JP2000026366A - Intermediate carboxylic acid and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain new intermediate carboxylic acids useful as intermediates for synthesizing an ACAT inhibitor and an antilipidimic agent comprising respectively specific carboxylic acids. SOLUTION: The new carboxylic acids are compounds of formula I (R1 is a 2-12C alkyl; R2a, R2b and R2d are each H or the like; R2c and R2e are each a 1-4C alkoxy or the like; R3 is H or the like), e.g. methyl (Z)-3-(2,4- dimethoxyphenyl)oct-2-enoate. The compound of formula I is obtained by reacting a lactone compound of formula II with 3-10 equiv. (1-4C) alkyl halide (e.g. methyl iodide, or the like) in an inert solvent (e.g. N,N-dimethylformamide, or the like) in the presence of 1-10 equiv. base (e.g. barium hydroxide, etc.) pref. at 10-40 deg.C for 2-30 h. to produce an ester compound of cis form of formula III and then by reacting the compound of formula III with 1-10 equiv. base (e.g. sodium hydroxide, or the like) in the presence of a water-containing inert solvent (e.g. methanol, or the like) pref. at 30-100 deg.C for 30 min.-5 h. to hydrolyze the compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to ACAT (acyl Co-A:
The present invention relates to carboxylic acids useful as synthetic intermediates for cholesterol acyltransferase) inhibitors and a method for producing the same.

[0002]

2. Description of the Related Art

[0003]

Embedded image (Wherein R ′ ₁ represents an alkyl group having 1 to 12 carbon atoms, and R ′ _2a , R ′ _2b , R ′ _2c and R ′ _2d represent a hydrogen atom and the like). A) is an excellent ACA
It is used as a synthetic intermediate of a T inhibitor, and is useful as a synthetic intermediate of an antihyperlipidemic agent (see, for example, JP-A-9-143137).
No.). Then, the compound (A) is converted into an isocyanate compound as shown below, and is led to a compound (B) having an extremely excellent ACAT inhibitory action by reaction with an aniline compound.

[0004]

Embedded image In addition, this compound (A) was synthesized from 2,4-dimethoxybenzaldehyde as a starting material in four steps including a condensation reaction with malonic acid and a conjugate addition reaction of an alkylmagnesium halide reagent, to give (S) -phenyl It is manufactured by optical resolution using ethylamine.

[0005]

However, this method has problems such as the use of alkylmagnesium halides having a high risk, the complicated operation of repeating recrystallization in optical resolution, and the low yield. However, it is not industrially suitable.

The present inventors have made intensive studies to solve these problems and to establish an industrial production method. As a result, the present inventors have developed novel cis-carboxylic acids derived from coumarin derivatives in higher yield. The inventors have found that asymmetric carboxylic acids containing compound (A) can be produced easily and in high yield by performing asymmetric catalytic reduction using a transition metal catalyst having an active ligand, and completed the present invention.

[0007]

According to the present invention, there is provided a compound of the general formula

[0008]

Embedded image(Where R¹Represents an alkyl group having 2 to 12 carbon atoms,
R^2a, R^2bAnd R^2dAre the same or different
, An alkyl group having 1 to 12 carbon atoms, 1 fluorine atom
Alkyl group of 1 to 4 carbon atoms substituted with up to 6 carbon atoms, protection
Protected amino group, hydroxyl group, protected hydroxyl group or carbon number
Represents 1 to 4 alkoxy groups;^2cAnd R^2eIs carbon
Represents an alkoxy group of 1 to 4 or R ^2bAnd R^2cBut
Together, alkylene dioxy having 1 to 6 carbon atoms
Group or cycloalkylenedioxy group having 3 to 6 carbon atoms
And R^ThreeIs a hydrogen atom or an alkyl having 1 to 4 carbon atoms.
Represents a hydroxyl group. Cis-carboxylic acids having the formula
General formula using this method and this compound

[0009]

Embedded image (Wherein, R ¹ , R ^2a , R ^2b , R ^2c , R ^2d and R ³ have the same meanings as described above).

The alkyl group having 2 to 12 carbon atoms in the definition of R ^{1 in} the compounds (I) and (III) is, for example, ethyl, propyl, isopropyl, butyl, isobutyl, s- Butyl group, t-butyl group, pentyl group,
Isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3- Dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl Group, 1-methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 1-propylbutyl group,
4,4-dimethylpentyl group, octyl group, 1-methylheptyl group, 2-methylheptyl group, 3-methylheptyl group, 4-methylheptyl group, 5-methylheptyl group,
6-methylheptyl group, 1-propylpentyl group, 2-
Ethylhexyl group, 5,5-dimethylhexyl group, nonyl group, 3-methyloctyl group, 4-methyloctyl group,
5-methyloctyl group, 6-methyloctyl group, 1-propylhexyl group, 2-ethylheptyl group, 6,6-dimethylheptyl group, decyl group, 1-methylnonyl group, 3
2 carbon atoms such as -methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl or dodecyl; To 12 straight-chain or branched alkyl groups, preferably a straight-chain alkyl group having 2 to 12 carbon atoms, and more preferably a straight-chain alkyl group having 2 to 8 carbon atoms. And most preferably a linear alkyl group having 4 to 6 carbon atoms.

The alkyl group having 1 to 12 carbon atoms in the definition of R ^2a , R ^2b and R ^2d is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl. Group, t-butyl group, pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group,
1-ethylpropyl group, hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group,
1-methylpentyl group, 3,3-dimethylbutyl group,
2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, heptyl group, 1- Methylhexyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 1-propylbutyl group,
4,4-dimethylpentyl group, octyl group, 1-methylheptyl group, 2-methylheptyl group, 3-methylheptyl group, 4-methylheptyl group, 5-methylheptyl group,
6-methylheptyl group, 1-propylpentyl group, 2-
Ethylhexyl group, 5,5-dimethylhexyl group, nonyl group, 3-methyloctyl group, 4-methyloctyl group,
5-methyloctyl group, 6-methyloctyl group, 1-propylhexyl group, 2-ethylheptyl group, 6,6-dimethylheptyl group, decyl group, 1-methylnonyl group, 3
1-carbon group such as -methylnonyl group, 8-methylnonyl group, 3-ethyloctyl group, 3,7-dimethyloctyl group, 7,7-dimethyloctyl group, undecyl group, 4,8-dimethylnonyl group or dodecyl group A straight-chain or branched alkyl group having 1 to 12 carbon atoms, preferably a straight-chain alkyl group having 1 to 12 carbon atoms, and more preferably a straight-chain alkyl group having 1 to 4 carbon atoms. Group, particularly preferably a methyl group or an ethyl group, and most preferably a methyl group.

In the definition of R ^2a , R ^2b and R ^2d , an alkyl group having 1 to 4 carbon atoms substituted by 1 to 6 fluorine atoms is, for example, a fluoromethyl group, a difluoromethyl group,
Trifluoromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group, 2,2-difluoroethyl group, 1,1,1-trifluoroethyl Group, 1,1,2-trifluoroethyl group, 1,2,2-trifluoroethyl group, 1,1,2,2-tetrafluoroethyl group,
1,1,1,2,2-pentafluoroethyl group, 1,1,2,2,3,3-hexafluoro-3-propyl group, 1,1,1,2,3,3-hexafluoro- 3-propyl group, 1,1,1,3,3,3-hexafluoro-2-propyl group or 1,1,1-trifluoro-4-butyl group, preferably a fluoromethyl group, difluoro It is a methyl group, a trifluoromethyl group, a 1-fluoroethyl group or a 2-fluoroethyl group, and most preferably a trifluoromethyl group.

The amino-protecting group of the protected amino group in the definition of R ^2a , R ^2b and R ^2d includes, for example, benzoyl, methylbenzoyl, methoxybenzoyl, fluorobenzoyl, chlorobenzoyl, C1-C4 alkyl such as naphthoyl group, C1-C4 akoxy, or C6-C10 aromatic acyl group which may be substituted with halogen; formyl group, acetyl group, propionyl group An aliphatic acyl group having 1 to 5 carbon atoms, such as butyryl group and pivaloyl group; and 2 to 5 carbon atoms such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group or t-butoxycarbonyl group. Alkoxycarbonyl groups, preferably a benzoyl group, having 2 to 4 carbon atoms.
Aliphatic acyl groups or an alkoxycarbonyl group having 2 to 3 carbon atoms or a t-butoxycarbonyl group,
Most preferably, it is an acetyl group.

In the definition of R ^2a , R ^2b and R ^2d , the hydroxyl-protecting group of the protected hydroxyl group may be, for example, alkyl having 1 to 4 carbon atoms or 1 to 4 carbon atoms in the amino-protecting group. Aromatic alkoxy groups having 6 to 10 carbon atoms which may be substituted with two akoxy or halogen atoms or 1 carbon atoms
5 to 5 aliphatic acyl groups; alkyl having 1 to 4 carbons such as benzyl, methylbenzyl, methoxybenzyl, fluorobenzyl, and chlorobenzyl, akoxy or halogen having 1 to 4 carbons A benzyl group which may be substituted; a trityl group; a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group,
tri-C 1-4 alkylsilyl groups such as t-butyldimethylsilyl group; methoxymethyl group; methoxyethoxymethyl group; benzyloxymethyl group, methylbenzyloxymethyl group, methoxybenzyloxymethyl group, fluorobenzyl Alkyl having 1 to 4 carbon atoms such as oxymethyl group, chlorobenzyloxymethyl group,
A benzyloxymethyl group having 1 to 4 carbon atoms which may be substituted by akoxy or halogen; tetrahydropyranyl group; such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, isopropyloxycarbonyl group, butoxycarbonyl group Carbon number 2
From 5 to 5 alkoxycarbonyl groups; or a benzyloxycarbonyl group, a methylbenzyloxycarbonyl group,
A benzyloxycarbonyl group which may be substituted with an alkyl having 1 to 4 carbons, an alkoxy or a halogen having 1 to 4 carbons such as a methoxybenzyloxycarbonyl group, a fluorobenzyloxycarbonyl group, a chlorobenzyloxycarbonyl group; And preferably acetyl or benzoyl.

The alkoxy group having 1 to 4 carbon atoms in the definition of R ^2a , R ^2b , R ^2c , R ^2d and R ^2e is, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group. An isobutoxy group, an s-butoxy group or
It is a linear or branched alkoxy group having 1 to 4 carbon atoms such as a t-butoxy group, preferably a methoxy group or an ethoxy group, and most preferably a methoxy group.

An alkylenedioxy group having 1 to 4 carbon atoms formed by R ^2b and R ^2c together includes, for example, methylenedioxy, methylmethylenedioxy, dimethylmethylenedioxy, methyl (ethyl) methylenedioxy It is an oxy, ethylenedioxy or trimethylenedioxy group, preferably a methylenedioxy, methylmethylenedioxy or dimethylmethylenedioxy group, and most preferably a methylenedioxy group.

The cycloalkylidenedioxy group having 3 to 6 carbon atoms formed by R ^2b and R ^2c together is, for example, cyclopropylidenedioxy, cyclobutylidenedioxy, cyclopentylidenedioxy or cyclohexylidene. A dendioxy group, preferably a cyclopentylidenedioxy or cyclohexylidenedioxy group,
Most preferably, it is a cyclohexylidenedioxy group.

The alkyl group having 1 to 4 carbon atoms in the definition of R ³ is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl. , Preferably a methyl group or an ethyl group, and most preferably a methyl group.

The compound having the general formula (I) is preferably
(1) Compound R ¹ is an alkyl group having 2 to 8 carbon atoms, (2) compounds wherein R ¹ is an alkyl group having 4 to 6 carbon atoms, (3) R ^2a is hydrogen or C R ^2b is a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms, R ^2c is an alkoxy group having 1 to 4 carbon atoms, R ^2d is a hydrogen atom, A compound in which R ^2e is a methyl group or an ethyl group, R ^2e is an alkoxy group having 1 to 4 carbon atoms, (4) R ^2a is a hydrogen atom, a methoxy group or an ethoxy group, and R ^2b is a hydrogen atom, a methoxy group or An ethoxy group, R ^2c is a methoxy group or an ethoxy group, R ^2d is a hydrogen atom or a methyl group,
A compound wherein R ^2e is a methoxy group or an ethoxy group, (5)
R ^2a is a hydrogen atom or a methoxy group, R ^2b is a hydrogen atom, R ^2c is a methoxy group or an ethoxy group, and R ^2d
Is a hydrogen atom or a methyl group and R ^2e is a methoxy group or an ethoxy group; (6) a compound wherein R ³ is a hydrogen atom, a methyl group or an ethyl group; or (7) a compound wherein R ³ is a hydrogen atom Can be given.

Further, R ¹ is selected from (1) or (2),
Compounds obtained by selecting R ^{2a to} R ^2e from (3) to (5) and selecting R ³ from (6) or (7) and arbitrarily combining them are also suitable, for example, (8) R ¹ is an alkyl group having 2 to 8 carbon atoms, R ^2a is a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms, and R ^2b
Is a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms, R ^2c is an alkoxy group having 1 to 4 carbon atoms,
^2d is a hydrogen atom, a methyl group or an ethyl group, R ^2e is the number 1 to 4 alkoxy groups carbons, R ³ is a hydrogen atom, a methyl group or an ethyl group compound (9) R ¹ carbon atoms An alkyl group having 2 to 8, R ^2a is a hydrogen atom, a methoxy group or an ethoxy group, R ^2b is a hydrogen atom, a methoxy group or an ethoxy group, R ^2c is a methoxy group or an ethoxy group, R ^2d is a hydrogen atom or a methyl group, R ^2e is methoxy or ethoxy, R ³
Is a hydrogen atom, a methyl group or an ethyl group, or (10) R ¹ is an alkyl group having 4 to 6 carbon atoms, R ^2a is a hydrogen atom or a methoxy group, and R ^2b is a hydrogen atom. , R ^2c is a methoxy group or an ethoxy group, R ^2d is a hydrogen atom or a methyl group, R ^2e is a methoxy group or an ethoxy group, and R ³ is a hydrogen atom.

Next, specific examples of the compound having the general formula (I) of the present invention are shown in Tables 1 and 2. The abbreviations in the table indicate the following groups. Me: methyl group, Et: ethyl group, Pr: propyl group, Bu: butyl group, Pn: pentyl group, Hx: hexyl group, Hp: heptyl group, Oc: octyl group

[0022]

[Table 1]

[0023]

Embedded image Compound number R ¹ R ^2a R ^2b R ^2c R ^2d R ^2e R ³ 1-1 Et HH OMe H OMe Me 1-2 Pr HH OMe H OMe Me 1-3 Bu HH OMe H OMe Me 1-4 Pn HH OMe H OMe Me 1-5 Hx HH OMe H OMe Me 1-6 Hp HH OMe H OMe Me 1-7 Oc HH OMe H OMe Me 1-8 Et HH OEt H OMe Me 1-9 Pr HH OEt H OMe Me 1-10 Bu HH OEt H OMe Me 1-11 Pn HH OEt H OMe Me 1 -12 Hx HH OEt H OMe Me 1-13 Hp HH OEt H OMe Me 1-14 Oc HH OEt H OMe Me 1-15 Et HH OPr H OMe Me 1-16 Pr HH OPr H OMe Me 1-17 Bu HH OPr H OMe Me 1-18 Pn HH OPr H OMe Me 1-19 Hx HH OPr H OMe Me 1-20 Hp HH OPr H OMe Me 1-21 Oc HH OPr H OMe Me 1-22 Et HH OBu H OMe Me 1- 23 Pr HH OBu H OMe Me 1-24 Bu HH OBu H OMe Me 1-25 Pn HH OBu H OMe Me 1-26 Hx HH OBu H OMe Me 1-27 Hp HH OBu H OMe Me 1-28 Oc HH OBu H OMe Me 1-29 Et HH OMe Me OMe Me 1-30 Pr HH OMe Me OMe Me 1-31 Bu HH OMe Me OMe Me 1-32 Pn HH OMe Me OMe Me 1-33 Hx HH OMe Me OMe Me 1-34 Hp HH OMe Me OMe Me 1-35 Oc HH OMe Me OMe Me 1-36 Et HH OEt Me OMe Me 1-37 Pr HH OEt Me OMe Me 1-38 Bu HH OEt Me OMe Me 1-39 Pn HH OEt Me OMe Me 1-40 Hx HH OEt Me OMe Me 1-41 Hp HH OEt Me OMe Me 1-42 Oc HH O Et Me OMe Me 1-43 Et HH OPr Me OMe Me 1-44 Pr HH OPr Me OMe Me 1-45 Bu HH OPr Me OMe Me 1-46 Pn HH OPr Me OMe Me 1-47 Hx HH OPr Me OMe Me 1 -48 Hp HH OPr Me OMe Me 1-49 Oc HH OPr Me OMe Me 1-50 Et HH OBu Me OMe Me 1-51 Pr HH OMe Me OMe Me 1-52 Bu HH OMe Me OMe Me 1-53 Pn HH OMe Me OMe Me 1-54 Hx HH OMe Me OMe Me 1-55 Hp HH OMe Me OMe Me 1-56 Oc HH OMe Me OMe Me 1-57 Et OMe H OMe H OMe Me 1-58 Pr OMe H OMe H OMe Me 1-59 Bu OMe H OMe H OMe Me 1-60 Pn OMe H OMe H OMe Me 1-61 Hx OMe H OMe H OMe Me 1-62 Hp OMe H OMe H OMe Me 1-63 Oc OMe H OMe H OMe Me 1-64 Et OMe H OEt H OMe Me 1-65 Pr OMe H OEt H OMe Me 1-66 Bu OMe H OEt H OMe Me 1-67 Pn OMe H OEt H OMe Me 1-68 Hx OMe H OEt H OMe Me 1-69 Hp OMe H OEt H OMe Me 1-70 Oc OMe H OEt H OMe Me 1-71 Et OMe H OPr H OMe Me 1-72 Pr OMe H OPr H OMe Me 1-73 Bu OMe H OPr H OMe Me 1-74 Pn OMe H OPr H OMe Me 1-75 Hx OMe H OPr H OMe Me 1-76 Hp OMe H OPr H OMe Me 1-77 Oc OMe H OPr H OMe Me 1-78 Et OMe H OBu H OMe Me 1-79 Pr OMe H OBu H OMe Me 1-80 Bu OMe H OB u H OMe Me 1-81 Pn OMe H OBu H OMe Me 1-82 Hx OMe H OBu H OMe Me 1-83 Hp OMe H OBu H OMe Me 1-84 Oc OMe H OBu H OMe Me 1-85 Et OEt H OEt H OMe Me 1-86 Pr OEt H OEt H OMe Me 1-87 Bu OEt H OEt H OMe Me 1-88 Pn OEt H OEt H OMe Me 1-89 Hx OEt H OEt H OMe Me 1-90 Hp OEt H OEt H OMe Me 1-91 Oc OEt H OEt H OMe Me 1-92 Et OPr H OPr H OMe Me 1-93 Pr OPr H OPr H OMe Me 1-94 Bu OPr H OPr H OMe Me 1-95 Pn OPr H OPr H OMe Me 1-96 Hx OPr H OPr H OMe Me 1-97 Hp OPr H OPr H OMe Me 1-98 Oc OPr H OPr H OMe Me 1-99 Et OBu H OBu H OMe Me 1-100 Pr OBu H OBu H OMe Me 1-101 Bu OBu H OBu H OMe Me 1-102 Pn OBu H OBu H OMe Me 1-103 Hx OBu H OBu H OMe Me 1-104 Hp OBu H OBu H OMe Me 1-105 Oc OBu H OBu H OMe Me 1-106 Et H OMe OMe H OMe Me 1-107 Pr H OMe OMe H OMe Me 1-108 Bu H OMe OMe H OMe Me 1-109 Pn H OMe OMe H OMe Me 1-110 Hx H OMe OMe H OMe Me 1-111 Hp H OMe OMe H OMe Me 1-112 Oc H OMe OMe H OMe Me 1-113 Et H OEt OEt H OMe Me 1-114 Pr H OEt OEt H OMe Me 1-115 Bu H OEt OEt H OMe Me 1-116 Pn H OEt OEt H OMe Me 1-117 Hx H OEt OEt H OMe Me 1-118 Hp H OEt OEt H OMe Me 1-119 Oc H OEt OEt H OMe Me 1-120 Et H OPr OPr H OMe Me 1-121 Pr H OPr OPr H OMe Me 1-122 Bu H OPr OPr H OMe Me 1-123 Pn H OPr OPr H OMe Me 1-124 Hx H OPr OPr H OMe Me 1-125 Hp H OPr OPr H OMe Me 1-126 Oc H OPr OPr H OMe Me 1-127 Et H OBu OBu H OMe Me 1-128 Pr H OBu OBu H OMe Me 1-129 Bu H OBu OBu H OMe Me 1-130 Pn H OBu OBu H OMe Me 1-131 Hx H OBu OBu H OMe Me 1-132 Hp H OBu OBu H OMe Me 1-133 Oc H OBu OBu H OMe Me 1-134 Et H OCH ₂ OH OMe Me 1-135 Pr H OCH ₂ OH OMe Me 1-136 Bu H OCH ₂ OH OMe Me 1-137 Pn H OCH ₂ OH OMe Me 1-138 Hx H OCH ₂ OH OMe Me 1-139 Hp H OCH ₂ OH OMe Me 1-140 Oc H OCH ₂ OH OMe Me

[0024]

[Table 2]

[0025]

Embedded image  Compound number R¹ R^2a R^2b R^2c R^2d R^2e 2-1 Et HH OMe H OMe 2-2 Pr HH OMe H OMe 2-3 Bu HH OMe H OMe 2-4 Pn HH OMe H OMe 2-5 Hx HH OMe H OMe 2-6 Hp HH OMe H OMe 2- 7 Oc HH OMe H OMe 2-8 Et HH OEt H OMe 2-9 Pr HH OEt H OMe 2-10 Bu HH OEt H OMe 2-11 Pn HH OEt H OMe 2-12 Hx HH OEt H OMe 2-13 Hp HH OEt H OMe 2-14 Oc HH OEt H OMe 2-15 Et HH OPr H OMe 2-16 Pr HH OPr H OMe 2-17 Bu HH OPr H OMe 2-18 Pn HH OPr H OMe 2-19 Hx HH OPr H OMe 2-20 Hp HH OPr H OMe 2-21 Oc HH OPr H OMe 2-22 Et HH OBu H OMe 2-23 Pr HH OBu H OMe 2-24 Bu HH OBu H OMe 2-25 Pn HH OBu H OMe 2-26 Hx HH OBu H OMe 2-27 Hp HH OBu H OMe 2-28 Oc HH OBu H OMe 2-29 Et HH OMe Me OMe 2-30 Pr HH OMe Me OMe 2-31 Bu HH OMe Me OMe 2- 32 Pn HH OMe Me OMe 2-33 Hx HH OMe Me OMe 2-34 Hp HH OMe Me OMe 2-35 Oc HH OMe Me OMe 2-36 Et HH OEt Me OMe 2-37 Pr HH OEt Me OMe 2-38 Bu HH OEt Me OMe 2-39 Pn HH OEt Me OMe 2-40 Hx HH OEt Me OMe 2-41 Hp HH OEt Me OMe 2-42 Oc HH OEt Me OMe 2-43 Et HH OPr Me OMe 2-44 Pr HH OPr Me OMe 2-45 Bu HH OPr Me OMe 2- 46 Pn HH OPr Me OMe 2-47 Hx HH OPr Me OMe 2-48 Hp HH OPr Me OMe 2-49 Oc HH OPr Me OMe 2-50 Et HH OBu Me OMe 2-51 Pr HH OMe Me OMe 2-52 Bu HH OMe Me OMe 2-53 Pn HH OMe Me OMe 2-54 Hx HH OMe Me OMe 2-55 Hp HH OMe Me OMe 2-56 Oc HH OMe Me OMe 2-57 Et OMe H OMe H OMe 2-58 Pr OMe H OMe H OMe 2-59 Bu OMe H OMe H OMe 2-60 Pn OMe H OMe H OMe 2-61 Hx OMe H OMe H OMe 2-62 Hp OMe H OMe H OMe 2-63 Oc OMe H OMe H OMe 2 -64 Et OMe H OEt H OMe 2-65 Pr OMe H OEt H OMe 2-66 Bu OMe H OEt H OMe 2-67 Pn OMe H OEt H OMe 2-68 Hx OMe H OEt H OMe 2-69 Hp OMe H OEt H OMe 2-70 Oc OMe H OEt H OMe 2-71 Et OMe H OPr H OMe 2-72 Pr OMe H OPr H OMe 2-73 Bu OMe H OPr H OMe 2-74 Pn OMe H OPr H OMe 2- 75 Hx OMe H OPr H OMe 2-76 Hp OMe H OPr H OMe 2-77 Oc OMe H OPr H OMe 2-78 Et OMe H OBu H OMe 2-79 Pr OMe H OBu H OMe 2-80 Bu OMe H OBu H OMe 2-81 Pn OMe H OBu H OMe 2-82 Hx OMe H OBu H OMe 2-83 Hp OMe H OBu H OMe 2-84 Oc OMe H OBu H OMe 2-85 Et OEt H OEt H OMe 2-86 Pr OEt H OEt H OMe 2-87 Bu OEt H OEt H OMe 2-88 Pn OEt H OEt H OMe 2-89 Hx OEt H OEt H OMe 2-90 Hp OEt H OEt H OMe 2-91 Oc OEt H OEt H OMe 2-92 Et OPr H OPr H OMe 2-93 Pr OPr H OPr H OMe 2-94 Bu OPr H OPr H OMe 2-95 Pn OPr H OPr H OMe 2-96 Hx OPr H OPr H OMe 2-97 Hp OPr H OPr H OMe 2-98 Oc OPr H OPr H OMe 2-99 Et OBu H OBu H OMe 2-100 Pr OBu H OBu H OMe 2-101 Bu OBu H OBu H OMe 2-102 Pn OBu H OBu H OMe 2-103 Hx OBu H OBu H OMe 2-104 Hp OBu H OBu H OMe 2-105 Oc OBu H OBu H OMe 2-106 Et H OMe OMe H OMe 2-107 Pr H OMe OMe H OMe 2-108 Bu H OMe OMe H OMe 2-109 Pn H OMe OMe H OMe 2-110 Hx H OMe OMe H OMe 2-111 Hp H OMe OMe H OMe 2-112 Oc H OMe OMe H OMe 2-113 Et H OEt OEt H OMe 2-114 Pr H OEt OEt H OMe 2-115 Bu H OEt OEt H OMe 2 -116 Pn H OEt OEt H OMe 2-117 Hx H OEt OEt H OMe 2-118 Hp H OEt OEt H OMe 2-119 Oc H OEt OEt H OMe 2-120 Et H OPr OPr H OMe 2-121 Pr H OPr OPr H OMe 2-122 Bu H OPr OPr H OMe 2-123 Pn H OPr OPr H OMe 2-124 Hx H OPr OPr H OMe 2-125 Hp H OPr OPr H OMe 2-126 Oc H OPr OPr H OMe 2- 127 Et H OBu OBu H OMe 2-128 Pr H OBu OB u H OMe 2-129 Bu H OBu OBu H OMe 2-130 Pn H OBu OBu H OMe 2-131 Hx H OBu OBu H OMe 2-132 Hp H OBu OBu H OMe 2-133 Oc H OBu OBu H OMe 2- 134 Et H OCH_TwoO H OMe 2-135 Pr H OCH_TwoO H OMe 2-136 Bu H OCH_TwoO H OMe 2-137 Pn H OCH_TwoO H OMe 2-138 Hx H OCH_TwoO H OMe 2-139 Hp H OCH_TwoO H OMe 2-140 Oc H OCH_TwoO H OMe Preferably, (1) (Z) -3- (2,4-dimethoxyphenyl)
Penta-2-enoic acid methyl ester (Compound No. 1-
1) (2) (Z) -3- (2,4-dimethoxyphenyl)
Hex-2-enoic acid methyl ester (Compound No. 1-
2) (3) (Z) -3- (2,4-dimethoxyphenyl)
Hept-2-enoic acid methyl ester (Compound No. 1-
3) (4) (Z) -3- (2,4-dimethoxyphenyl)
Octa-2-enoic acid methyl ester (Compound No. 1-
4) (5) (Z) -3- (2,4-dimethoxyphenyl)
Nona-2-enoic acid methyl ester (Compound No. 1-5) (6) (Z) -3- (2,4-dimethoxyphenyl)
Deca-2-enoic acid methyl ester (Compound No. 1-6) (7) (Z) -3- (2,4-dimethoxyphenyl)
Undec-2-enoic acid methyl ester (Compound No. 1-
7) (8) (Z) -3- (2,4-dimethoxyphenyl)
Penta-2-enoic acid (Compound No. 2-1) (9) (Z) -3- (2,4-dimethoxyphenyl)
Hex-2-enoic acid (Compound No. 2-2) (10) (Z) -3- (2,4-dimethoxyphenyl)
B) Hept-2-enoic acid (Compound No. 2-3) (11) (Z) -3- (2,4-dimethoxyphenyl)
B) Oct-2-enoic acid (Compound No. 2-4) (12) (Z) -3- (2,4-dimethoxyphenyl)
L) Nona-2-enoic acid (Compound No. 2-5) (13) (Z) -3- (2,4-dimethoxyphenyl)
B) Dec-2-enoic acid (Compound No. 2-6) (14) (Z) -3- (2,4-dimethoxyphenyl)
G) undec-2-enoic acid (Compound No. 2-7)
And more preferably (3), (4), (5), (10),
The compound of (11) or (12).

[0026]

BEST MODE FOR CARRYING OUT THE INVENTION The compounds of the present invention are easily produced by the following methods.

[0027]

Embedded image In the above formula, R ¹ , R ^2a , R ^2b , R ^2c , R ^2d and R ³ have the same meaning as described above.

Step A1 is a cis-ester compound (Ia)
Is carried out by reacting the lactone compound (II) with an alkyl halide having 1 to 4 carbon atoms in an inert solvent in the presence of a base.

The alkyl halide having 1 to 4 carbon atoms used is, for example, methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, propyl iodide, propyl bromide,
It is butyl iodide, butyl bromide or butyl chloride, preferably methyl iodide, ethyl iodide or ethyl bromide, most preferably methyl iodide. The amount of the alkyl halide used is 3 to 10 equivalents.

The base used is, for example, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, calcium hydroxide, barium hydroxide,
Alkaline earth metal hydroxides such as magnesium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate or alkali metal hydrogencarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate Yes, preferably an alkali metal hydroxide or an alkaline earth metal hydroxide, more preferably an alkaline earth metal hydroxide, most preferably
Barium hydroxide. The amount of the base used is 1 to 10 equivalents. The inert solvent used is, for example,
Amides such as N, N-dimethylformamide or N, N-dimethylacetamide; Sulfoxides such as dimethylsulfoxide; N-methyl-2-pyrrolidone; 1,3-dimethyl-2-imidazolidinone; -Dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone; benzene, toluene,
Aromatic hydrocarbons such as xylene or mesitylene; nitriles such as acetonitrile; or ethers such as diethyl ether, 1,3-dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably an amide. Or sulfoxides, more preferably N, N-
Dimethylformamide, N, N-dimethylacetamide and dimethylsulfoxide, particularly preferably N, N-dimethylformamide.

The reaction temperature is usually from 0 ° C. to 100 ° C., preferably from 10 ° C. to 40 ° C.
Although it depends on the reaction temperature and the like, it is 1 hour to 48 hours, preferably 2 hours to 30 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by appropriately distilling off the solvent from the reaction mixture, adding water, extracting with a water-immiscible solvent such as ethyl acetate, drying the extract, and distilling off the solvent. Further, if necessary, it can be further purified by a conventional method, for example, column chromatography or the like.

Step A2 is a desired hydrolysis step.
The hydrolysis reaction is achieved by reacting compound (Ia) with a base in a water-containing inert solvent.

The base used is, for example, the one used in the above-mentioned step A1, and is preferably an alkali metal hydroxide, more preferably sodium hydroxide. The amount of the base used is 1 to 10 equivalents.

The reaction temperature is usually from 0 ° C. to 150 ° C., preferably from 30 ° C. to 100 ° C. The reaction time varies depending on the type and amount of the reagent, the reaction temperature and the like. Yes, preferably for 30 minutes to 5 hours.

The inert solvents used are, for example, alcohols such as methanol, ethanol, 2-propanol, 1-propanol or 2-methyl-2-propanol;
Amides such as N-dimethylformamide or N, N-dimethylacetamide; Sulfoxides such as dimethylsulfoxide; N-methyl-2-pyrrolidone, 1,3-dimethyl-2
-Imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone; aromatic hydrocarbons such as benzene, toluene, xylene or mesitylene; nitriles such as acetonitrile Ethers such as diethyl ether, tetrahydrofuran, 1,3-dioxane or 1,2-dimethoxyethane, preferably alcohols, particularly preferably methanol or ethanol. In addition, all inert solvents contain one equivalent or more of water.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, concentrating the reaction mixture, adding water, acidifying the solution with an acid, extracting with a water-immiscible solvent such as ethyl acetate, drying the extract, and distilling off the solvent. Can be. Further, if necessary, it can be further purified by a conventional method, for example, a recrystallization method, column chromatography or the like.

The step A3 is a step of producing the compound (III), which is carried out by catalytically reducing the compound (I) in the presence of a transition metal catalyst having an optically active ligand. It is carried out in an inert solvent in the presence of hydrogen.

The optically active ligand used is, for example,
(S)-and (R)-(diphenylphosphino) -1,1'-binaphthyl
(BINAP), (S, S)-and (R, R) -bis (diphenylphosphino) butane (CHIRAPHOS), (R) -N, N-dimethyl-1-[(S) -1 ', 2
-Bis (diphenylphosphino) ferrocenyl] ethylamine, (S)-and (R) -1,2-bis (diphenylphosphino) propane (PROPHOS), (R) -N, N-dimethyl-1-[(S ) -2- (Diphenylphosphino) ferrocenyl] ethylamine, (2S, 4S) -4-
(Diphenylphosphino) -2- (diphenylphosphinomethyl) pyrrolidine, (R) -1-[(S) -2- (diphenylphosphino)
Ferrocenyl] ethyl methyl ether, (S) -N, N-dimethyl-1-[(R) -1 ', 2-bis (diphenylphosphino) ferrocenyl] ethylamine, (S, S)-and (R, R) -2,3-O-isopropylidene-2,3-dihydroxy-4,4-bis (diphenylphosphino) butane (DIOP) or (+)-and (-)-neomenthyldiphenylphosphine (NMDPP), Preferably, (S)-and (R) -BINAP, (S, S)-and (R, R) -CHIRAPHOS, (R) -1-[(S)
2- (diphenylphosphino) ferrocenyl] ethyl methyl ether, (S) -N, N-dimethyl-1-[(R) -1 ′, 2-bis (diphenylphosphino) ferrocenyl] ethylamine, which is particularly preferable. Are (S)-and (R) -BINAP.

The transition metal used is, for example, rhodium, ruthenium, palladium or platinum, which is zero-valent or divalent, preferably divalent ruthenium.

The amount of the catalyst used is 0.01 to 100 mol% equivalent, preferably 0.01 to 1 mol% equivalent.

The pressure of the hydrogen used is 1 to 120 atm, preferably 5 to 100 atm, more preferably 5 to 10 atm.

The solvent used is water; methanol, ethanol, 2-propanol, 1-propanol, or 2-methyl
Alcohols such as -2-propanol; or a water-containing solvent with alcohols, preferably methanol or 2-
It is propanol.

The reaction temperature is usually from 0 ° C. to 150 ° C., preferably from 50 ° C. to 120 ° C., and the reaction time depends on the amount and type of the catalyst, the amount and type of the solvent, the reaction temperature,
Although it depends on the pressure of hydrogen and the like, it is 30 minutes to 48 hours, preferably 1 hour to 10 hours.

After completion of the reaction, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, the desired product can be obtained by concentrating the reaction mixture. Also, if necessary, an aqueous alkali solution is added, and after heating and refluxing for 2 hours, the solvent is distilled off, water is added, and the solution is appropriately acidified with an acid, followed by extraction with a water-immiscible solvent such as ethyl acetate. It can be obtained by drying the extract and distilling off the solvent. Further, if necessary, it can be further purified by a conventional method, for example, a recrystallization method, column chromatography or the like.

Compound (Ia) wherein R ³ is an alkyl group
Is subjected to catalytic reduction in this step, and then the obtained ester is hydrolyzed in the same manner as in the step A2,
Compounds in which R ³ is a hydrogen atom can be produced.

The starting compound (II) of Method A is easily produced according to the following method.

[0048]

Embedded image In the above formula, R ¹ , R ^2a , R ^2b , R ^2c and R ^2d have the same meanings as described above, and R ⁴ , R ⁵ and R ⁶ are the same or different and have 1 to 4 carbon atoms. X represents an alkyl group, and X represents a halogen atom (preferably, a chlorine or bromine atom).

Step B1 is a step for producing a compound having the general formula (VI) in an inert solvent (for example, benzene,
Aromatic hydrocarbons such as toluene, xylene or mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride; or diethyl ether, 1,3-dioxane, tetrahydrofuran or 1,2-dimethoxyethane. Such ethers, preferably halogenated hydrocarbons, especially methylene chloride), in the presence of a base (e.g. pyridine, 4-dimethylaminopyridine,
Triethylamine, organic amines such as dimethylaniline, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, lithium carbonate, sodium carbonate, alkali metal carbonates such as potassium carbonate or lithium hydrogen carbonate, Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, preferably organic amines, especially pyridine), a compound having general formula (IV) and a compound having general formula (V) at -10 ° C
30 to 100 ° C. (preferably 10 to 50 ° C.)
The reaction is carried out by reacting for a period of minutes to 20 hours (preferably 1 hour to 10 hours).

Step B2 is a step of preparing a compound having the general formula (VII) in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene, xylene or mesitylene; methylene chloride, chloroform, Halogenated hydrocarbons such as carbon tetrachloride; or ethers such as diethyl ether, 1,3-dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably aromatic hydrocarbons), compounds (VI ) With an alcohol having the general formula (VII) at 10 ° C to 150 ° C (preferably 50 ° C).
C. to 100.degree. C.) for 30 minutes to 20 hours (preferably 2 hours to 15 hours). This reaction can be suitably carried out even if a large excess of alcohol is used also as a solvent.

Step B3 is a step of producing compound (II) in an inert solvent (for example, aromatic hydrocarbons such as benzene, toluene, xylene or mesitylene; methylene chloride, chloroform and carbon tetrachloride). Halogenated hydrocarbons; or ethers such as diethyl ether, 1,3-dioxane, tetrahydrofuran or 1,2-dimethoxyethane, preferably aromatic hydrocarbons, especially toluene), the presence of an acid Below (e.g., mineral acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carboxylic acids such as acetic acid, trifluoroacetic acid, benzoic acid, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid;
Ion exchange resin such as Amberlyst 15, Dowex 50W, Amberlite 200C, Diaion PK204
(However, those other than Amberlyst 15 are vacuum-dried at 100 ° C. for 8 hours), methanesulfonic acid, benzenesulfonic acid, sulfonic acid such as toluenesulfonic acid, preferably toluenesulfonic acid, Amberlyst 15, particularly ,
Amberlyst 15), compound (VIII) and compound having general formula (IX) at 20 ° C. to 200 ° C. (preferably 50 ° C. to 150 ° C.) for 30 minutes to 20 hours (preferably 1 hour to (10 hours).

After completion of each reaction, the target compound of each step is collected from the reaction mixture according to a conventional method. For example, if insolubles are present, the insolubles are appropriately filtered off, the reaction mixture is concentrated, water is added, extracted with a water-immiscible solvent such as ethyl acetate, the extract is dried, and the solvent is removed. It can be obtained by distillation. Further, if necessary, a conventional method, for example,
It can be further purified by a recrystallization method, column chromatography or the like.

The compound (IV) and the compound (IX) used in this method are known or prepared according to known methods (for example, Klarmann, Gatyas, Shternov, J. Am.
Chem. Soc., 53, 3397-3404 (1931) .JR Anderson,
RL Edwards, AJS Whalley; Metabolites of Hi
gher Fungi. Part 22. 2-Butyl-3-methysuccinic Acid
and 2-Hexylidene-3-methysuccinic Acid from Xylaria
ceous Fungi; J. Chem. Soc., Perkin Trans. 1, 1995,
1481-1485.AJ Hoefnagel, EA Gunnewegh, RS
Downing, and H. van Bekkum; Synthesis of 7-Hydroxy
coumarins catalysed by Solid Acid Catalysts; J. Ch
em.Soc., Chem. Commun., 1995, 225-226.DG Crosb
y; Improved Synthesis of Scopoletin; J. Org. Che
m., 1961 (26), 1215-1217.EVO John, SS Israel
stam; Use of Cation Exchange Resins in Organic Rea
ctions. I. The von Peckmann Reaction; I. Org. Che
m., 1961 (26), 240-242. Kojima Kohei, Osawa Reiko; Synthetic Studies on Coumarin Derivatives. I. Condensation of Resorutin and Ethyl Alkylacetoacetate with Sulfuric Acid;
6-919.RN Lacey; Derivatives Acetoacetic Acid. P
art VIII. The Synthesis of Coumarins from Aryl Ace
Toacetates .; J. Chem. Soc., 1954, 854-860.) Hereinafter, the present invention will be described with reference to Examples and Reference Examples, but the present invention is not limited thereto.

[0054]

EXAMPLES Example 1 Methyl (Z) -3- (2,4-dimethoxyphenyl) oct-2-enoate (Exemplary Compound No. 1-4) Barium hydroxide octahydrate (72.73 g, 3.15 eq) 7-Hydroxy-4-pentylcoumarin (17.0 g, 73.19 mmol) and methyl iodide (36.4 ml, 8e) in a suspension of dimethylform (255 ml, x15).
q) was added in sequence and stirred. Since heat of reaction was gradually generated, cooling was performed so that the internal temperature became 20 to 25 ° C.
After stirring at room temperature for 24 hours, toluene (255 ml) and water (255 ml) were added, and the generated Harz was filtered. After liquid separation, the organic layer was washed with water (255 ml) and concentrated under reduced pressure to give the title compound as an oil (22.35 g, 104.45%). 1H-NMR spectrum (CDCl ₃ , 400 MHz, δppm): 0.85 (3H, t, J =
7.2Hz), 1.20-1.50 (6H, m), 2.41 (2H, t, J = 8.0Hz), 3.54 (3H,
s), 3.75 (3H, s), 3.83 (3H, s), 5.91 (1H, s), 6.47 (2H, m), 6.9
1 (1H, m).

Example 2 (Z) -3- (2,4-dimethoxyphenyl) oct-2-enoic acid (Exemplary Compound No. 2-4) A solution of sodium hydroxide (5.85 g, 2 eq) in water (29.3 ml) To (Z)-
3- (2,4-Dimethoxyphenyl) oct-2-enoic acid methyl ester (22.35 g: the compound of Example 1) in ethanol (270 m
l) The solution was added and refluxed for 1 hour. After evaporating the solvent under reduced pressure,
(300 ml) and concentrated hydrochloric acid (13 ml) were added, and extracted with toluene (350 ml). The organic layer was washed twice with water (300 ml) and concentrated to dryness. Add hexane (200 ml), dissolve at 70 ° C, and cool under ice
Stirred for 0 minutes. The resulting crystals are filtered and cold hexane (70
ml), and dried in vacuo to give the title compound as colorless crystals (1
8.68 g, 91.70% from 7-hydroxy-4-pentyl coumarin)
As obtained. 1H-NMR spectrum (CDCl ₃ , 400 MHz, δ ppm): 0.84 (3H, t, J =
6.8Hz), 1.20-1.40 (6H, m), 2.41 (2H, t, J = 6.8Hz), 3.71 (3H,
s), 3.81 (3H, s), 5.88 (1H, s), 6.46 (2H, m), 6.90 (1H, m).

Example 3 (Z) -3- (2,4) was added to methanol (20 ml, x1) in which nitrogen (S) -3- (2,4-dimethoxyphenyl) octanoate was passed for 2 hours.
-Dimethoxyphenyl) oct-2-enoic acid (20.0 g, 71.85 mm
ol: the compound of Example), (R) -binap-ruthenium acetate [BINAP-Ru (OAc) ₂ ] (25 mg), and the mixture was placed under a nitrogen atmosphere. After replacing the nitrogen atmosphere with a hydrogen atmosphere,
The mixture was vigorously stirred at a temperature of 5.5 ° C. and a hydrogen pressure of 5.5 kg / cm 2 for 3.5 hours. The reaction solution was concentrated to dryness to obtain a crude title compound (21.44 g). Sodium hydroxide (4.37 g, 1.5 eq), water (22 ml, x1.1) and ethanol (150 ml, x7.5) were added, and the mixture was heated under reflux for 2 hours. After concentrating the reaction solution, water (300 ml, x15) and concentrated hydrochloric acid (9.8 ml) were added to adjust the pH to 2 or less, and the mixture was extracted with toluene (300 ml, x15). The organic layer was washed with water (300 ml, x15) and concentrated to dryness to give the title compound as crystals (20.16 g, 100.0%, net 98.04%). 1H-NMR (270 MHz, CDCl ₃ ): 0.78 to 0.91 (3H, m), 1.06 to 1.32 (6
H, m), 1.50-1.76 (2H, m), 2.58-2.69 (2H, m), 3.39 (1H, qui
ntet, J = 7.5Hz), 3.77 (3H, s), 3.79 (3H, s), 6.42-6.49 (2
H, m), 7.01 (1H, d, J = 8.5 Hz) Reference Example 1 Caproyl Meldrum's Acid Meldrum's acid (39.70 g, 257.446 mmol) in pyridine (50 ml,
Under ice-cooling (0 to 10 ° C), a solution of caproyl chloride (40.0 g, 1.08 eq) in methylene chloride (100 ml, x2.5) was added dropwise to the suspension, and the mixture was stirred at room temperature for 4.5 hours. Reacted. Then cold 2
Normal hydrochloric acid (300 ml) was added, and the organic layer was separated. The aqueous layer was extracted with methylene chloride (50 ml), the organic layers were combined, and water (100 m
Washed in l). After drying over anhydrous sodium sulfate and concentration under reduced pressure, the title compound was obtained as a red oil (67.63 g, 101.34%).

Reference Example 2 Ethyl caproyl acetate Caproyl Meldrum acid (67.63 g, Meldrum acid 39.70 g
Equivalent: A solution of the compound of Reference Example 1) in ethanol (200 ml, x3) was refluxed for 7 hours. The reaction was concentrated under reduced pressure. The obtained oil was distilled under reduced pressure to give the title compound as a colorless oil (93.64% from Meldrum's acid). Boiling point: 84-85 ° C / 2mmHg.

Reference Example 3 Resorcinol was added to a solution of ethyl 7-hydroxy-4-pentylcoumarin caproyl acetate (15.0 g, 80.537 mmol: the compound of Reference Example 2) in toluene (150 ml, x10).
(17.74 g, 2.0 eq), Amberlite 15 (registered trademark: 7.5 g,
x0.5), and the mixture was dehydrated and refluxed for 5.5 hours using a Dien-Stark apparatus. After filtration while hot, water (50 ml, x3.3) was added to the mother liquor, and the mixture was stirred under ice-cooling for 30 minutes. After filtration, the crystals were washed with a small amount of water and toluene and dried to obtain the title compound as pale yellow crystals (14.41 g, 81.22%). 1H-NMR spectrum (CD ₃ OD, 400 MHz, δ ppm): 0.91 (3H, t, J =
6.6Hz), 1.30-1.50 (4H, m), 1.60-1.75 (2H, m), 2.76 (2H, m
t, J = 7.8Hz), 3.30 (3H, s), 6.06 (1H, s), 6.65-6.85 (2H,
m), 7.61 (1H, m).

Reference Example 4 (R) -binap-ruthenium acetate [BINAP-Ru (OA
c) ₂ ] The preparation was carried out at an oxygen concentration of 5% or less, and all solvents used were degassed.

[RuCl ₂ (benzene)] ₂ (800 mg, 1.60 mmol)
A solution of (R) -BINAP (1.89 g, 3.04 mmol) in DMF (30 mL) at 100 ° C.
Heated for 10 minutes. After cooling, sodium acetate (5.20 g, 63.4
mmol) in methanol (50 mL), stirred for 5 minutes, added toluene (25 mL) and water (50 mL), shaken, and separated the toluene layer. The aqueous layer was extracted twice with toluene (25 mL), and after matching the organic layers, washing with water (10 mL) was performed four times. The solvent was distilled off under reduced pressure, and the residue was evaporated to dryness. Toluene (20 mL) was added for dissolution, and hexane (80 mL) was added for crystallization. After stirring for 2 hours under ice cooling, the mixture was filtered and dried to obtain the title compound (1.8 g, 71%) as yellow crystals. IH-NMR spectrum _{(CDCl 3, 400MHz, δppm)} : 1.80
(6H, t), 6.47-7.84 (32H, m).

[0061]

The compound (I) of the present invention is derived from a coumarin derivative in a higher yield, and is subjected to asymmetric catalytic reduction using a transition metal catalyst having an optically active ligand to give AC.
Since compound (III), which is useful as an intermediate for synthesizing AT inhibitors, can be produced easily and in high yield, it is effective as an intermediate for synthesizing ACAT inhibitors and as an industrial production method.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hiroshi Tomori 173 Nakahara Kamishuku, Hiratsuka-shi, Kanagawa Sankyo Stock Company In-house F-term (reference) 4C062 EE02 EE27 4H006 AA01 AA02 AB84 AC13 AC46 AC48 BJ50 BM10 BM71 BN30 BP30 BS10

Claims (3)

[Claims] 1. A compound of the general formula(Where R¹Represents an alkyl group having 2 to 12 carbon atoms;^2a, R^2bAnd R^2dAre the same or different
, An alkyl group having 1 to 12 carbon atoms, 1 fluorine atom
Alkyl group of 1 to 4 carbon atoms substituted with up to 6 carbon atoms, protection
Protected amino group, hydroxyl group, protected hydroxyl group or carbon number
Represents 1 to 4 alkoxy groups;^2cAnd R^2eIs carbon
Represents an alkoxy group of 1 to 4 or R ^2bAnd R^2cBut
Together, alkylene dioxy having 1 to 6 carbon atoms
Group or cycloalkylenedioxy group having 3 to 6 carbon atoms
And R^ThreeRepresents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
You. ). 2. A compound of the general formula(Where R¹Represents an alkyl group having 2 to 12 carbon atoms.
Then R^2a, R^2bAnd R^2dAre the same or different
, An alkyl group having 1 to 12 carbon atoms, 1 fluorine atom
Alkyl group of 1 to 4 carbon atoms substituted with up to 6 carbon atoms, protection
Protected amino group, hydroxyl group, protected hydroxyl group or carbon number
Represents 1 to 4 alkoxy groups;^2cAnd R^2eIs carbon
Represents an alkoxy group of 1 to 4 or R ^2bAnd R^2cBut
Together, alkylene dioxy having 1 to 6 carbon atoms
Group or cycloalkylenedioxy group having 3 to 6 carbon atoms
And R^ThreeRepresents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
You. ) Having a lactone compound in the presence of a base,
The compound is reacted with an alkyl halide of 1 to 4 to obtain a compound represented by the general formula:(Where R¹, R^2a, R^2b, R^2cAnd R^2dIs as described above
Has the same meaning as^3aRepresents alkyl having 1 to 4 carbon atoms
You. A cis-ester compound having the formula
General formula, characterized in that hydrolysis is carried out if desired.(Where R¹, R^2a, R^2b, R^2c, R^2dAnd R^ThreeWas mentioned earlier
The meaning is the same as Cis-carboxylic acids having)
Manufacturing method. 3. A compound of the general formula(Where R¹Represents an alkyl group having 2 to 12 carbon atoms.
Then R^2a, R^2bAnd R^2dAre the same or different
, An alkyl group having 1 to 12 carbon atoms, 1 fluorine atom
Alkyl group of 1 to 4 carbon atoms substituted with up to 6 carbon atoms, protection
Protected amino group, hydroxyl group, protected hydroxyl group or carbon number
Represents 1 to 4 alkoxy groups;^2cAnd R^2eIs carbon
Represents an alkoxy group of 1 to 4 or R ^2bAnd R^2cBut
Together, alkylene dioxy having 1 to 6 carbon atoms
Group or cycloalkylenedioxy group having 3 to 6 carbon atoms
And R^ThreeRepresents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
You. ) Having an optically active coordination
Catalytic reduction in the presence of a transition metal catalyst having
Wherein the compound is hydrolyzed by the following general formula:(Where R¹, R^2a, R^2b, R^2c, R^2dAnd R^ThreeWas mentioned earlier
The meaning is the same as ) Having saturated carboxylic acids
Manufacturing method.