, m).

Synthesis Example 36b 4-[[3- (4-Isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-ylamino] carbonyl] methyl benzoate 3- (4-isopropylphenyl) -2,2,4,6
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxycarbonylbenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 92%. 220-223 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.52 (3H, s), 1.82 (3H, s), 2.19 (6H, s),
2.85 (1H, septet, J = 7.0 Hz), 3.95 (3H, s), 4.14
(1H, s), 6.88 (2H, br s), 7.07-7.11 (2H, m), 7.30
(1H, s), 7.92-7.96 (2H, m), 8.11-8.16 (2H, m).

Synthesis Example 37b 4-[[3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-ylamino] carbonyl] benzoic acid 4-[[3- (4-isopropylphenyl) -2,2
4,6,7-Pentamethyl-2,3-dihydro-1-benzofuran-5-ylamino] carbonyl] methylbenzoate (341.7 mg, 0.70 mmol) in tetrahydrofuran (10 mL) and methanol (2.5 m
L) solution was added to a 1N aqueous sodium hydroxide solution (0.75
mL, 0.75 mmol) and stirred at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and the product was extracted twice with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give the desired product (60% yield). 258-261 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (3H, s), 1.17 (6H, d, J
= 7.0 Hz), 1.47 (3H, s), 1.71 (3H, s), 2.07 (3H, s)
s), 2.13 (3H, s), 2.84 (1H, septet, J = 7.0 Hz),
4.24 (1H, s), 6.90 (2H, br), 7.15 (2H, d, J = 7.6
Hz), 8.04 (4H, s), 9.47 (1H, s), 1H Not confirmed.

Synthesis Example 38b 5- (4-methoxybenzylamino) -2,4,6,7
-Tetramethyl-3-phenyl-1-benzofuran hydrochloride 2,4,6,7-tetramethyl-3-phenyl-1-benzofuran-5-amine (0.50 g, 1.88 mmol)
l) and 4-methoxybenzaldehyde (282 mg,
2.07 mmol) in methanol (15 mL) at room temperature in sodium cyanoborohydride (130 mg, 2.
07 mmol) and stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, the residue was neutralized with a 1N aqueous sodium hydroxide solution, and extracted twice with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 0.37 g of an oily free base. The free base (0.3
(7 g, 0.96 mmol) was dissolved in a hydrochloric acid-methanol solution, the solvent was concentrated under reduced pressure, and the obtained residue was crystallized from methanol to obtain 0.21 g (yield 27%) of the desired product. 200-203 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.97 (3H, s), 2.30 (3H, s), 2.3
4 (3H, s), 2.37 (3H, s), 3.73 (3H, s), 4.53 (3H,
s), 6.69 (2H, d, J = 8.4 Hz), 7.11-7.25 (4H, m), 7.
32-7.37 (3H, m), 1H Not confirmed.

Synthesis Example 39b 4-Fluoro-N- (2,4,6,7-tetramethyl-
3-Phenyl-1-benzofuran-5-yl) benzamide Using 2,4,6,7-tetramethyl-3-phenyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride according to Synthesis Example 1b Was synthesized.
Yield 80%. Melting point 242-245 [deg.] C. (Ethyl acetate-
Hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.96 (3H, s), 2.25 (3H, s), 2.3
2 (3H, s), 2.45 (3H, s), 7.04-7.14 (2H, m), 7.24-
7.50 (6H, m), 7.84-7.93 (2H, m).

Synthesis Example 40b N- (4-Fluorobenzyl) -2,4,6,7-tetramethyl-3-phenyl-1-benzofuran-5-amine 4-fluoro-N- (2,4,6, 7-tetramethyl-
Using 3-phenyl-1-benzofuran-5-yl) benzamide, the target compound was synthesized according to Synthesis Example 2b.
Yield 56%. 135-136 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 2.00 (3H, s), 2.30 (3H, s), 2.3
5 (3H, s), 2.45 (3H, s), 3.08 (1H, br s), 3.92 (2
H, s), 6.95-7.06 (2H, m), 7.28-7.47 (7H, m).

Synthesis Example 41b N- [3- (4-isopropylphenyl) -2,4,
6,7-tetramethyl-1-benzofuran-5-yl]
-Benzamide 3- (4-isopropylphenyl) -2,4,6,7-
Using tetramethyl-1-benzofuran-5-amine and benzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 91%. 225-227 ° C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J = 7.0 Hz), 2.01
(3H, s), 2.30 (3H, s), 2.33 (3H, s), 2.47 (3H, s),
2.95 (1H, septet, J = 7.0 Hz), 7.25 (4H, s), 7.39
(1H, br s), 7.41-7.62 (3H, m), 7.88-7.97 (2H, m).

Synthesis Example 42b N-benzyl-3- (4-isopropylphenyl)-
2,4,6,7-tetramethyl-1-benzofuran-5
-Amine N- [3- (4-isopropylphenyl) -2,4,
6,7-tetramethyl-1-benzofuran-5-yl]
-Using benzamide, the target product was synthesized according to Synthesis Example 2b. Yield 55%. 94-95 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 7.0 Hz), 1.95
(1H, br s), 2.04 (3H, s), 2.31 (3H, s), 2.37 (3H,
s), 2.45 (3H, s), 2.97 (1H, septet, J = 7.0Hz), 3.
96 (2H, s), 7.23-7.44 (9H, m).

Synthesis Example 43b [N- [3- (4-isopropylphenyl) -2,4,
6,7-tetramethyl-1-benzofuran-5-yl]]-4-methoxybenzamide 3- (4-isopropylphenyl) -2,4,6,7-
Using tetramethyl-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 49%. Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J = 7.0 Hz), 1.99
(3H, s), 2.28 (3H, s), 2.32 (3H, s), 2.46 (3H, s)
s), 2.95 (1H, septet, J = 7.0 Hz), 3.86 (3H, s),
6.95 (2H, d, J = 8.8 Hz), 7.24 (4H, s), 7.33 (1H,
br s), 7.88 (2H, d, J = 8.8 Hz).

Synthesis Example 44b [N- [3- (4-isopropylphenyl) -2,4,
6,7-tetramethyl-1-benzofuran-5-yl]]-4-methoxyphenylacetamide 3- (4-isopropylphenyl) -2,4,6,7-
Synthesis Example 1b using tetramethyl-1-benzofuran-5-amine and 4-methoxyphenylacetyl chloride
Was synthesized according to the procedure. Yield 42%. Melting point 202
-204 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 7.0 Hz), 1.84
(3H, s), 2.13 (3H, s), 2.28 (3H, s), 2.40 (3H,
s), 2.95 (1H, septet, J = 7.0 Hz), 3.72 (2H, s),
3.81 (3H, s), 6.58 (1H, br s), 6.92 (2H, d, J = 8.
8 Hz), 7.20-7.33 (6H, m).

Synthesis Example 45b 3- (4-Isopropylphenyl) -N- (4-methoxybenzyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine hydrochloride [N- [3- (4-isopropylphenyl) -2,4
6,7-tetramethyl-1-benzofuran-5-yl]]-4-methoxyphenylacetamide,
The target compound was synthesized according to Synthesis Example 6b. Yield 87%.
Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 7.0 Hz), 2.00
(3H, s), 2.30 (3H, s), 2.32 (3H, s), 2.35 (3H,
s), 2.94 (1H, septet, J = 7.0 Hz), 3.72 (3H, s),
4.53 (2H, s), 6.68-6.72 (4H, m), 7.07-7.25 (4H,
m), 10.9 (1H, br s), 1H Not confirmed.

Synthesis Example 46b 4-Fluoro-N- [3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-yl] benzamide 3- (4-isopropylphenyl) −2,4,6,7−
Using tetramethyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 72%. Melting point 242-24
5 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 7.0 Hz), 1.98
(3H, s), 2.26 (3H, s), 2.33 (3H, s), 2.45 (3H, s),
2.95 (1H, septet, J = 7.0 Hz), 7.06-7.17 (2H, m),
7.24 (4H, s), 7.39 (1H, br s), 7.86-7.95 (2H, m).

Synthesis Example 47b N- (4-Fluorobenzyl) -3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine Aluminum chloride (807 mg, 6.05 mmol) ) In a suspension of lithium aluminum hydride (230 mg, 6.05 mm) under ice-cooling.
ol) was added little by little and stirred at the same temperature for 10 minutes. To this mixture was added 4-fluoro-N- [3- (4-isopropylphenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-yl] benzamide (0.52 g, 1.
21 mmol) and heated under reflux for 3 hours. The reaction mixture was added to ice water, neutralized with 8N aqueous sodium hydroxide, and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered,
It was concentrated under reduced pressure. The residue was crystallized from ethanol to obtain 0.27 g of the desired product (yield 54%). Melting point 95-9
7 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (6H, d, J = 7.0 Hz), 1.98
(1H, br s), 2.02 (3H, s), 2.31 (3H, s), 2.34 (3H,
s), 2.45 (3H, s), 2.96 (1H, septet, J = 7.0Hz), 3.
92 (2H, s), 6.95-7.06 (2H, m), 7.24-7.40 (6H, m).

Synthesis Example 48b N- [3- (4-fluorophenyl) -2,4,6,7
-Tetramethyl-1-benzofuran-5-yl] -4-
Methoxybenzamide Using 3- (4-fluorophenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 75%. Melting point 225-227
° C. (Ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 1.96 (3H, s), 2.27 (3H, s), 2.3
0 (3H, s), 2.45 (3H, s), 3.86 (3H, s), 6.95 (2H,
d, J = 8.8 Hz), 7.03-7.13 (2H, m), 7.24-7.36 (3H,
m), 7.88 (2H, d, J = 8.8 Hz).

Synthesis Example 49b N- (4-methoxybenzyl) -3- (4-fluorophenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine N- [3- (4- Fluorophenyl) -2,4,6,7
-Tetramethyl-1-benzofuran-5-yl] -4-
The target compound was synthesized using methoxybenzamide according to Synthesis Example 2b. Yield 75%. Melting point 100-102
° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 2.01 (3H, s), 2.20-2.60 (10H,
m), 3.81 (3H, s), 3.89 (2H, s), 6.87 (2H, d, J = 8.
8 Hz), 7.05-7.16 (2H, m), 7.23-7.34 (4H, m).

Synthesis Example 50b 4-Fluoro-N- [3- (4-fluorophenyl)-
2,4,6,7-tetramethyl-1-benzofuran-5
-Yl] benzamide Using 3- (4-fluorophenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the desired product was synthesized according to Synthesis Example 1b. . Yield 75%. Melting point 232-234
° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.97 (3H, s), 2.28 (3H, s), 2.3
1 (3H, s), 2.46 (3H, s), 7.03-7.37 (7H, m), 7.86-
7.98 (2H, m).

Synthesis Example 51b N- (4-fluorobenzyl) -3- (4-fluorophenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine 4-fluoro-N- [3 -(4-fluorophenyl)-
2,4,6,7-tetramethyl-1-benzofuran-5
[-Yl] benzamide was used to synthesize the desired product according to Synthesis Example 2b. Yield 66%. Melting point 107-109
° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.87 (1H, br s), 1.99 (3H, s),
2.28 (3H, s), 2.34 (3H, s), 2.45 (3H, s), 3.92 (2
H, s), 6.94-7.13 (4H, m), 7.20-7.43 (4H, m).

Synthesis Example 52b N- [3- (4-isopropylphenyl) -1 ′, 4,
6,7-tetramethylspiro [benzofuran-2 (3
H), 4'-Piperidin] -5-yl] -4-methoxybenzamide 3- (4-isopropylphenyl) -1 ', 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
Synthesis Example 1b using 4′-piperidine] -5-amine
Was synthesized according to the procedure. Yield 40%. Melting point 277
-278 ° C. (Ethanol-isopropyl ether) ¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 7.0 Hz), 1.35-
1.45 (2H, m), 1.81 (3H, s), 2.18-2.91 (16H, m), 3.
86 (3H, s), 4.09 (1H, s), 6.6-7.1 (6H, m), 7.19 (1
H, br), 7.83-7.88 (2H, m).

Synthesis Example 53b 3- (4-isopropylphenyl) -N- (4-methoxybenzyl) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4′-piperidine]- 5
-Amine N- [3- (4-isopropylphenyl) -1 ′, 4,
6,7-tetramethylspiro [benzofuran-2 (3
H) Using 4'-piperidin] -5-yl] -4-methoxybenzamide, the target compound was synthesized according to Synthesis Example 2b. Yield 59%. Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 7.0 Hz), 1.3-
1.4 (2H, m), 1.79 (3H, s), 1.8-2.0 (3H, m), 2.21 (3
H, s), 2.27 (3H, s), 2.31 (3H, s), 2.4-2.7 (4H,
m), 2.85 (1H, septet, J = 7.0 Hz), 3.79 (3H, s),
3.85 (2H, s), 4.05 (1H, s), 6.6-7.1 (6H, m), 7.23-
7.27 (2H, m).

Synthesis Example 54b 4-Fluoro-N- [3- (4-isopropylphenyl) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4′-piperidine] -5 Il]
Benzamide 3- (4-isopropylphenyl) -1 ′, 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
Using 4'-piperidine] -5-amine and 4-fluorobenzoyl chloride, the target product was synthesized according to Synthesis Example 1b. Yield 38%. 271-272 ° C. (Methanol-isopropyl ether) ¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 7.0 Hz), 1.30-
1.40 (2H, m), 1.81 (3H, s), 2.02-2.12 (2H, m), 2.1
8 (3H, s), 2.22 (3H, s), 2.30 (3H, s), 2.37-2.71
(4H, m), 2.85 (1H, septet, J = 7.0 Hz), 4.10 (1H,
s), 6.6-7.2 (6H, m), 7.24 (1H, br), 7.86-7.93 (2H,
m).

Synthesis Example 55b N- (4-Fluorobenzyl) -3- (4-isopropylphenyl) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4′-piperidine]- 5
-Amine 4-fluoro-N- [3- (4-isopropylphenyl) -1 ', 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4'-piperidin] -5-yl]
The target compound was synthesized using benzamide according to Synthesis Example 2b. Yield 83%. Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 7.0 Hz), 1.34-
1.42 (2H, m), 1.75 (3H, s), 1.80-2.05 (3H, m), 2.2
1 (3H, s), 2.26 (3H, s), 2.31 (3H, s), 2.35-2.72
(4H, m), 2.85 (1H, septet, J = 7.0 Hz), 3.87 (2H,
s), 4.04 (1H, s), 6.5-7.1 (6H, m), 7.23-7.30 (2H,
m).

Synthesis Example 56b 4-chloro-N- [3- (4-isopropylphenyl)
-1 ', 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4'-piperidin] -5-yl] benzamide 3- (4-isopropylphenyl) -1', 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
Using 4'-piperidine] -5-amine and 4-chlorobenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 58%. 293-295 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.09 (6H, d, J = 7.0 Hz), 1.3-
1.4 (2H, m), 1.7-2.7 (18H, m), 2.84 (1H, septet, d
= 7.0 Hz), 4.09 (1H, s), 6.6-7.1 (4H, m), 7.33 (1
H, br), 7.40-7.44 (2H, m), 7.79-7.83 (2H, m).

Synthesis Example 57b N- (4-chlorobenzyl) -3- (4-isopropylphenyl) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4′-piperidine]- 5
-Amine 4-chloro-N- [3- (4-isopropylphenyl)
Using -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4′-piperidin] -5-yl] benzamide, the target product was synthesized according to Synthesis Example 2b. Yield 96%. Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.22 (6H, d, J = 7.0 Hz), 1.3-
1.4 (2H, m), 1.74 (3H, s), 1.8-2.1 (3H, m), 2.21 (3
H, s), 2.25 (3H, s), 2.30 (3H, s), 2.34-2.69 (4H,
m), 2.86 (1H, septet, J = 7.0 Hz), 3.83 (2H, s),
4.04 (1H, s), 6.6-7.1 (4H, m), 7.24 (4H, s).

Synthesis Example 58b N- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -3,4-dimethoxybenzamide 3- (4-isopropylphenyl) -2,2,4,6
Using 7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 3,4-dimethoxybenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 71%. 171-173 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.52 (3H, s), 1.82 (3H, s), 2.19 (6H, s),
2.85 (1H, septet, J = 7.0 Hz), 3.938 (3H, s), 3.94
3 (3H, s), 4.13 (1H, s), 6.80-7.00 (3H, m), 7.09
(2H, d, J = 7.6Hz), 7.22 (1H, br s), 7.42 (1H, dd,
J = 8.4, 2.2 Hz), 7.52 (1H, d, J = 2.2 Hz).

Synthesis Example 59b N- (3,4-dimethoxybenzyl) -3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5- Amine hydrochloride N- [3- (4-isopropylphenyl) -2,2,
Using 4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl] -3,4-dimethoxybenzamide, the target compound was synthesized according to Synthesis Example 6b.
Yield 76%. 181-184 ° C. (Ethanol-
Hexane) ¹ H-NMR (DMSO-d ₆ ) δ: 0.92 (3H, s), 1.19 (6H, d, J
= 7.0 Hz), 1.42 (3H, s), 1.69 (3H, s), 2.10 (3H, s)
s), 2.22 (3H, s), 2.85 (1H, septet, J = 7.0 Hz),
3.66 (3H, s), 3.75 (3H, s), 4.17 (1H, s), 4.20-4.4
2 (2H, m), 6.40-6.90 (5H, m), 7.13 (2H, d, J = 7.4
Hz), 10.0 (1H, br s), 1H Not confirmed.

Synthesis Example 60b (+)-4-Fluoro-N- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,
3-dihydro-1-benzofuran-5-yl] benzamide (+)-3- (4-isopropylphenyl) -2,2.
Using 4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b.
Yield 91%. Melting point 251-253 [deg.] C. (Ethyl acetate-
Hexane) [α] D = + 74.4 ° (c = 0.501,
Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.19 (6H, d, J =
6.8 Hz), 1.50 (3H, s), 1.78 (3H, s), 2.15 (3H,
s), 2.17 (3H, s), 2.83 (1H, septet, J = 6.8 Hz),
4.12 (1H, s), 6.60-7.40 (7H, m), 7.80-7.91 (2H,
m).

Synthesis Example 61b (+)-N- (4-Fluorobenzyl) -3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran- 5-Amine hydrochloride Lithium aluminum hydride (190 mg, 5.05 mm) was added to a suspension of aluminum chloride (0.67 g, 5.05 mmol) in tetrahydrofuran (15 mL) under ice cooling.
ol) was added little by little and stirred at the same temperature for 10 minutes. This mixture was added to (+)-4-fluoro-N- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl].
Benzamide (0.45 g, 1.01 mmol) was added, and the mixture was heated under reflux for 3 hours. The reaction mixture was added to ice water, neutralized with 8N aqueous sodium hydroxide solution, and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and reduced in pressure. Concentration gave 0.29 g of oily free base. The free base (0.29 g,
0.67 mmol) in a hydrochloric acid-methanol solution,
The solvent was concentrated under reduced pressure, and the obtained residue was crystallized from methanol to obtain 0.27 g of the desired product (yield: 56%). 158-160 ° C. [Α] D = + 70.7 ° (c =
0.461, methanol) ¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (3H, s), 1.20 (6H, d, J
= 6.6 Hz), 1.41 (3H, s), 1.55 (3H, s), 2.11 (3H,
s), 2.31 (3H, s), 2.85 (1H, septet, J = 6.6 Hz),
4.13 (1H, s), 4.31 (1H, d, J = 12.8 Hz), 4.45 (1H,
d, J = 12.8 Hz), 7.02-7.29 (8H, m), 10.3 (1H, br
s), 10.8 (1H, br s).

Synthesis Example 62b (-)-4-Fluoro-N- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,
3-dihydro-1-benzofuran-5-yl] benzamide (-)-3- (4-isopropylphenyl) -2,2,
Using 4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b.
Yield 91%. 253-254 ° C. [Α] D = -7
7.4 ° (c = 0.500, methanol). ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.51 (3H, s), 1.81 (3H, s), 2.18 (6H,
s), 2.85 (1H, septet, J = 7.0 Hz), 4.13 (1H, s),
6.8-7.4 (7H, m), 7.86-7.93 (2H, m).

Synthesis Example 63b (-)-N- (4-Fluorobenzyl) -3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran- 5-Amine hydrochloride Lithium aluminum hydride (101 mg, 2.67 mm) was added to a suspension of aluminum chloride (351 mg, 2.63 mmol) in tetrahydrofuran (35 mL) under ice-cooling.
ol) was added little by little and stirred at the same temperature for 10 minutes. This mixture was added to (-)-4-fluoro-N- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl].
Benzamide (528 mg, 1.19 mmol) was added, and the mixture was heated under reflux for 2 hours. The reaction mixture was added to ice water, neutralized with 8N aqueous sodium hydroxide solution, and the product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and reduced in pressure. Concentration gave 502 mg of the oily free base. This free base (502 mg,
1.17 mmol) in a hydrochloric acid-methanol solution,
The solvent was concentrated under reduced pressure, and the obtained residue was crystallized from methanol to obtain 115 mg (yield: 21%) of the desired product. 148-151 ° C. [Α] D = -70.5 ° (c =
0.503, methanol). ¹ H-NMR (DMSO-d ₆ ) δ: 0.92 (3H, s), 1.19 (6H, d, J
= 6.8 Hz), 1.41 (3H, s), 1.54 (3H, s), 2.11 (3H,
s), 2.32 (3H, s), 2.85 (1H, septet, J = 6.8Hz), 4.
16 (1H, s), 4.29-4.45 (2H, m), 6.6-7.4 (8H, m), 1
0.2-10.6 (2H, m).

Synthesis Example 64b 3,4-Dimethoxy-N- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] Benzamide 2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5
Using -amine and 3,4-dimethoxybenzoyl chloride, the target compound was synthesized according to Synthesis Example 1b. Yield 9
0%. Melting point 169-171 [deg.] C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.51 (3H, s), 1.8
0 (3H, s), 2.19 (6H, s), 2.29 (3H, s), 3.92 (6H,
s), 4.13 (1H, s), 6.60-7.20 (5H, m), 7.29 (1H, br
s), 7.42 (1H, dd, J = 8.2, 2.0 Hz), 7.51 (1H, d, J
= 2.0 Hz).

Synthesis Example 65b N- (3,4-dimethoxybenzyl) -2,2,4
6,7-pentamethyl-3- (4-methylphenyl)-
2,3-dihydro-1-benzofuran-5-amine hydrochloride 3,4-dimethoxy-N- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro Using -1-benzofuran-5-yl] benzamide, the desired product was synthesized according to Synthesis Example 6b. Yield 6
8%. 195-198 ° C. (Ethanol-hexane) ¹ H-NMR (DMSO-d ₆ ) δ: 0.93 (3H, s), 1.41 (3H, s),
1.65 (3H, s), 2.10 (3H, s), 2.23 (3H, s), 2.27 (3H, s)
s), 3.66 (3H, s), 3.73 (3H, s), 4.16 (1H, s), 4.2
3 (1H, d, J = 12.4 Hz), 4.35 (1H, d, J = 12.4 Hz),
6.40-6.82 (5H, m), 7.08 (2H, d, J = 7.0 Hz), 10.2
(1H, br s), 1H Not confirmed.

Synthesis Example 66b N- [2,2,4,6,7-pentamethyl-3- (4-
Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -1,3-benzodioxole-5-carboxamide 2,2,4,6,7-pentamethyl-3- (4-methyl Phenyl) -2,3-dihydro-1-benzofuran-5
Using -amine and 1,3-benzodioxole-5-carbonyl chloride, the desired product was synthesized according to Synthesis Example 1b. Yield 65%. 164-165 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.51 (3H, s), 1.7
9 (3H, s), 2.17 (3H, s), 2.18 (3H, s), 2.30 (3H, s)
s), 4.12 (1H, s), 6.03 (2H, s), 6.62-7.12 (5H, m),
7.16 (1H, br s), 7.34-7.45 (2H, m).

Synthesis Example 67b N- (1,3-benzodioxol-5-ylmethyl)
-2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-
5-amine hydrochloride N- [2,2,4,6,7-pentamethyl-3- (4-
Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -1,3-benzodioxole-5-carboxamide was used to synthesize the desired product according to Synthesis Example 6b. Yield 62%. 147-149 ° C. (Ethanol-hexane) ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.42 (3H, s), 1.7
2 (3H, s), 2.10 (3H, s), 2.25 (3H, s), 2.27 (3H, s)
s), 4.17 (1H, s), 4.28 (2H, s), 5.97 (1H, s), 6.01
(1H, s), 6.40-7.18 (8H, m), 10.2 (1H, br s). The chemical structural formula of the compound obtained in the above synthesis example is shown below.

[0172]

[Table 3]

[0173]

[Table 4]

[0174]

[Table 5]

[0175]

[Table 6]

[0176]

[Table 7]

Formulation Example 1b (1) Compound obtained in Synthesis Example 19b 50 mg (2) Lactose 34 mg (3) Maize starch 10.6 mg (4) Maize starch (paste-like) 5 mg (5) Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg The above (1) to (6) are mixed according to a conventional method, and the mixture is tableted with a tableting machine to produce tablets.

[Compound (Ic)] Reference Example 1c Concentrated sulfuric acid (0.5 mL) was added to a solution of α-bromophenylacetic acid (3.00 g, 13.9 mmol) in ethanol (30 mL) at room temperature.
The mixture was heated under reflux for 1 hour. After cooling the reaction mixture, add 2
It was extracted twice, and the combined organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2.50 g (yield 79%) of the desired product. Oil. ¹ H-NMR (CDCl ₃ ) δ: 3.78 (3H, s), 5.36 (1H, s), 7.2
9-7.42 (3H, m), 7.48-7.61 (2H, m). Reference Example 2c 1-bromo-4- (4-morpholinyl) benzene (4-morpholinyl) benzene (10.0 g, 61.3 mmol)
In ethanol (100 mL) at 0 ° C was added bromine (10.8 g,
67.4 mmol) and stirred at room temperature for 1 hour. Pour water (100 mL) into the reaction mixture, extract twice with ethyl acetate, and combine the combined organic layers with saturated aqueous sodium hydrogen carbonate solution.
After washing with water, it was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give 10.7 g (yield 72%) of the desired product. 118-120 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.98-3.22 (4H, m), 3.71-3.92 (4
H, m), 6.72-6.83 (2H, m), 7.31-7.42 (2H, m). Reference Example 3c 1-bromo-4- (4-methyl-1-piperazinyl) benzene 1-phenylpiperazine (10.0 g, 61.6 mmol) of N,
To a solution of N-dimethylformamide (80 mL) at 0 ° C was added sodium hydride (60% liquid paraffin dispersion, 2.70 g,
67.8 mmol) and stirred at the same temperature for 10 minutes. Iodomethane (8.74 g, 67.8 mmol) was added to the reaction solution, and
Stirred for 0 minutes. The reaction mixture was poured into water (80 mL), extracted twice with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was crystallized from hexane-isopropyl ether to give 7.40 g of 1-methyl-4-phenylpiperazine. Add 0 ° C to a solution of this compound in ethanol (80 mL).
Then, bromine (7.00 g, 43.8 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Water (80 mL) was poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 8.1 g of the desired product (yield: 52%). Melting point 78-
80 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.35 (3H, s), 2.52-2.63 (4H,
m), 3.13-3.26 (4H, m), 6.78 (2H, d, J = 8.8 Hz),
7.33 (2H, d, J = 8.8 Hz).

Reference Example 4c 2-Methyl-1- [4- (4-morpholinyl) phenyl] propan-1-one 1-bromo-4- (4-morpholinyl) benzene (10.0
g, 41.3 mmol) in tetrahydrofuran (100 mL) at -78 ° C at n-butyllithium (1.6 M, 25.8 mL, 4 mL).
1.3 mmol) and stirred at the same temperature for 20 minutes. N-isobutyrylpropyleneimine (5.77 g, 45.4 mmo
l) was added and the mixture was stirred at room temperature for 30 minutes. Water to the reaction mixture
(40 mL), extracted twice with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain 6.50 g (yield 67%) of the desired product. 75-77 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 7.0 Hz), 3.22-
3.33 (4H, m), 3.50 (1H, septet, J = 7.0 Hz), 3.81-
3.92 (4H, m), 6.81-6.92 (2H, m), 7.85-8.95 (2H,
m). Reference Example 5c Reference Example using 2-methyl-1- [4- (4-methyl-1-piperazinyl) phenyl] propan-1-one 1-bromo-4- (4-methyl-1-piperazinyl) benzene The desired product was synthesized according to 4.
Yield 81%. 74-76 ° C. (Methanol) ¹ H-NMR (CD
Cl ₃ ) δ: 1.19 (6H, d, J = 6.6 Hz), 2.35 (3H, s),
2.46-2.63 (4H, m), 3.32-3.41 (4H, m), 3.50 (1H, se
ptet, J = 7.0 Hz), 6.84-6.92 (2H, m), 7.85-7.95 (2
H, m). Reference Example 6c 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -2-methyl-1- [4- (4-morpholinyl) phenyl] propan-1-ol 1-bromo-2,5 -Dimethoxy-3,4,6-trimethylbenzene (7.52 g, 29.0 mmol) in tetrahydrofuran (50 mL) at -78 ° C was added to n-butyllithium.
(1.6M, 18.1 mL, 29.0 mmol) was added, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was added with 2-methyl-1- [4- (4-morpholinyl) phenyl] propan-1-one (6.15 g, 26.
4 mmol) and stirred at room temperature for 30 minutes. Pour water (40 mL) into the reaction mixture, extract three times with ethyl acetate, wash the combined organic layers with water, dry over magnesium sulfate,
After filtration and concentration under reduced pressure. The residue was crystallized from ethanol to give 8.40 g (yield 90%) of the desired product. Melting point 191-193
° C. ¹ H-NMR (CDCl ₃ ) δ: 0.87-1.10 (6H, m), 2.11 (3H,
s), 2.18 (3H, s), 2.45 (3H, s), 2.80-3.18 (8H, m),
3.62 (3H, s), 3.75-3.90 (4H, m), 6.41 (1H, brs),
6.82 (2H, d, J = 8.8 Hz), 7.34 (2H, d, J = 8.8 H
z).

Reference Example 7c 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -2-methyl-1- [4- (4-methyl-1-
Reference Example 6 using piperazinyl) phenyl] propan-1-ol 2-methyl-1- [4- (4-methyl-1-piperazinyl) phenyl] propan-1-one
Was synthesized according to the procedure. Yield 43%. Melting point 114-116
° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 0.97 (6H, t, J = 6.6 Hz), 2.11
(3H, s), 2.18 (3H, s), 2.34 (3H, s), 2.45 (3H, s),
2.50-2.62 (4H, m), 2.76-3.00 (1H, m), 3.02 (3H, s),
3.10-3.28 (4H, m), 3.62 (3H, s), 6.40 (1H, br s),
6.84 (2H, d, J = 8.8 Hz), 7.33 (2H, d, J = 8.8 H
z). Reference Example 8c 3- (4-isopropylphenyl) -2,2-dimethyl-2,3-dihydrobenzofuran-5-ol 1-bromo-2,5-dimethoxybenzene (7.2 g, 33.
2 mmol) in tetrahydrofuran (20 mL).
N-butyllithium at 1.6 ° C (1.6M, 20.8 mL, 33.2 mmol)
Was added and stirred at the same temperature for 20 minutes. 1- (4
-Isopropylphenyl) -2-methylpropane-1-
ON (5.70 g, 30.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Water (30 mL) was poured into the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 48% with residue
A mixture of hydrobromic acid (30 mL) was added under argon atmosphere for 2 hours.
The mixture was refluxed for 4 hours. After cooling, water (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to obtain 2.1 g (yield 70%) of the desired product. Melting point 102-10
4 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.96 (3H, s), 1.25 (6H, d, J =
7.0 Hz), 1.57 (3H, s), 2.90 (1H, septet, J = 7.0 H
z), 4.28 (1H, s), 4.67 (1H, s), 6.53-6.85 (3H, m),
7.02 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 8.0 H
z). Reference Example 9c 2,2,4,6,7-pentamethyl-3- [4- (4-
Morpholinyl) phenyl] -2,3-dihydrobenzofuran-5-ol 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -2-methyl-1- [4- (4-morpholinyl) phenyl] Propan-1-ol (8.00 g, 19.3 mm
ol) and 48% hydrobromic acid (100 mL) were heated to reflux for 3 hours under an argon atmosphere. After cooling, a saturated aqueous solution of sodium hydrogen carbonate (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to give the desired product
6.40 g (90% yield) were obtained. 91-93 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.46 (3H, s), 1.8
2 (3H, s), 2.15 (3H, s), 2.17 (3H, s), 2.98-3.24
(4H, m), 3.71-3.99 (4H, m), 4.04 (1H, s), 4.18 (1
H, s), 6.44-7.10 (4H, m).

Reference Example 10c 2,2,4,6,7-pentamethyl-3- [4- (4-
Methyl-1-piperazinyl) phenyl] -2,3-dihydrobenzofuran-5-ol 1- (2,5-dimethoxy-3,4,6-trimethylphenyl) -2-methyl-1- [4- (4- Methyl-1-
Using piperazinyl) phenyl] propan-1-ol, the target compound was synthesized according to Reference Example 9. 55% yield.
159-161 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.46 (3H, s), 1.8
1 (3H, s), 2.17 (6H, s), 2.34 (3H, s), 2.48-2.65
(4H, m), 3.08-3.22 (4H, m), 4.03 (1H, s), 6.58-7.2
0 (4H, m), 1H Not confirmed. Reference Example 11c 1- (4-isopropylphenyl) propan-1-ol Aluminum chloride (16.7 g, 125 mmol) and cumene (18.
0 g, 150 mmol) in carbon disulfide (30 mL).
Then, propionyl chloride (11.6 g, 125 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, the organic layer was separated, saturated aqueous sodium hydrogen carbonate solution,
After washing with water, drying over magnesium sulfate, filtration, and concentration under reduced pressure were performed to give 1- (4-isopropylphenyl) -propane-
24.7 g of 1-one was obtained. This compound (13.0 g, 68.4 m
mol) in ethanol (80 mL), sodium borohydride (1.29 g, 34.2 mmol) was added under ice-cooling, and the mixture was added at room temperature.
Stir for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. Wash the organic layer with water, dry over magnesium sulfate,
After filtration and concentration under reduced pressure, 11.5 g (79%) of the desired product was obtained. Oil. ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.4 Hz), 1.25
(6H, d, J = 7.0 Hz), 1.63-1.92 (2H, m), 1.94 (1H,
br s), 2.90 (1H, septet, J = 7.0 Hz), 4.47-4.61 (1
H, m), 7.16-7.29 (4H, m). Reference Example 12c 2- [1- (4-isopropylphenyl) propyl]-
3,5,6-Trimethyl-1,4-benzoquinone Under nitrogen atmosphere, 1- (4-isopropylphenyl) propan-1-ol (5.00 g, 28.0 mmol) and trimethylhydroquinone (4.30 g, 28.0 mmol) in 1, To a suspension of 2-dichloroethane (100 mL) was added dropwise boron trifluoride ethyl ether complex (1.30 g, 9.33 mmol) at 60 ° C, and the mixture was stirred at the same temperature for 3 hours. After cooling, the reaction mixture was washed with an aqueous iron (III) chloride solution and water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 30: 1) to give the desired product 5.40. g (62% yield). 61-63 ° C.
(Methanol) ¹ H-NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.4 Hz), 1.22
(6H, d, J = 6.8 Hz), 1.83-2.11 (11H, m), 2.85 (1H,
septet, J = 6.8 Hz), 4.02-4.23 (1H, m), 7.02-4.24
(4H, m).

Reference Example 13c 3- (4-isopropylphenyl) -2,4,6,7-
Tetramethylbenzofuran-5-ol 2- [1- (4-isopropylphenyl) propyl]-
3,5,6-trimethyl-1,4-benzoquinone (1.0
(0 g, 0.324 mmol) in ethanol (1.00 L) was stirred for 5 hours while irradiating with 400 W bromcinelite delux (manufactured by LPL Co.) while cooling with ice water to keep the room temperature. The solvent is concentrated under reduced pressure, and the residue is subjected to silica gel column chromatography (hexane-ethyl acetate 20: 1).
Then, 0.90 g (yield 90%) of the target product was obtained. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 7.0 Hz), 1.98
(3H, s), 2.28 (3H, s), 2.30 (3H, s), 2.43 (3H, s),
2.97 (1H, septet, J = 7.0 Hz), 4.43 (1H, s), 7.26
(4H, s). Reference Example 14c 2,3,6-trimethyl-4-[(3-phenyl-2-
[Propenyl) oxy] phenyl acetate To a solution of 4-hydroxy-2,3,6-trimethylphenyl acetate (10.0 g, 51.5 mmol) in N, N-dimethylformamide (100 mL) was added 1-chloro-3-phenyl-2-acetate. Propene (7.86 g, 51.5 mmol) was added, followed by potassium carbonate (7.10 g, 51.5 mmol), and the mixture was stirred at 60 ° C for 2 hours under an argon atmosphere. Water was added to the reaction solution, and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from methanol to give the desired product 13.0
g (81% yield) was obtained. 104-107 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.06 (3H, s), 2.13 (3H, s), 2.1
8 (3H, s), 2.34 (3H, s), 4.66 (2H, dd, J = 5.6, 1.
2 Hz), 6.43 (1H, dt, J = 16.2, 5.6 Hz), 5.63 (1H,
s), 6.74 (1H, d, J = 16.2 Hz), 7.24-7.46 (5H, m). Reference Example 15c 4-hydroxy-2,3,6-trimethyl-5- (1-
Phenyl-2-propenyl) phenyl acetate 2,3,6-trimethyl-4-[(3-phenyl-2-
Propenyl) oxy] phenyl acetate (10.0 g,
A solution of 32.2 mmol) in N, N-dimethylaniline (70 mL) was stirred at 200 ° C. for 3 hours under an argon atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 2N hydrochloric acid and water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give 7.80 g of the desired product (78% yield). 136-138 ° C. ¹ H-NMR (CDCl ₃ ) δ: 2.06 (6H, s), 2.11 (3H, s), 2.
33 (3H, s), 4.83-5.18 (2H, m), 5.36 (1H, d, J = 10.
0 Hz), 6.32-6.58 (1H, m), 7.18-7.37 (5H, m), 1H Not confirmed.

Reference Example 16c 2,4,6,7-Tetramethyl-3-phenylbenzofuran-5-yl acetate 4-hydroxy-2,3,6-trimethyl-5- (1-
Phenyl-2-propenyl) phenyl acetate (5.
10 g, 16.4 mmol) and calcium carbonate (2.13 g, 21.3 mmo
l) tetrahydrofuran (20 mL)-methanol (20 m
To the suspension of L) was slowly added benzyltrimethylammonium iododichloride (6.28 g, 18.0 mmol).
The reaction was stirred at room temperature for 30 minutes. After filtering off the insoluble matter, the solvent was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with a 10% aqueous sodium hydrate sulfite solution, water, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure.
5.30 g of 2-iodomethyl-4,6,7-trimethyl-3-phenyl-2,3-dihydrobenzofuran-5-
I got il acetate. This compound (5.30 g, 12.1 m
mol) and 1,8-diazabicyclo [5,4,0] -7-
Undecene (9.0 mL, 60.0 mmol) in toluene (20 mL)
The solution was stirred at 100 ° C. for 3 hours under an argon atmosphere.
Water was added to the reaction solution, which was extracted twice with ethyl acetate. The extract was washed with 2N hydrochloric acid and water, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 20: 1) to give the desired product 4.
0 g (79% yield) was obtained. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.85 (3H, s), 2.15 (3H, s), 2.3
0 (3H, s), 2.33 (3H, s), 2.44 (3H, s), 7.32-7.48
(5H, m). Reference Example 17c 2,4,6,7-Tetramethyl-3-phenylbenzofuran-5-ol 2,4,6,7-Tetramethyl-3-phenylbenzofuran-5-yl acetate (4.00 g, 13.0 mmol) An 8 N aqueous sodium hydroxide solution (2.0 mL) was added dropwise to a mixed solution of tetrahydrofuran (32 mL) and methanol (8 mL), and the mixture was stirred at 40 ° C for 1 hour. The organic solvent was extracted by concentration under reduced pressure, 2N hydrochloric acid was added to the residue, and the product was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from isopropyl ether-hexane,
3.0 g (87% yield) of the desired product was obtained. 102-104 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.96 (3H, s), 2.28 (3H, s), 2.2
9 (3H, s), 2.44 (3H, s), 4.42 (1H, s), 7.28-7.43
(5H, m). Reference Example 18c 1- (2,4-dimethoxyphenyl) -1- (4-isopropylphenyl) -2-methylpropan-1-ol 1-bromo-2,4-dimethoxybenzene and 1- (4-
The target product was synthesized according to Reference Example 6 using isopropylphenyl) -2-methylpropan-1-one. yield
56%. 80-81 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 0.75 (3H, d, J = 6.6 Hz), 1.08
(3H, d, J = 6.6 Hz), 1.20 (6H, d, J = 7.0 Hz), 2.6
6 (1H, septet, J = 7.0 Hz), 2.80 (1H, septet, J =
6.6 Hz), 3.48 (3H, s), 3.79 (3H, s), 4.71 (1H, s),
6.39-6.40 (1H, m), 6.50-6.56 (1H, m), 7.04-7.08 (2
H, m), 7.19-7.23 (2H, m), 7.40-7.44 (1H, m).

Reference Example 19c 3- (4-Isopropylphenyl) -2,2-dimethyl-2,3-dihydrobenzofuran-6-ol Under an argon atmosphere, 1- (2,4-dimethoxyphenyl) -1- ( 4-isopropylphenyl) -2-
Methylpropan-1-ol (5.58 g, 17.0 mmol) and 4
A mixture of 8% hydrobromic acid (30 mL) was heated at reflux for 24 hours. After cooling the reaction mixture to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, the product was extracted twice with ethyl acetate, and the combined extracts were washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. did. The residue was purified by silica gel column chromatography (hexane-
Ethyl acetate 20: 1 → 10: 1) to give 2.43 g of the desired product (yield
51%). 114-115 ° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.24 (6H, d, J =
7.0 Hz), 1.57 (3H, s), 2.89 (1H, septet, J = 7.0 H
z), 4.25 (1H, s), 6.15 (1H, br), 6.34-6.38 (2H,
m), 6.84-6.88 (1H, m), 6.99-7.03 (2H, m), 7.13-7.1
7 (2H, m). Reference Example 20c 4- (4-isopropylbenzoyl) piperidine 1-acetylisonipecotic acid (41.74 g, 243.8 mmol)
To the mixture was added thionyl chloride (200 mL), and the mixture was stirred at room temperature for 30 minutes. Petroleum ether was added to the reaction solution, and the solid was collected by filtration and washed with petroleum ether to obtain 1-acetylisonipecotinyl chloride. 1-Acetylisonipecotinyl chloride was added to cumene (120 mL) and aluminum chloride (69.6
g, 522 mmol).
Stirred at 0 ° C. for 1 hour. The reaction solution was cooled to room temperature, poured into ice water, and the product was extracted twice with ethyl acetate. The combined extracts were washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Concentrated hydrochloric acid (100 mL) was added to the residue,
The mixture was refluxed for 12 hours. The reaction mixture was cooled to room temperature and washed with diethyl ether. To the obtained aqueous layer, an 8 N aqueous sodium hydroxide solution was added until the solution became basic, and the product was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 23.5 g of the desired product (yield 41%). 55-57 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 6.8 Hz), 1.57-
2.70 (5H, m), 2.70-2.83 (2H, m), 2.97 (1H, septet,
J = 6.8 Hz), 3.16-3.22 (2H, m), 3.34-3.46 (1H,
m), 7.30-7.34 (2H, m), 7.87-7.91 (2H, m). Reference Example 21c 1-benzyl-4- (4-isopropylbenzoyl) piperidine 4- (4-isopropylbenzoyl) piperidine (14.8
4 g, 64.15 mmol) of N, N-dimethylformamide (1
(00 mL) Potassium carbonate (9.60 g, 69.5 mmol) and benzyl bromide (8.50 g, 71.5 mmol) were added to the solution, and the mixture was stirred at room temperature for 20 hours. The mixture was poured into water and the product was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane to obtain 13.53 g (yield 66%) of the desired product. Melting point 76-77
° C. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, d, J = 7.0 Hz), 1.79-
1.90 (4H, m), 2.07-2.20 (2H, m), 2.92-2.99 (3H, m),
3.15-3.30 (1H, m), 3.55 (2H, s), 7.24-7.32 (7H,
m), 7.85-7.89 (2H, m).

Reference Example 22c (1-Benzyl-4-piperidyl) (2,5-dimethoxy-3,4,6-trimethylphenyl) (4-isopropylphenyl) methanol In an argon atmosphere, 1-bromo-2,5 -Dimethoxy-3,4,6-trimethylbenzene (4.89 g, 1
8.87 mmol) in tetrahydrofuran (100 mL)
N-Butyl lithium (1.6 M, 12.0 mL, 19.2 mmo) at 8 ° C
l) was added and the mixture was stirred at the same temperature for 30 minutes. Add 1-benzyl-4- (4-isopropylbenzoyl) piperidine to the reaction mixture.
(5.02 g, 15.6 mmol) in tetrahydrofuran (10 mL)
The solution was added and stirred at room temperature for 30 minutes. Water was poured into the reaction mixture, and the product was extracted twice with ethyl acetate. After washing the combined extract with saturated saline, drying over magnesium sulfate,
It was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 6.54 g of the desired product (83% yield). Melting point 105-108
° C. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 6.6 Hz), 1.2-1.
5 (2H, m), 1.8-2.0 (4H, m), 2.09 (3H, s), 2.17 (3
H, s), 2.39 (3H, s), 2.4-2.5 (1H, m), 2.78-2.88 (3
H, m), 2.97 (3H, s), 3.51 (2H, s), 3.60 (3H, s),
6.37 (1H, br), 7.08-7.12 (2H, m), 7.26-7.34 (7H,
m). Reference Example 23c 1'-benzyl-3- (4-isopropylphenyl)-
4,6,7-trimethylspiro [benzofuran-2 (3
H), 4'-Piperidin] -5-ol Under an argon atmosphere, (1-benzyl-4-piperidyl) (2,5-dimethoxy-3,4,6-trimethylphenyl) (4-isopropylphenyl) methanol
To a solution of (6.41 g, 12.8 mmol) in acetic acid (50 mL) was added 48% hydrobromic acid (60 mL), and the resulting mixture was heated to reflux for 15 hours. After cooling the reaction mixture to room temperature, an 8 N aqueous sodium hydroxide solution was added until the solution became basic, the product was extracted twice with ethyl acetate, and the combined extracts were washed with a saturated aqueous sodium hydrogen carbonate solution. It was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 4.44 g (yield 76%) of the desired product. 190-192 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (6H, d, J = 7.0 Hz), 1.21-
1.41 (2H, m), 1.71-2.00 (5H, m), 2.17 (3H, s), 2.20
(3H, s), 2.27-2.90 (5H, m), 3.54 (2H, s), 4.02 (1
H, s), 6.6-7.1 (4H, m), 7.20-7.32 (5H, m), 1H Not confirmed. Reference Example 24c 3- (4-isopropylphenyl) -4,6,7-trimethylspiro [benzofuran-2 (3H), 4′-piperidin] -5-ol hydrochloride 1′-benzyl-3- (4-isopropyl) Phenyl)-
4,6,7-trimethylspiro [benzofuran-2 (3
H), 4'-Piperidin] -5-ol (3.51 g, 7.70
mmol) and a solution of triethylamine (1.1 mL, 7.9 mmol) in chloroform (40 mL) were cooled to 0 ° C., and 1-chloroethyl chloroformate (2.30 g, 16.1 mmol) was added. The reaction mixture was heated under reflux for 1 hour and concentrated under reduced pressure. Methanol (20 mL) was added to the residue, and the mixture was heated under reflux for 1 hour and concentrated under reduced pressure. The residue was crystallized from ethanol-ethyl acetate to give 2.80 g (yield 90%) of the desired product.
Melting point> 245 ° C (decomposition). ¹ H-NMR (d ₆ -DMSO) δ: 1.18 (6H, d, J = 6.6 Hz), 1.34
(2H, br), 1.71 (3H, s), 1.97 (2H, br), 2.08 (3H,
s), 2.11 (3H, s), 2.8-3.3 (5H, m), 4.26 (1H, s), 6.
6-7.2 (4H, m), 7.53 (1H, s), 8.78 (1H, s), 1H Not confirmed.

Reference Example 25c 3- (4-isopropylphenyl) -1 ′, 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
4'-piperidin] -5-ol 3- (4-isopropylphenyl) -4,6,7-trimethylspiro [benzofuran-2 (3H), 4'-piperidin] -5-ol hydrochloride (2.80 g, 6.97 mmol), formic acid (30 mL), and 37% formalin (30 mL).
Stirred at C for 15 hours. After cooling the reaction mixture to room temperature, an 8 N aqueous sodium hydroxide solution was added to make the mixture basic, and the product was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), hexane-ethyl acetate 1: 1) to obtain 2.05 g (yield 77%) of the desired product. 114-117 ° C
(Ethyl acetate-hexane). ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.39 (8H, m), 1.72-2.91 (19
H, m), 4.02 (1H, m), 6.6-7.1 (4H, m), 1H Not confirmed. Reference Example 26c (1-benzyl-4-piperidyl) (2,5-dimethoxy-3,4,6-trimethylphenyl) methanol Under an argon atmosphere, 1-bromo-2,5-dimethoxy-3,4,6- Trimethylbenzene (8.00 g, 3
0.87 mmol) in tetrahydrofuran (80 mL).
N-butyllithium at 1.6 ° C (1.6M, 19.5 mL, 31.2 mmol)
Was added and stirred at the same temperature for 30 minutes. 1-benzyl-
A solution of 4-formylpiperidine (6.23 g, 30.65 mmol) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Pour water into the reaction mixture and wash the product with ethyl acetate.
Extracted times. The combined extracts were washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate),
6.17 g (52% yield) of the desired product was obtained. Oily substance. ¹ H-NMR (CDCl ₃ ) δ: 1.17-2.05 (7H, m), 2.16 (3H, s),
2.17 (3H, s), 2.24 (3H, s), 2.79-2.85 (1H, m), 2.9
8-3.05 (1H, m), 3.48 (2H, s), 3.61 (3H, s), 3.75 (3
H, s), 4.59 (1H, m), 7.23-7.32 (5H, m), 1H Not confirmed. Reference Example 27c 1′-benzyl-4,6,7-trimethylspiro [benzofuran-2 (3H), 4′-piperidin] -5-ol Under an argon atmosphere, (1-benzyl-4-piperidyl) (2 5-Dimethoxy-3,4,6-trimethylphenyl) methanol (6.10 g, 15.90 mmol) in acetic acid
(30 mL) To the solution was added 48% hydrobromic acid (40 mL), and the resulting mixture was heated to reflux for 2.5 hours. After cooling the reaction mixture to room temperature, an 8 N aqueous sodium hydroxide solution was added until the solution became basic, and the product was extracted twice with ethyl acetate. The combined extracts were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 1: 1) to give 4.60 g of the desired product (yield 8
6%). Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.71-2.00 (6H, m), 2.10 (3H, s),
2.11 (3H, s), 2.12 (3H, s), 2.58 (2H, m), 2.87 (2
H, s), 3.56 (2H, s), 7.25-7.38 (5H, m), 1H unconfirmed.

Synthesis Example 1c 5-benzyloxy-3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2 , 4,6,
7-pentamethyl-2,3-dihydrobenzofuran-5
-Ol (0.5 g, 1.54 mmol) in N, N-dimethylformamide (20 mL) at 0 ° C was treated with sodium hydride (6 mL).
(0% liquid paraffin dispersion, 68 mg, 1.70 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes. Benzyl bromide (290 mg, 1.70 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Pour the reaction mixture into water (30 mL) and add ethyl acetate.
The organic layer was extracted twice, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from methanol to obtain 380 mg of the desired product (yield 60%).
79-81 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.22 (6H, d, J =
6.8 Hz), 1.50 (3H, s), 1.83 (3H, s), 2.16 (3H, s),
2.24 (3H, s), 2.86 (1H, septet, J = 6.8 Hz), 4.09
(1H, s), 4.70 (2H, s), 6.70-7.00 (2H, br), 7.09 (2
H, d, J = 8.4 Hz), 7.30-7.50 (5H, m). Synthesis Example 2c 5-benzyloxy-3- [4- (dimethylamino) phenyl] -2,2,4,6,7-pentamethyl-2,3
-Dihydrobenzofuran 3- [4- (dimethylamino) phenyl] -2,2,
Using 4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and benzyl bromide, the target compound was synthesized according to Synthesis Example 1c. Yield 40%. Melting point 110-
112 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, s), 1.48 (3H, s), 1.8
7 (3H, s), 2.16 (3H, s), 2.23 (3H, s), 2.91 (6H,
s), 4.04 (1H, s), 4.70 (2H, s), 6.48-7.16 (4H, m),
7.20-7.48 (5H, m). Synthesis Example 3c 5-benzyloxy-2,4,6,7-tetramethyl-
2- (4-phenyl-1-piperazinyl) methyl-2,
3-dihydrobenzofuran 2,4,6,7-tetramethyl-2- (4-phenyl-
Using 1-piperazinyl) methyl-2,3-dihydrobenzofuran-5-ol and benzyl bromide, the target compound was synthesized according to Synthesis Example 1c. Yield 48%. Melting point 120-
121 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, s), 2.09 (3H, s), 2.1
6 (3H, s), 2.20 (3H, s), 2.58-2.92 (7H, m), 3.08-
3.22 (5H, m), 4.71 (2H, s), 6.78-6.94 (3H, m), 7.2
0-7.52 (7H, m).

Synthesis Example 4c 3- (4-Isopropylphenyl) -5- (4-methoxybenzyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl ) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
Using -ol and 4-methoxybenzyl chloride, the target compound was synthesized according to Synthesis Example 1c. Yield 49%. Melting point
95-96 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.49 (3H, s), 1.82 (3H, s), 2.16 (3H, s),
2.23 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 3.81
(3H, s), 4.08 (1H, s), 4.63 (2H, s), 6.70-7.18 (6
H, m), 7.35 (2H, d, J = 8.8 Hz). Synthesis Example 5c 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2-dimethyl-2 The target product was synthesized according to Synthesis Example 1c using 2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride. 75% yield. 124-126 ° C. (Ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.25 (6H, d, J =
7.0 Hz), 1.57 (3H, s), 2.90 (septet, 1H, J = 7.0 H
z), 3.71 (3H, s), 4.30 (1H, s), 4.87 (2H, s), 6.65
-7.35 (11H, m). Synthesis Example 6c 3- [4- (dimethylamino) phenyl] -5- (4-
(Methoxybenzyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 3- [4- (dimethylamino) phenyl] -2,2,
Using 4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the target compound was synthesized according to Synthesis Example 1c. Yield 42
%. 105-107 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.48 (3H, s), 1.8
4 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 2.92 (6H,
s), 3.81 (3H, s), 4.04 (1H, s), 4.58-4.69 (2H, m),
6.54-6.93 (6H, m), 7.30-7.42 (2H, m).

Synthesis Example 7c 5- (4-methoxybenzyloxy) -3- [4- (4
-Morpholinyl) phenyl] -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 2,2
4,6,7-pentamethyl-3- [4- (4-morpholinyl) phenyl] -2,3-dihydrobenzofuran-5
-Ol and 4-methoxybenzyl chloride,
The target compound was synthesized according to Synthesis Example 1c. Yield 38%. 110-112 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.48 (3H, s), 1.8
3 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 3.02-3.26
(4H, m), 3.71-3.99 (7H, m), 4.05 (1H, s), 4.57-4.9
0 (2H, m), 6.60-7.00 (6H, m), 7.35 (2H, d, J = 6.8
Hz). Synthesis Example 8c 5- (4-methoxybenzyloxy) -2,2,4,
6,7-pentamethyl-3- [4- (4-methyl-1-
Piperazinyl) phenyl] -2,3-dihydrobenzofuran 2,2,4,6,7-pentamethyl-3- [4- (4-
Methyl-1-piperazinyl) phenyl] -2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride were used to synthesize the desired product according to Synthesis Example 1c. Yield 42%. 121-122 ° C. (Ethyl ether-hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.48 (3H, s), 1.8
3 (3H, s), 2.15 (3H, s), 2.23 (3H, s), 2.34 (3H,
s), 2.52-2.63 (4H, m), 3.13-3.24 (4H, m), 3.81 (3
H, s), 4.05 (1H, s), 4.58-4.67 (2H, m), 6.60-7.07
(6H, m), 7.35 (2H, d, J = 8.8 Hz). Synthesis Example 9c 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (4-methylthiobenzyloxy) -2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
Using -ol and 4- (bromomethyl) phenylmethyl sulfide, the target compound was synthesized according to Synthesis Example 1c.
70% yield. 118-120 ° C. (Ethanol) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.49 (3H, s), 1.82 (3H, s), 2.16 (3H, s),
2.22 (3H, s), 2.48 (3H, s), 2.86 (1H, septet, J =
7.0 Hz), 4.08 (1H, s), 4.65 (2H, s), 6.80-7.02 (2
H, br), 7.08 (2H, d, J = 8.0 Hz), 7.25 (2H, d, J =
8.4 Hz), 7.36 (2H, d, J = 8.4 Hz).

Synthesis Example 10c 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- [4- (methylsulfinyl)
[Benzyloxy] -2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (4-methylthiobenzyloxy) -2,3-dihydrobenzofuran (1.50 g, 3.26 m
mol) of ethanol (80 mL) -water (8 mL), sodium periodate (0.766 g, 3.58 mmol) was added, and the mixture was refluxed for 2 hours. Ethyl acetate and water were added to the reaction mixture, and the two layers were separated.The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and dried over magnesium sulfate.
After filtration and concentration under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to obtain 1.23 g (79%) of the desired product.
132-134 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.22 (6H, d, J =
6.8 Hz), 1.50 (3H, s), 1.82 (3H, s), 2.17 (3H, s),
2.23 (3H, s), 2.71, 2.72 (1.5H x2, s x2), 2.86 (1
H, septet, J = 6.8 Hz), 4.09 (1H, s), 4.76 (2H,
s), 6.71-7.15 (4H, m), 7.57-7.69 (4H, m). Synthesis Example 11c 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- [4- (methylsulfonyl)
[Benzyloxy] -2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- [4- (methylsulfinyl)
Benzyloxy] -2,3-dihydrobenzofuran (1.
50 g, 3.15 mmol) of ethanol (80 mL)-water (8 mL)
In the mixed solution, add sodium periodate (2.02 g, 9.45 m
mol), and the mixture was heated under reflux for 18 hours. Ethyl acetate and water were added to the reaction mixture, two layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give the desired product (1.05 g, 68%)
I got Yield 68%. 161-162 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.50 (3H, s), 1.82 (3H, s), 2.17 (3H, s),
2.22 (3H, s), 2.87 (1H, septet, J = 7.0 Hz), 3.05
(3H, s), 4.09 (1H, s), 4.80 (2H, s), 6.70-7.13 (4
H, m), 7.67 (2H, d, J = 8.4 Hz), 7.95 (2H, d, J =
8.4 Hz).

Synthesis Example 12c 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (3-phenyl-2-propen-1-yloxy) -2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
Using -ol and 3-bromo-1-phenyl-1-propene, the desired product was synthesized according to Synthesis Example 1c. Yield 7
1%. 106-107 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.00 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.49 (3H, s), 1.86 (3H, s), 2.16 (3H, s),
2.24 (3H, s), 2.85 (1H, septet, J = 7.0 Hz), 4.08
(1H, s), 4.36 (2H, d, J = 6.0 Hz), 6.42 (1H, dt, J
= 15.4, 6.0 Hz), 6.66-7.15 (5H, m), 7.20-7.48 (5
H, m). Synthesis Example 13c 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (2-quinolylmethyloxy)
-2,3-dihydrobenzofuran hydrochloride 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
-Ol (1.0 g, 3.08 mmol) in N, N-dimethylformamide (30 mL) at 0 ° C.
(0% liquid paraffin dispersion, 136 mg, 3.39 mmol) was added, and the mixture was stirred at the same temperature for 10 minutes. 2- (Chloromethyl) quinoline hydrochloride (730 mg, 3.39 mmol) was added to the reaction solution, and 8
The mixture was stirred at 0 ° C for 30 minutes. The reaction mixture was poured into water (40 mL), extracted twice with ethyl acetate, and the combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. After adding 4N hydrochloric acid-ethanol to the residue and distilling off the solvent, the residue was crystallized from ethanol-hexane to obtain 1.1 g (yield 71%) of the desired product. 136-139 ° C. ¹ H-NMR (DMSO-d6) δ: 0.94 (3H, s), 1.18 (6H, d, J
= 7.0 Hz), 1.45 (3H, s), 1.78 (3H, s), 2.11 (3H, s)
s), 2.22 (3H, s), 2.85 (1H, septet, J = 7.0 Hz),
4.19 (1H, s), 4.20-4.90 (1H, br), 5.10 (1H, d, J =
15.8 Hz), 5.19 (1H, d, J = 15.8 Hz), 6.65-7.05 (2
H, br), 7.13 (2H, d, J = 8.8 Hz), 7.72-7.85 (1H,
m), 7.91-8.02 (2H, m), 8.15-8.30 (2H, m), 8.80 (1
H, d, J = 8.8 Hz).

Synthesis Example 14 5- (3,3-diphenylpropyloxy) -3- (4
-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
Using -ol and 3,3-diphenylpropylmethanesulfonate, the target product was synthesized according to Synthesis Example 1c.
55% yield. Oil. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.45 (3H, s), 1.71 (3H, s), 2.08 (3H, s),
2.10 (3H, s), 2.48 (1H, d, J = 6.6 Hz), 2.55 (1H,
d, J = 6.6 Hz), 2.76-2.93 (1H, m), 3.60 (2H, t, J
= 6.6 Hz), 4.07 (1H, s), 4.25 (1H, t, J = 8.0 H
z), 6.60-7.00 (2H, br), 7.06 (2H, d, J = 7.6 Hz),
7.10-7.34 (10H, m). Synthesis Example 15c 4-[[3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yl] oxymethyl] methyl benzoate 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
Using -ol and methyl 4- (bromomethyl) methylbenzoate, the target compound was synthesized according to Synthesis Example 1c. yield
82%. 108-110 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.50 (3H, s), 1.82 (3H, s), 2.16 (3H, s),
2.22 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 3.92
(3H, s), 4.09 (1H, s), 4.76 (2H, s), 6.65-7.00 (2
H, br), 7.08 (2H, d, J = 8.0 Hz), 7.51 (2H, d, J =
8.0 Hz), 8.04 (2H, d, J = 8.2 Hz).

Synthesis Example 16c α-[[3- (4-isopropylphenyl) -2,2,
4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-yl] oxy] phenylacetate methyl 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
Using -ol and methyl α-bromophenylacetate, the target product was synthesized according to Synthesis Example 1c. 82% yield. Oil. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.21, 1.23 (6H, e
ach d, J = 7.0 Hz), 1.47 (3H, s), 1.57, 1.60 (3H,
each s), 2.00, 2.04 (3H, each s), 2.09, 2.11 (3H, e
ach s), 2.75-2.98 (1H, m), 3.70, 3.74 (3H, each
s), 4.01 (1H, s), 5.07 (1H, s), 6.60-6.95 (2H, br),
7.06 (2H, d, J = 8.0 Hz), 7.24-7.50 (5H, m). Synthesis Example 17c 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (2-pyridylmethyloxy)
-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
-Ol and 2-chloromethylpyridine hydrochloride,
The target compound was synthesized according to Synthesis Example 1c. Yield 17%. 88-89 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.51 (3H, s), 1.83 (3H, s), 2.17 (3H, s),
2.24 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 4.10
(1H, s), 4.80 (1H, d, J = 15.8 Hz), 4.89 (1H, d, J
= 15.8 Hz), 6.72-7.02 (2H, br), 7.09 (2H, d, J =
8.2 Hz), 7.15-7.25 (1H, m), 7.67-7.81 (2H, m), 8.50
-8.58 (1H, m).

Synthesis Example 18c 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (3-pyridylmethyloxy)
-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
Using -ol and 3-chloromethylpyridine hydrochloride,
The target compound was synthesized according to Synthesis Example 1c. Yield 76%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.50 (3H, s), 1.82 (3H, s), 2.16 (3H, s),
2.22 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 4.09
(1H, s), 4.73 (2H, s), 6.63-7.02 (2H, br), 7.09 (2
H, d, J = 8.2 Hz), 7.24 (1H, dd, J = 7.8, 5.0 Hz),
7.78 (1H, d, J = 7.6 Hz), 8.56 (1H, d, J = 4.0 H
z), 8.60-8.71 (1H, br). Synthesis Example 19c 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (4-pyridylmethyloxy)
-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
Using -ol and 4-chloromethylpyridine hydrochloride,
The target compound was synthesized according to Synthesis Example 1c. Yield 52%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.50 (3H, s), 1.82 (3H, s), 2.16 (3H, s),
2.21 (3H, s), 2.78-2.93 (1H, m), 4.08 (1H, s), 4.73
(2H, s), 6.62-7.01 (2H, br), 7.09 (2H, d, J = 8.4
Hz), 7.38 (2H, d, J = 5.8 Hz), 8.60 (2H, d, J =
5.8 Hz).

Synthesis Example 20c 3- (4-isopropylphenyl) -5- (2,4-dinitrophenyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran 3- (4- Isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
-Ol (2.0 g, 6.16 mmol) in N, N-dimethylformamide (30 mL) at 0 ° C was treated with sodium hydride (6 mL).
0% liquid paraffin dispersion, 270 mg, 6.75 mmol) was added, and the mixture was stirred at the same temperature for 20 minutes. 1-chloro-
2,4-Dinitrobenzene (1.37 g, 6.78 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. Water the reaction mixture (50 mL)
And extracted twice with ethyl acetate. The combined organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 1.5 g (yield 50%) of the desired product. Yield 50%. Melting point 1
37-139 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, s), 1.22 (6H, d, J =
7.0 Hz), 1.57 (3H, s), 1.66 (3H, s), 2.03 (3H, s),
2.19 (3H, s), 2.86 (1H, septet, J = 7.0 Hz), 4.13
(1H, s), 6.62-6.95 (3H, m), 7.11 (2H, d, J = 8.0 H
z), 8.26 (1H, dd, J = 9.2, 2.6 Hz), 8.75-8.86 (1H,
m). Synthesis Example 21c 5- (2,4-bisacetylaminophenyloxy)-
3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -5- (2,4-dinitrophenyloxy) -2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran ( 800mg, 1.63
mmol) and 10% palladium-carbon (hydrated) (80 mg)
Was suspended in ethanol (40 mL), and the suspension was heated to 60 ° C under a hydrogen atmosphere.
For 4 hours. The catalyst was removed by filtration and concentrated under reduced pressure to give 5-
(2,4-diaminophenoxy) -3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-
710 mg of 2,3-dihydrobenzofuran was obtained. The obtained compound (710 mg, 1.65 mmol) and triethylamine (2
90 mg, 1.70 mmol) in chloroform (30 mL).
Acetyl chloride (0.26 mL, 3.63 mmol) was added at ℃, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water (30 mL), extracted twice with ethyl acetate, and the combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 5: 1) to obtain 640 mg (yield 76%) of the desired product. Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.04 (3H, s), 1.22 (6H, d, J =
6.8 Hz), 1.52 (3H, s), 1.64 (3H, s), 2.00 (3H, s),
2.12 (3H, s), 2.18 (3H, s), 2.23 (3H, s), 2.86 (1
H, septet, J = 6.8 Hz), 4.11 (1H, s), 6.30 (1H, d,
J = 9.2 Hz), 6.60-7.03 (2H, br), 7.05 (2H, d, J =
8.4 Hz), 7.54 (1H, dd, J = 9.2, 2.6 Hz), 7.69 (1
H, br s), 8.02 (1H, s), 8.21 (1H, d, J = 2.6 Hz).

Synthesis Example 22c α- [3- (4-isopropylphenyl) -2,2,
4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yloxy] phenylacetic acid α- [3- (4-isopropylphenyl) -2,2
Methyl 4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-yloxy] phenylacetate (1.20 g,
To a mixed solution of 2.54 mmol) in tetrahydrofuran (24 mL) -methanol (6 mL) was added a 2N aqueous sodium hydroxide solution (2.5 mL) dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, 2N hydrochloric acid was added, and the mixture was diluted with ethyl acetate.
Extracted times. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was recrystallized from hexane to give the desired product (0.31 g, 27%) as a diastereomer mixture (mixing ratio: 8: 1). 163-166 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 1.12-1.25 (6H,
m), 1.41-1.56 (6H, m), 1.92-2.10 (6H, m), 2.87 (1
H, septet, J = 6.6 Hz), 3.99 (1H, s), 5.08-5.10 (1
H, m), 5.20-6.00 (1H, br), 6.60-7.17 (4H, m), 7.20
-7.39 (5H, m). Synthesis Example 23c α- [3- (4-isopropylphenyl) -2,2,
4,6,7-Pentamethyl-2,3-dihydrobenzofuran-5-yloxy] phenylacetic acid The filtrate obtained in Synthesis Example 22c was concentrated under reduced pressure, and 0.50 g (43%) of an amorphous target product was obtained as a diastereomeric mixture. (Mixing ratio 1: 3)
As obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 1.16-1.26 (6H,
m), 1.39-1.56 (6H, m), 1.91- 2.10 (6H, m), 2.84
(1H, septet, J = 6.8 Hz), 4.00 (1H, m), 5.07-5.10
(1H, s), 5.40-6.30 (1H, br), 6.50-7.14 (4H, m), 7.
20-7.40 (5H, m).

Synthesis Example 24c 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (3-phenyl-1-propyl) oxy-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (3-phenyl-2-propen-1-yl) oxy-2,3-dihydrobenzofuran
(800 mg, 1.82 mmol) and 10% palladium-carbon
(Water-containing) (80 mg) was suspended in ethanol (20 mL) and stirred at room temperature for 3 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crystallized from methanol to obtain 610 mg of the desired product (yield: 76%). 78-80 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (3H, s), 1.22 (6H, d, J =
6.8 Hz), 1.48 (3H, s), 1.81 (3H, s), 2.02-2.22 (8
H, m), 2.76-2.91 (3H, m), 3.68 (2H, t, J = 6.4 H
z), 4.07 (1H, s), 6.70-6.92 (2H, br), 7.07 (2H, d,
J = 8.8 Hz), 7.15-7.32 (5H, m). Synthesis Example 25c 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-5- (2-phenylethyl) oxy-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2,4,6
7-pentamethyl-2,3-dihydrobenzofuran-5
-Ol (1.0 g, 3.08 mmol), 2-phenylethanol (414 mg, 3.39 mmol), triphenylphosphine (89
0 mg, 3.39 mmol) and diethyl azodicarboxylate (590 mg, 3.39 mmol) in tetrahydrofuran (20
mL) solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100: 1) to give the desired product (150 m).
g (11% yield). 72-74 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 0.98 (3H, s), 1.21 (6H, d, J =
7.0 Hz), 1.46 (3H, s), 1.72 (3H, s), 2.10 (3H, s),
2.12 (3H, s), 2.83 (1H, septet, J = 7.0 Hz), 3.05
(2H, t, J = 7.0 Hz), 3.85 (2H, t, J = 7.0 Hz), 4.0
3 (1H, s), 6.65-7.00 (2H, br), 7.06 (2H, d, J = 8.
0 Hz), 7.15-7.50 (5H, m).

Synthesis Example 26c 3- (4-isopropylphenyl) -2,4,6,7-
Tetramethylbenzofuran-5-yl 4-methoxybenzoate 3- (4-isopropylphenyl) -2,4,6,7-
Tetramethylbenzofuran-5-ol (0.90 g, 2.92
mmol) and 4-methoxybenzoyl chloride (0.55 g, 3.2
Triethylamine (0.45 mL, 3.21 mmol) was added to a solution of 1 mmol) in chloroform (15 mL) at room temperature.
Stir for 3 hours. Pour water (30 mL) into the reaction mixture, extract twice with ethyl acetate, and combine the combined organic layers with 1 N hydrochloric acid,
After washing with saturated sodium bicarbonate, it was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from ethanol to give 0.52 g (yield 79%) of the desired product. Melting point 1
13-115 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (6H, d, J = 6.8 Hz), 1.90
(3H, s), 2.18 (3H, s), 2.33 (3H, s), 2.46 (3H, s),
2.95 (1H, septet, J = 6.8 Hz), 3.89 (3H, s), 6.99
(2H, d, J = 9.0 Hz), 7.25 (4H, s), 8.20 (2H, d, J
= 8.8 Hz). Synthesis Example 27c 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,4,6,7-tetramethylbenzofuran 3- (4-isopropylphenyl) -2,4,6,7-
The target compound was synthesized according to Synthesis Example 1 using tetramethylbenzofuran-5-ol and 4-methoxybenzyl chloride. Yield 64%. Oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 6.8 Hz), 2.06
(3H, s), 2.31 (3H, s), 2.34 (3H, s), 2.43 (3H, s),
2.97 (1H, septet, J = 6.8 Hz), 3.82 (3H, s), 4.66
(2H, s), 6.91 (2H, d, J = 8.8 Hz), 7.26 (4H, s),
7.40 (2H, d, J = 8.8 Hz).

Synthesis Example 28c 2,4,6,7-Tetramethyl-3-phenylbenzofuran-5-yl 4-methoxybenzoate 2,4,6,7-Tetramethyl-3-phenylbenzofuran-5-ol and 4 The target compound was synthesized according to Synthesis Example 26 using -methoxybenzoyl chloride. Yield 6
Four%. 152-154 ° C. (Methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.88 (3H, s), 2.18 (3H, s), 2.
32 (3H, s), 2.46 (3H, s), 3.89 (3H, s), 6.99 (2H,
d, J = 9.2 Hz), 7.29-7.43 (5H, m), 8.20 (2H, d, J =
9.2 Hz). Synthesis Example 29c 3- (4-isopropylphenyl) -6- (4-methoxybenzyloxy) -2,2-dimethyl-2,3-dihydrobenzofuran 3- (4-isopropylphenyl) -2,2-dimethyl-2 , 3-Dihydrobenzofuran-6-ol (1.12
g, 4.00 mmol) of N, N-dimethylformamide (15 m
L) To the solution was added sodium hydride (60% liquid paraffin dispersion, 179.0 mg, 4.48 mmol) at 0 ° C, and the mixture was stirred at the same temperature for 30 minutes. 4-methoxybenzyl chloride (636.8 m
g, 4.07 mmol) and stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and the product was extracted twice with ethyl acetate.
The combined extracts were washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 5: 1) to obtain 1.19 g of the desired product (74% yield). 86-88
° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, s), 1.24 (6H, d, J =
7.0 Hz), 1.58 (3H, s), 2.89 (1H, septet, J = 7.0 H
z), 3.82 (3H, s), 4.27 (1H, s), 4.96 (2H, s), 6.47
-6.52 (2H, m), 6.90-6.95 (3H, m), 7.02 (2H, d, J =
8.1 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.37 (2H, d, J
= 8.8 Hz). Synthesis Example 30c 1′-benzyl-3- (4-isopropylphenyl)-
5- (4-methoxybenzyloxy) -4,6,7-trimethylspiro [benzofuran-2 (3H), 4'-piperidine] 1'-benzyl-3- (4-isopropylphenyl)-
4,6,7-trimethylspiro [benzofuran-2 (3
H), 4'-Piperidin] -5-ol (824.0 mg, 1.
To a solution of 81 mmol) in N, N-dimethylformamide (15 mL) was added sodium hydride (60% liquid paraffin dispersion, 81.4 mg, 2.04 mmol) at 0 ° C, and the mixture was stirred at the same temperature for 30 minutes. 4-methoxybenzyl chloride (319.9 mg, 2.04
mmol) and stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and the product was extracted twice with ethyl acetate. The combined extracts were washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 3: 1) to give the desired product.
539 mg (52% yield) were obtained. Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6.8 Hz), 1.27-
1.39 (2H, m), 1.81 (3H, s), 1.86-1.96 (2H, m), 2.1
9 (3H, s), 2.23 (3H, s), 2.35-2.87 (5H, m), 3.52 (2
H, s), 3.80 (3H, s), 4.04 (1H, s), 4.62 (2H, s),
6.6-6.9 (4H, m), 7.04-7.08 (2H, m), 7.22-7.36 (7H,
m).

Synthesis Example 31c 1′-benzyl-5- (4-methoxybenzyloxy)
-4,6,7-trimethylspiro [benzofuran-2
(3H), 4'-piperidine] N, N of 1'-benzyl-4,6,7-trimethylspiro [benzofuran-2 (3H), 4'-piperidin] -5-ol (1.01 g, 2.98 mmol) -To a solution of dimethylformamide (15 mL) at 0 ° C was added sodium hydride (60% liquid paraffin dispersion, 134.6 mg, 3.37 mmol),
The mixture was stirred at the same temperature for 30 minutes. 4-methoxybenzyl chloride
(584.9 mg, 3.43 mmol), and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and the product was extracted twice with ethyl acetate. The combined extracts were washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate
2: 1) to give 1.15 g (yield 85%) of the desired product. 85-86 ° C (hexane). ¹ H-NMR (CDCl ₃ ) δ: 1.80-2.00 (4H, m), 2.10 (3H,
s), 2.15 (3H, s), 2.18 (3H, s), 2.60 (4H, br), 2.8
7 (2H, s), 3.58 (2H, s), 3.83 (3H, s), 4.62 (2H,
s), 6.90-6.95 (2H, m), 7.30-7.43 (7H, m). Synthesis Example 32c 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4′-piperidine] 3- ( 4-isopropylphenyl) -1 ', 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
4'-piperidin] -5-ol (509.0 mg, 1.34 mmo
l) in N, N-dimethylformamide (25 mL) solution
Sodium hydride at 60 ° C (60% liquid paraffin dispersion, 6
4.3 mg, 1.61 mmol) and stirred at the same temperature for 30 minutes.
4-methoxybenzyl chloride (244.0 mg, 1.56 mmol)
Was added and stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and the product was extracted twice with ethyl acetate. After washing the combined extract with saturated saline, drying over magnesium sulfate,
It was concentrated under reduced pressure. The residue was subjected to column chromatography (Chro
matorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical);
The residue was subjected to hexane-ethyl acetate (1: 1) to obtain 262 mg of the desired product (yield: 39%). Amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 7.0 Hz), 1.3-
1.4 (2H, m), 1.82 (3H, s), 1.99-2.04 (2H, m), 2.19
(3H, s), 2.23 (3H, s), 2.30 (3H, s), 2.37-2.70 (4
H, m), 2.82 (1H, septet, J = 7.0 Hz), 3.81 (3H,
s), 4.05 (1H, s), 4.62 (2H, s), 6.6-6.9 (4H, m),
7.05-7.09 (2H, m), 7.33-7.37 (2H, m). Synthesis Example 33c 3- (4-isopropylphenyl) -1 ′, 4,6,7
-Tetramethyl-5- (4-pyridylmethyloxy) spiro [benzofuran-2 (3H), 4'-piperidine] 3- (4-isopropylphenyl) -1 ', 4,6,7
-Tetramethylspiro [benzofuran-2 (3H),
4'-piperidin] -5-ol (817.7 mg, 2.15 mmo
l) in N, N-dimethylformamide (30 mL) solution at 0 ° C with sodium hydride (60% liquid paraffin dispersion, 187.3
mg, 4.98 mmol) and stirred at the same temperature for 30 minutes. 4-
Chloromethylpyridine hydrochloride (364.5 mg, 2.22 mmol)
Was added and stirred at the same temperature for 30 minutes. The reaction mixture was poured into water and the product was extracted twice with ethyl acetate. After washing the combined extract with saturated saline, drying over magnesium sulfate,
It was concentrated under reduced pressure. The residue was subjected to column chromatography (Chro
matorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical);
The residue was subjected to hexane-ethyl acetate 4: 1) to obtain 575 mg (yield 57%) of the desired product. 96-98 ° C. (Hexane) ¹ H-NMR (CDCl ₃ ) δ: 1.21 (6H, d, J = 7.0 Hz), 1.34-
1.41 (2H, m), 1.82 (3H, s), 1.92-2.11 (2H, m), 2.19
(3H, s), 2.21 (3H, s), 2.30 (3H, s), 2.37-2.65 (4
H, m), 2.85 (1H, septet, J = 7.0 Hz), 4.05 (1H,
s), 4.72 (2H, s), 6.6-7.1 (4H, m), 7.36-7.39 (2H,
m), 8.58-8.61 (2H, m).

The chemical structural formula of the compound obtained in the above synthesis example is shown below.

[Table 8]

[Table 9]

[Table 10]

Formulation Example 1c (1) Compound obtained in Synthesis Example 4c 50 mg (2) Lactose 34 mg (3) Maize starch 10.6 mg (4) Maize starch (paste-like) 5 mg (5) Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg The above (1) to (6) were mixed according to a conventional method, and the mixture was tableted with a tableting machine to obtain tablets.

EXPERIMENTAL EXAMPLE 1 Dopamine neuronal cell body regeneration promoting action of MPP ⁺ human-induced neurodegeneration in cultured rat fetal midbrain dopamine neurons cultured on rat neonatal glial cells Experimental method Rat neonatal glial cells are SD line 1 -Prepared from 2-day old cerebrum. Subculture was performed 14 days after DIV, and the cells were seeded on a 96-well culture plate coated with polyerysine. Rat fetal dopamine neurons were prepared from the midbrain of 14-day-old SD embryos and seeded on the glial cells on a culture of 50,000 SK-N-SH cells. After 2 days of culture, 3 mM MPP ⁺ was added and 24
Incubate for hours to destroy dopamine nerves. Twenty-four hours later, the medium was replaced with the compound, and culturing was further performed for four days. After completion of the culture, the cells were fixed with paraformaldehyde, and then the dopamine nerve was stained with an anti-tyrosine hydroxylase antibody, and the number of tyrosine hydroxylase-positive dopamine neurons was counted. The results are shown in FIG. FIG. 1 shows that the agent for promoting proliferation and differentiation of stem cells and neural progenitor cells containing the compound (I) of the present invention promotes differentiation of neural stem cells.

Experimental Example 2 Neurogenesis-Promoting Effect in Rat Mixed Glial Culture a) Experimental Materials SD neonatal rats were purchased from Charles River Japan. A 40 micron diameter nylon cell strainer was purchased from Becton Dickinson. DMEM / F12
Medium, antibiotics, and N2 additives were purchased from Life Technology. Anti-βIII-tubulin antibody was purchased from Sigma. D
AKO EnVision + / HRP kit was purchased from Dako Japan. Other reagents used were commercial grade products. b) Experimental method Rat glial mixed culture Rat mixed glial culture was prepared from the hippocampus of 2 day old neonates of SD strain. The newborn was anesthetized on ice and decapitated and killed.
I quickly removed my brain. The meninges were carefully removed and the cerebral cortex was separated. The hippocampus was physically crushed through a 40 micron diameter nylon cell strainer. The cell dispersion was overlaid on the serum, and the cells were fractionated by discontinuous density gradient centrifugation. The precipitate was washed twice with growth medium (DMEM / F12 plus 10% FBS and antibiotics) and dispersed. Mixed glial cultures were plated on a 96-well collagen-coated multiplate at 1 per well.
The cells were seeded at a rate of x10 ⁵ cells and cultured for 5 days. 2. Differentiation Assay After 5 days of culture, mixed glial cultures were used for differentiation assays. The growth medium was replaced with serum-free medium (DMEM / F12 plus N2 additive and antibiotics), and compounds were added at the same time. After differentiation for 5 days, the cells were fixed with 4% paraformaldehyde, and immunostained with a mouse anti-βIII-tubulin monoclonal antibody and a DAKO EnVison + / HRP kit. βIII-tubulin-positive cells were measured, and a comparison was made between the case where compound (I) was added (1 μM) and the case where compound (I) was not added (control). The results of the activity of each compound (I) expressed as a percentage relative to when no compound was added (control) are shown in the table below.

[0205]

[Table 11] Synthetic example compounds Differentiation / new-generation promoting activity (%) It can be seen that the proliferation / differentiation promoting agent has the action of promoting differentiation / regeneration into βIII-tubulin-positive neural progenitor cells.

[0206]

EFFECT OF THE INVENTION The agent for promoting the proliferation and differentiation of stem cells and neural progenitor cells comprising the compound (I) of the present invention or a salt thereof, or a prodrug thereof, has an excellent effect of promoting the proliferation and differentiation of endogenous neural stem cells, In addition, it has an effect of promoting engraftment / differentiation in neural stem cell / neural cell transplantation, and is useful for prevention / treatment of central nervous system diseases such as neurodegenerative diseases.

[Brief description of the drawings]

FIG. 1 is a graph showing the effect of a test compound on promoting differentiation of neural stem cells.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4747 A61K 31/4747 A61P 25/28 A61P 25/28 43/00 107 43/00 107 123 123 C07D 307/78 C07D 307/78 405/04 405/04 405/12 405/12 407/12 407/12 409/12 409/12 491/056 491/056 491/107 491/107 C12N 5/06 C12N 5 / 00 E (72) Inventor Masaomi Miyamoto 4-12-11, Gotenyama, Takarazuka-shi, Hyogo (72) Inventor Masahiro Okura 2-6-1, Shibuya, Ikeda-shi, Osaka F-term (reference) 4B065 AA91X BA18 BB13 CA44 4C050 AA01 AA04 AA08 BB04 BB07 CC16 CC17 EE01 FF01 FF02 FF03 FF05 GG01 HH02 4C063 AA01 BB02 BB09 CC76 CC81 CC92 DD07 DD12 DD76 EE01 4C086 AA01 AA02 BA06 BA13 BB02 BC17 BC02 GA01 GA02

Claims (33)

[Claims] 1. The formula: embedded image [Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent; ¹
And R ² may form a 3- to 8-membered homo- or heterocyclic ring which may have a substituent together with an adjacent carbon atom, and R ³ may be a hydrogen atom or a substituent have a good hydrocarbon group or a substituent shown also heterocyclic group, - - - represents a single bond or a double bond, W is (i)
Formula: Wherein, in the formula, ring A represents a benzene ring which may have a substituent, and ring B represents a 5- to 7-membered nitrogen-containing heterocyclic ring which may have a substituent. (Ii) Formula: [In the formula, R ⁴ is (1) an aliphatic hydrocarbon group optionally substituted with an aromatic group, and further optionally having a substituent or (2) a substituent. An acyl group containing an aromatic group which may be substituted, R ⁵ represents a hydrogen atom,
C _1-6 alkyl or a group represented by the acyl group showing a] or (iii) formula: 4] ^R 4c -X- (Wc) ^{wherein, R 4c} may have a substituent Aromatic groups,
X represents an aliphatic hydrocarbon group or an acyl group which may have a substituent, X represents an oxygen atom or a sulfur atom which may be oxidized], Y represents an oxygen atom,
It represents a sulfur atom which may be oxidized or an imino which may have a substituent, and the ring C represents a benzene ring which may further have a substituent in addition to the group represented by W. Or an agent for promoting proliferation and differentiation of stem cells and / or neural progenitor cells, comprising the compound or a salt thereof or a prodrug thereof. 2. The agent according to claim 1, wherein the stem cells are embryonic stem cells or neural stem cells. 3. The agent according to claim 1, which is an agent for promoting engraftment / differentiation in neural stem cell, neural progenitor cell and / or neural cell transplantation. 4. An agent for promoting proliferation / differentiation of neural stem cells, neural progenitor cells and / or neural cells for transplantation.
Agents as described. 5. The agent according to claim 1, which is an agent for promoting proliferation and differentiation of endogenous neural stem cells. 6. The agent according to claim 1, which is used for prevention / treatment of a central nervous system disease. 7. The agent according to claim 1, which is a nerve regeneration promoter. 8. The agent according to claim 1, which is an agent for promoting neurogenesis. 9. - - - is agent according to claim 1 is a single bond. 10. The agent according to claim 1, wherein Y is an oxygen atom. 11. The agent according to claim 1, wherein W is a group represented by the formula (Wa). 12. R ¹ and R ² are each a C _1-6 alkyl group, and R ³ is a phenyl group optionally having 1 to 3 substituents selected from a C _1-6 alkyl and a halogen atom. , The C ring further comprises C _1-6 alkyl and C
A substituent selected from _1-6 alkoxy benzene ring which may have three from 1, - - - is a single bond, Y is an oxygen atom, a group represented by formula (Wa) has the formula: Embedded image [In the formula, ring A ¹ represents a benzene ring which may have 1 to 3 substituent (s) selected from halogen, C _1-6 alkoxy and C _1-6 alkylenedioxy. The agent according to claim 11, which is a group represented by the formula: 13. The agent according to claim 12, wherein the group represented by the formula (Wa) is substituted at the 5-position of the benzofuran ring. 14. [2- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] isoindoline;
5,6-dimethoxy-2- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] isoindoline,
5,6-dimethoxy-2- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,
3-dihydro-1-benzofuran-5-yl] isoindoline, 5,6-dimethoxy-2- [2,2,4,
6,7-pentamethyl-3- (4-methylphenyl)-
2,3-dihydro-1-benzofuran-5-yl] -2
H-isoindole, 6- [3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,
3-dihydro-1-benzofuran-5-yl] -6,7
-Dihydro-5H- [1,3] dioxolo [4,5-
f] isoindole, 6- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] -6H- [1,
3] dioxolo [4,5-f] isoindole, 6-
(2,2,4,6,7-pentamethyl-3-phenyl-
2,3-dihydro-1-benzofuran-5-yl)-
6,7-dihydro-5H- [1,3] dioxolo [4,
5-f] isoindole, (R) -5,6-dimethoxy-2- [2,2,4,6,7-pentamethyl-3-
(4-Methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] isoindoline or (R)-
Contains 5,6-dimethoxy-2- [2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-yl] isoindoline hydrochloride. The agent according to claim 11, which comprises: (15) (R) -5,6-dimethoxy-2-
[2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-
12. The agent according to claim 11, comprising [5-yl] isoindoline. 16. The agent according to claim 1, wherein W is a group represented by the formula (Wb). 17. R¹And R²Is a methyl group
And R³Is selected from fluorine, methyl and isopropyl
A phenyl group optionally having 1 to 3 substituents
And the C ring is further C_1-6Alkyl and C_1-6Al
Even if it has 1 to 3 substituents selected from
A good benzene ring, Y is an oxygen atom, R ⁴Is fluorine,
1 substituents selected from toxic and methylenedioxy
Benzyl or phenyl optionally having 3 to 3 each
With a phenethyl group, R⁵Is a hydrogen atom or a methyl group
17. The agent according to claim 16. 18. (1) N- (4-fluorobenzyl)
-2,2,4,6,7-pentamethyl-3-phenyl-
2,3-dihydro-1-benzofuran-5-amine,
(2) N-benzyl-3- (4-isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, (3) 3-
(4-isopropylphenyl) -N- (4-methoxybenzyl) -N, 2,2,4,6,7-hexamethyl-
2,3-dihydro-1-benzofuran-5-amine,
(4) 3- (4-isopropylphenyl) -N- [2-
(4-methoxyphenyl) ethyl] -2,2,4,6
7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, (5) N- (4-fluorobenzyl)
-3- (4-Isopropylphenyl) -2,2,4
6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, (6) N- (1,3-benzodioxol-5-ylmethyl) -3- (4-isopropylphenyl) -2 , 2,4,6,7-pentamethyl-2,
3-dihydro-1-benzofuran-5-amine, (7)
N- (4-fluorobenzyl) -3- (4-fluorophenyl) -2,2,4,6,7-pentamethyl-2,3
-Dihydro-1-benzofuran-5-amine, (8) N
-(4-methoxybenzyl) -2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine, (9) N-
(4-fluorobenzyl) -2,2,4,6,7-pentamethyl-3- (4-methylphenyl) -2,3-dihydro-1-benzofuran-5-amine, (10) 3- (4
-Isopropylphenyl) -N- (4-methoxybenzyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine, (11) N- (4-fluorobenzyl)
-3- (4-Isopropylphenyl) -2,4,6,7
-Tetramethyl-1-benzofuran-5-amine, (1
2) N- (4-fluorobenzyl) -3- (4-fluorophenyl) -2,4,6,7-tetramethyl-1-benzofuran-5-amine, (13) N- (4-fluorobenzyl) -3- (4-isopropylphenyl) -1 ′,
4,6,7-tetramethylspiro [benzofuran-2
(3H), 4'-piperidin] -5-amine or (1
4) (R) -N- (4-fluorobenzyl) -3- (4
-Isopropylphenyl) -2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-
17. The agent according to claim 16, comprising an amine hydrochloride. 19. The agent according to claim 1, wherein W is a group represented by the formula (Wc). 20. The formula: [Wherein, R ¹ and R ² are each a C _1-6 alkyl _optionally having a 6-membered saturated cyclic amino substituted with phenyl, or R ¹ and R ² together with an adjacent carbon atom , _{C 1-6} alkyl or _{C 7-16} form piperidine substituted aralkyl; ^{R 3} is (i) hydrogen atom or (ii) _{(1) C 1-6} alkyl, (2) di -C
Phenyl ^optionally having 1 to 3 substituents selected from _1-6 alkylamino and (3) 6-membered saturated cyclic amino optionally having C _1-6 alkyl; R ^4c is (i) Phenyl optionally having 1 to 3 substituents selected from nitro and C _1-6 alkyl-carboxamide, (ii) C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkoxy-carbonyl, C _1-6 has alkylsulfonyl and C _1-6 alkylsulfinyl, 1 to substituents selected from the Le may have three each phenyl, quinolyl or pyridyl 1 to 3, respectively, phenyl as substituent, carboxy or _{C 1-6} alkoxy - optionally _{C 1 -6} alkyl optionally having carbonyl respectively or _{C 2-6} alkenyl or, (Iii) formula ^{- (C = O) -R 5} ' acyl represented ^by' wherein, R ^{5 ''} is a phenyl substituted with _{C 1-6} alkoxy]; and C ^'rings, further A benzene ring optionally having 1 to 3 C _1-6 alkyl], a salt thereof, or a prodrug thereof. 21. 3- (4-isopropylphenyl)-
5- (4-methoxybenzyloxy) -2,2,4
6,7-pentamethyl-2,3-dihydrobenzofuran, 3- (4-methylphenyl) -2,4,6,7-tetramethylbenzofuran-5-yl 4-methoxybenzoate, 3- (4-isopropylphenyl) −2,
4,6,7-tetramethylbenzofuran-5-yl 4
-Methoxybenzoate, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -2,
4,6,7-tetramethylbenzofuran, 3- (4-isopropylphenyl) -5- (4-methoxybenzyloxy) -1 ′, 4,6,7-tetramethylspiro [benzofuran-2 (3H), 4 '-Piperidine] or a salt thereof. 22. A method for culturing stem cells, neural progenitor cells and / or neural cells, comprising culturing stem cells, neural progenitor cells and / or neural cells in the presence of the compound according to claim 1 or a salt thereof. 23. The method according to claim 22, wherein the stem cells are embryonic stem cells or neural stem cells. 24. The method according to claim 2, wherein cells for transplantation treatment are prepared.
3. The culture method according to 2. 25. A cell obtained by the method according to claim 22. 26. A stem cell for transplantation, a neural progenitor cell, and / or a compound comprising the compound according to claim 1 or a salt thereof.
Or a growth / differentiation promoter in culture of nerve cells. 27. The agent according to claim 1, which is a therapeutic agent for cognitive impairment or memory impairment. 28. The agent according to claim 1, which is a therapeutic agent for mild cognitive impairment or mild memory impairment. 29. Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for producing an engraftment / differentiation promoting agent in neural stem cell and / or nerve cell transplantation. 30. Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for producing a neural stem cell and / or nerve cell growth / differentiation promoter for transplantation. 31. Use of the compound according to claim 1 or a salt thereof or a prodrug thereof for the manufacture of a prophylactic / therapeutic agent for central nervous system diseases. 32. A method for transplanting and treating stem cells, neural progenitor cells and / or neural cells, which comprises administering the compound according to claim 1 or a salt thereof or a prodrug thereof. 33. A method for preventing or treating a central nervous system disease in a mammal, which comprises administering the compound according to claim 1 or a salt thereof or a prodrug thereof to a mammal in need thereof.