JP2002308838A - Method for producing optically active 3-substituted-4- substituted oxybutylamines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce optically active 3-substituted-4-substituted oxybutylamines and their derivatives which are useful as the intermediates for producing pharmaceuticals, agricultural chemicals, and the like. SOLUTION: The method for producing optically active 3-substituted-4- substituted oxybutylamines to be represented by formula (5) (wherein R<1> is a 1-6C alkyl group or the like) comprises reducing 2-substituted-3-cyanopropionic esters to be represented by formula (4) (wherein R<1> is the same as defined above; and R<2> is a 1-6C alkyl group, a 2-6C alkenyl group or the like), and the method for producing compounds to be represented by formula (6) (wherein R<4> is a protective group of the hydroxy group) comprises protecting the hydroxy group in the 3-substituted-4-substituted oxybutylamines of formula (5) which have been obtained in the above production method.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11 which is useful as an agent for improving abnormal urination.
-Hexahydro-5- (4-hydroxymethylphenyl) -9-methyl-6,13-dioxo-13H-
Optically active 3-substituted-4, which is a compound useful as an intermediate for producing [1,4] -diazosino [2,1-g] [1,7] naphthyridine and as an intermediate for producing other medical and agricultural chemicals -Hydroxy-butylamines and their derivatives.

[0002]

BACKGROUND OF THE INVENTION Conventionally, optically active 3-substituted-4
-Production methods for hydroxy-butylamines and derivatives thereof are described in Tetrahedron 39, 3107 (1983), and Journal of Medicinal Chemistry (J. Med. Chem.) 30, 30 1948 (1987). Refer to (S) -3
A method of synthesizing (R) -3-methyl-4- (2-tetrahydropyranyloxy) butylamine using -hydroxy-2-methylpropionic acid methyl ester is reported in Japanese Patent Application Laid-Open No. 10-109989. However, it is not satisfactory as a method for producing optically active 3-substituted-4-hydroxy-butylamines and derivatives thereof, and a more industrially advantageous method is required.

A method for producing optically active 2-substituted-3-cyanopropanoic acid esters is disclosed in JP-A-11-8011.
No. 3 discloses an optical activity of 2 from racemic methyl 2-methyl-3-cyanopropionate by fermentation and enzymatic methods.
A method for synthesizing methyl-methyl-3-cyanopropionate has been reported. Also, The Journal of Organic Chemistry (J. Org. Chem.) 60
2627-2629 (1995), the optical activity (S)
A method has been reported in which ethyl-2-[(methanesulfonyl) oxy] propanoate is reacted in the presence of cesium fluoride, but is satisfactory as a method for producing optically active 2-substituted-3-cyanopropanoic esters. Instead, more industrially advantageous methods are being sought. In addition, in the literature, 1-allyl-4-ethyl 2-cyano-3-methylbutanediate was refluxed with dioxane for 8 hours in the presence of ammonium formate to give ethyl 2-methyl-3-cyanopropionate in a yield of 55%. However, there is a demand for an industrially advantageous method with a higher yield.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found an efficient manufacturing method and completed the present invention.

That is, the present invention provides the following formula (4)

[0006]

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Wherein R ¹ is a straight, branched or cyclic C 1
_1-6 alkyl group, straight-chain, branched or cyclic C _2-6 alkenyl group, straight-chain, branched or cyclic C _2-6 alkynyl group,
R ² represents a hydrogen atom, an alkali metal, an alkaline earth metal, a linear, branched or cyclic C _1-6 alkyl group, a linear, branched or cyclic C _2-6 alkenyl; Represents a group, linear, branched or cyclic C _2-6 alkynyl group, phenyl group or benzyl group. ),
Formula (5), wherein 2-substituted-3-cyanopropanoic acid esters or their enantiomers are reduced.

[0008]

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(Wherein, R ¹ has the same meaning as described above.)
And a method for producing a 3-substituted-4-hydroxybutylamine or an enantiomer thereof; and a 3-substituted-4- compound represented by the formula (5) obtained by the above-mentioned production method.
Formula (6), wherein the hydroxyl group of hydroxybutylamines or its enantiomer is protected.

[0010]

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(In the formula, R ⁴ represents a hydroxyl-protecting group.)
A method for producing a 3-substituted-4-substituted oxy-butylamine or an enantiomer thereof represented by the formula: and a formula (4):

[0012]

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(Wherein R ¹ and R ² have the same meanings as described above), and the 2-substituted-3-cyanopropanoic acid esters or their enantiomers are reduced to give a compound of the formula (7)

[0014]

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(In the formula, R ¹ has the same meaning as described above.)
A compound represented by the formula (5), which is reduced after being converted to a 3-substituted-4-hydroxybutyronitrile or an enantiomer thereof represented by the formula:

[0016]

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(In the formula, R ¹ has the same meaning as described above.)
And a method for producing a 3-substituted-4-hydroxybutylamine or an enantiomer thereof; and a 3-substituted-4- compound represented by the formula (5) obtained by the above-mentioned production method.
Formula (6), wherein the hydroxyl group of hydroxybutylamines or its enantiomer is protected.

[0018]

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(In the formula, R ⁴ represents a hydroxyl-protecting group.)
A method for producing a 3-substituted-4-substituted oxy-butylamine or an enantiomer thereof represented by the formula: and a formula (4):

[0020]

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(Wherein R ¹ and R ² have the same meanings as described above), by reducing a 2-substituted-3-cyanopropanoic acid ester or an enantiomer thereof,
Equation (7)

[0022]

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(Wherein, R ¹ has the same meaning as described above.)
A 3-substituted-4-hydroxybutyronitrile or an enantiomer thereof represented by the formula: and then protecting a hydroxyl group by the following formula (8):

[0024]

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Wherein R ¹ and R ⁴ have the same meanings as described above, and a process for producing 3-substituted-4-substituted oxy-butyronitriles or enantiomers thereof; Reducing a 3-substituted-4-substituted oxy-butyronitrile or an enantiomer thereof represented by the formula (8) obtained by the method, characterized by the formula (6)

[0026]

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(In the formula, R ⁴ represents a hydroxyl-protecting group.)
And a method for producing a 3-substituted-4-substituted oxy-butylamine or an enantiomer thereof.

[0028]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail.

First, the terms in the substituents R ¹ , R ² , R ³ and X will be described.

In this specification, “n” represents normal,
"I" is iso, "s" is secondary, "t" is tertiary, "c" is cyclo, "o" is ortho, "m" is meta, "p" is para. means.

Examples of the linear, branched or cyclic C _1-6 alkyl group include a methyl group, an ethyl group, an n-propyl group and an i-
Propyl, c-propyl, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, n
-Pentyl group, c-pentyl group, n-hexyl group and c
-Hexyl group and the like.

Examples of the linear, branched or cyclic C _2-6 alkenyl group include a vinyl group, an allyl group, a 2-propenyl group,
1-methylvinyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group,
1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-ethyl-2-vinyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group A 1,2-dimethyl-1-propenyl group, 1,2
-Dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 2-
Methyl-1-butenyl group, 1-i-propylvinyl group,
2,4-pentadienyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5
-Hexenyl group, 2,4-hexadienyl group, 1-methyl-1-pentenyl group, 1-c-pentenyl group and 1-
c-hexenyl group and the like.

The linear, branched or cyclic C _2-6 alkynyl group includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- Pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-hexynyl group, 2
-Hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group and the like.

Examples of the alkali metal include lithium, sodium and potassium.

Examples of the alkaline earth metal include magnesium and calcium.

[0036] Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The C _1-4 alkylsulfonyloxy group includes straight-chain, branched and cyclic alkylsulfonyloxy groups, methanesulfonyloxy group, ethanesulfonyloxy group, n-propylsulfonyloxy group, i-propyl Sulfonyloxy group, c-propylsulfonyloxy group, n-butylsulfonyloxy group, i-butylsulfonyloxy group, s-butylsulfonyloxy group, t
-Butylsulfonyloxy group and c-butylsulfonyloxy group.

Examples of the arylsulfonyloxy group include benzenesulfonyloxy, o-toluenesulfonyloxy, m-toluenesulfonyloxy, p-toluenesulfonyloxy, α-naphthalenesulfonyloxy and β-naphthalenesulfonyloxy. Is mentioned.

Examples of the halogenated alkylsulfonyloxy group include a trifluoromethanesulfonyloxy group.

The protecting group for the hydroxyl group is not particularly limited as long as it is a protecting group generally known as a protecting group for a hydroxyl group. For example, a trimethylsilyl group, a triethylsilyl group,
Trisubstituted silyl groups such as triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group; methoxymethyl group, methoxyethoxymethyl group, 1
-1- (alkoxy) alkyl groups such as (ethoxy) ethyl group and methoxyisopropyl group; 2-oxacycloalkyl groups such as tetrahydrofuranyl group and tetrahydropyranyl group; alkyl groups such as t-butyl group; benzyl group and para group Aralkyl groups such as methoxybenzyl group; alkenyl groups such as allyl group and propenyl group; aryl groups such as paramethoxyphenyl group; acetyl group, trifluoroacetyl group, propionyl group, butyryl group, pivaloyl group, benzoyl group, methylbenzoyl group Acyl groups such as methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, isopropyloxycarbonyl group, butyloxycarbonyl group, isobutyloxycarbonyl group, t-butyloxycarbonyl group, etc. Etc., and 2-oxa-cycloalkyl group and acyl group are preferable in terms of usability as intermediates, for example, a tetrahydropyranyl group and a benzoyl group.

Preferred R ¹ , R ² , R ³ and X will be described.

[0042] Preferred R ^1, straight-chain, branched or cyclic C _1-6 alkyl group and a phenyl group and a benzyl group, more preferably a methyl group, an ethyl group, n- propyl group, i- propyl Groups, n-butyl group, i-butyl group, s-butyl group, t-butyl group, benzyl group and phenyl group, and more preferably a methyl group.

Preferred R ² is a linear, branched or cyclic C _1-6 alkyl group, a linear, branched or cyclic C _1-6 alkyl group.
_2-6 alkenyl group, linear, branched or cyclic C _2-6 alkynyl group, phenyl group and benzyl group, more preferably methyl group, ethyl group, n-propyl group, i
-Propyl group, n-butyl group, i-butyl group, t-butyl group, n-pentyl group, n-hexyl group, benzyl group and phenyl group, more preferably methyl group, ethyl group and benzyl group. No.

Preferred R ³ is a straight-chain, branched or cyclic C _1-6 alkyl group, a straight-chain, branched or cyclic C _1-6 alkyl group.
_2-6 alkenyl group, linear, branched or cyclic C _2-6 alkynyl group, phenyl group and benzyl group, more preferably methyl group, ethyl group, n-propyl group, i
-Propyl group, n-butyl group, i-butyl group, t-butyl group, allyl group, 2-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 2 -Pentenyl group, 1,2-dimethyl-2-propenyl group, 1-
Ethyl-2-propenyl group, 1-methyl-2-butenyl group, 2,4-pentadienyl group, 2-hexenyl group,
2,4-hexadienyl group and benzyl group,
More preferred are a methyl group, an ethyl group, a t-butyl group, an allyl group, and a benzyl group.

Preferred X is a halogen atom and C
_1-4 alkylsulfonyloxy group, more preferably, chlorine atom, bromine atom and methanesulfonyloxy group, further preferably, chlorine atom.

Preferred combinations of R ¹ , R ² , R ³ and X are shown below.

R ¹ is a methyl group, R ² is a linear, branched or cyclic C _1-6 alkyl group, a linear, branched or cyclic C _2-6 alkenyl group, linear, branched or cyclic C _2-6 alkynyl group, a phenyl group or a benzyl group, X is a chlorine atom, R ³ is a linear, branched or cyclic C _1-6 alkyl group, straight chain, branched or cyclic A C _2-6 alkenyl group, a linear, branched or cyclic C _2-6 alkynyl group, a phenyl group or a benzyl group;

A preferred production method is shown below. (1) Equation (3)

[0049]

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(Wherein, R ¹ and R ² have the same meanings as described above, and R ³ is a hydrogen atom, an alkali metal, an alkaline earth metal, a linear, branched or cyclic C _1-6 alkyl group) A straight-chain, branched or cyclic C _2-6 alkenyl group, a straight-chain, branched or cyclic C _2-6 alkynyl group, a phenyl group or a benzyl group. Formula (4) produced by decarboxylation of cyanobutanedicarboxylic acids or their enantiomers

[0051]

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(Wherein R ¹ and R ² have the same meanings as described above), characterized in that they reduce 2-substituted-3-cyanopropanoic acid esters or their enantiomers. Equation (5)

[0053]

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(In the formula, R ¹ has the same meaning as described above.)
A method for producing a 3-substituted-4-hydroxybutylamine or an enantiomer thereof represented by the formula: (2) Equation (1)

[0055]

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(Wherein, R ¹ and R ² have the same meanings as described above, and X represents a halogen atom, a C _1-4 alkylsulfonyloxy group, a halogenated alkylsulfonyloxy group or an arylsulfonyloxy group.) An optically active 2-substituted acetic acid or an enantiomer thereof represented by the formula (2):

[0057]

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(Wherein, R ³ has the same meaning as described above), which is produced by reacting a cyanoacetic acid represented by the formula (3) in the presence of a base.

[0059]

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(Wherein R ¹ , R ² and R ³ have the same meanings as described above), characterized by using 3-substituted-2-cyanobutanedicarboxylic acids or their enantiomers. (1) A method for producing a 3-substituted-4-hydroxybutylamine or an enantiomer thereof according to (1).

The process for producing the 3-substituted-4-hydroxybutylamines and derivatives thereof of the present invention is represented by the following reaction scheme.

[0062]

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By reducing the optically active 2-substituted-3-cyanopropanoic acid esters (4), the optically active 3-
The substituted 4-hydroxybutylamines (5) can be produced, and the ester of the optically active 2-substituted-3-cyanopropanoic acid esters (4) is selectively reduced to give the optically active 3-substituted After being converted to 4-hydroxybutyronitriles (7), the optically active 3-
Substituted-4-hydroxybutylamines (5) can also be produced.

The optically active 3-substituted-4-hydroxybutylamines (5) can be protected by protecting the hydroxyl group to form the optically active 3-substituted-4-substituted oxy-butylamines (6).
It can be.

The optically active 3-substituted-4-substituted oxy-butylamines (6) also protect the hydroxyl group of the optically active 3-substituted-4-hydroxybutyronitriles (7) to give an optically active 3-substituted oxy-butylamine. 4-substituted oxy-butyronitriles (8)
, And then can be produced by reduction.

The optically active 2-substituted-3-cyanopropanoic acid esters (4) are prepared by a condensation reaction of the optically active 2-substituted acetic acids (1) with cyanoacetic acids.
It can be produced by decarboxylating 2-cyanobutanedicarboxylic acids (3).

The production steps of the above reaction scheme can be carried out sequentially, but can be made continuous by selecting conditions.

The obtained compound (6) was prepared according to the method described in
No. 9989 can be derived.

[Production of Compound (3) from Compound (1)]
An optically active 2-substituted acetic acid (1) or an enantiomer thereof is reacted with a cyanoacetic acid (2) in the presence of a base to give a 3-substituted-2-cyanobutanedicarboxylic acid (3) or an enantiomer thereof. Can be manufactured.

The reaction can be carried out in the air, but is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

The base used includes an inorganic base and an organic base.

Examples of the inorganic base include an alkali metal hydride such as lithium hydride, sodium hydride and potassium hydride, an alkaline earth metal hydride such as calcium hydride, and an alkali metal such as lithium metal, sodium metal and potassium potassium. Metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and cesium carbonate;
Metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide, metal alkoxides such as potassium t-butoxide, sodium methoxide and sodium ethoxide, lithium hydroxide,
Metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide are exemplified.

Examples of the organic base include aliphatic amines such as triethylamine, pyrrolidine, piperidine and morpholine, and aromatic amines such as pyridine.

Preferred bases include inorganic bases, such as alkali metal hydrides and metal carbonates. Also, for example, lithium hydride, sodium hydride, potassium hydride, lithium carbonate, sodium carbonate,
Examples include potassium carbonate, calcium carbonate and cesium carbonate, and also include, for example, sodium hydride, potassium carbonate and cesium carbonate.

The operation and conditions of the reaction differ somewhat depending on the type of base used.

When a highly basic base such as an alkali metal hydride, alkaline earth metal hydride, alkali metal, metal amide, or metal alkoxide is used, the reaction can be carried out under the following conditions.

That is, when the above reaction is carried out, a base may be added to the cyanoacetic acid (2) (without solvent or diluted with a solvent). ) Can be added. After stirring the solution containing the cyanoacetic acid (2) and the base, the optically active 2-substituted acetic acid (1) or an enantiomer thereof (without solvent or diluted with a solvent) may be added and reacted. A reaction solution prepared by adding a base to cyanoacetic acid (2) (without solvent or diluted with a solvent) is added to the optically active 2-substituted acetic acid (1) or its enantiomer (without solvent or diluted with solvent). , Can also react.

The temperature at which the base is added to the cyanoacetic acid (2) or when the cyanoacetic acid (2) is added to the base is as follows:
The reaction can be usually carried out within the range of -110 ° C to the boiling point of the solvent used in the reaction, preferably in the range of -50 to 70 ° C, more preferably in the range of -5 to 50 ° C.

The time for adding the base to the cyanoacetic acid (2) or adding the cyanoacetic acid (2) to the base is as follows.
There is no particular limitation as long as the internal temperature rise falls within a range of 0 to 10 ° C. from the initial temperature, but it can be performed in a range of 1 minute to 24 hours, and preferably in a range of 1 minute to 10 hours. .

The temperature at which a base is added to the cyanoacetic acid (2) or the base is added and the stirring is carried out can be from -110 ° C. to the boiling point of the solvent used in the reaction. , Preferably in the range of -10 to 100C, more preferably in the range of 0 to 70C.

The time when a base is added to the cyanoacetic acids (2) or when the cyanoacetic acids (2) are added to the base and stirred is as follows:
Usually, the reaction can be carried out for 0.1 to 10 hours, preferably 0.25 to 1 hour.

The optically active 2-substituted acetic acid (1) or its enantiomer is added to a reaction solution prepared by adding a base to cyanoacetic acid (2), or a base is added to cyanoacetic acid (2). The temperature range for adding the adjusted reaction solution to the optically active 2-substituted acetic acid (1) or its enantiomer can be from -110 ° C to the boiling point of the solvent used in the reaction, preferably-. The temperature is in the range of 50 to 100C, and more preferably in the range of -10 to 100C.

The optically active 2-substituted acetic acid (1) or its enantiomer is added to a reaction solution prepared by adding a base to cyanoacetic acid (2), or a base is added to cyanoacetic acid (2). The time for adding the prepared reaction solution to the optically active 2-substituted acetic acid (1) or its enantiomer is as follows:
There is no particular limitation as long as the internal temperature rise falls within a range of 0 to 10 ° C. from the initial temperature, but it can be carried out in a range of 1 minute to 24 hours, preferably 1 minute to 10 hours. is there.

The reaction temperature is not particularly limited, but it can be usually from -110 ° C to the boiling point of the solvent used in the reaction, preferably from -10 to 1
It is in the range of 00 ° C.

The reaction time varies depending on the reaction temperature and cannot be specified unconditionally. For example, when the reaction temperature is 25 ° C., the reaction time is usually in the range of 1 to 50 hours, preferably 3 to 20 hours. Is enough.

When a base not so basic such as a metal carbonate is used, the reaction can be carried out under the following conditions.

That is, in carrying out the above reaction, the cyanoacetic acid (2), the optically active 2-substituted acetic acid (1) and the base can be added in an arbitrary order. 2) Any method may be used as long as three optically active 2-substituted acetic acids (1) and a base are mixed. In addition, the temperature at that time can be carried out usually in the range of -110 ° C to the boiling point of the solvent used in the reaction,
The temperature is preferably in the range of -50 to 70C, and more preferably in the range of -5 to 50C. The time for adding is not particularly limited.

The reaction temperature is not particularly limited, but it can be usually from -110 ° C to the boiling point of the solvent used in the reaction, preferably from -10 to -1.
It is in the range of 00 ° C.

The reaction time varies depending on the reaction temperature and cannot be specified unconditionally. For example, when the reaction temperature is 25 ° C., the reaction time is usually in the range of 1 to 50 hours, preferably 3 to 20 hours. Is enough.

As the optically active 2-substituted acetic acid (1) or its enantiomer, a synthetic product can be used, but a commercial product can also be used as it is.

The molar ratio of the optically active 2-substituted acetic acid (1) or its enantiomer to the cyanoacetic acid (2) can be arbitrarily set, but is usually from 0.5 to 5 ((2) / (1)). And a molar ratio of from 0.8 to 2.1 ((2) /
(1)) The range of the molar amount is mentioned.

The molar ratio of the base used to the cyanoacetic acids (2) can also be set arbitrarily. When using a highly basic base such as alkali metal hydride, alkaline earth metal hydride, alkali metal, metal amide, and metal alkoxide,
Usually, a 0.5 to 5 (base / (2)) mole is used, but when the base is 1 mole or more, racemization proceeds. Therefore, to suppress racemization, 1 mole or less is preferable. Preferably, the range is 0.8 to 1 mole.

When a base having a not so high basicity such as a metal carbonate is used, the molar ratio is usually 0.5 to 5 (base / (2)) times, and preferably 0.8 to 2.5 times. The molar range is 0 times, for example, the range of 0.8 to 1.5 times, and for example, the range of 0.8 to 1.2 times.

The reaction proceeds even without solvent, but it is usually preferable to use a solvent. Examples of the solvent include aromatic compounds such as benzene, toluene, xylene and chlorobenzene, and carbonized compounds such as hexane, heptane and cyclohexane. Hydrogens, halogenated hydrocarbons such as chloroform and methylene chloride, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and isobutyronitrile, N , N-dimethylformamide, N-methylpyrrolidone, amides such as N, N'-dimethylimidazolinone, dimethylsulfoxide and mixtures thereof, preferably amides, more preferably N, N- Dimethylformamide, N-methylpyrroli Emissions and N, N'-dimethyl imidazolinone and the like.

The amount of the solvent to be used can be usually 0.1 to 30 times by mass, preferably 5.0 to 20 times by mass, based on the reaction substrate.

The amount of the solvent used here means that the optically active 2-substituted acetic acid (1) or its enantiomer, cyanoacetic acid (2), a base or the like is diluted with a solvent. In this case, the total amount of the used solvents means the sum of the amounts of the solvents.

If the conversion of the reaction is too high, the rate of racemization increases, so that a preferable conversion is, for example, 95% or less, or for example, 98% or less. .

After completion of the reaction, the reaction mixture is poured into cold water or the like, or cold water or the like is poured into the reaction mixture, and then an acid such as hydrochloric acid is added to make the mixture neutral to acidic.
An extraction operation is performed by adding a solvent such as toluene as an extraction solvent. In the separated organic layer, an aqueous solution of sodium bicarbonate,
Washing operation is performed by adding a saline solution or the like. The separated organic layer is dried with a desiccant such as magnesium sulfate, and the solvent is distilled off under reduced pressure.
-Substituted-2-cyanobutanedicarboxylic acids (3) or enantiomers thereof can be obtained. Further, it can be easily purified by silica gel column chromatography, distillation or recrystallization.

[Production of Compound (4) from Compound (3)]
Compound (4) can be produced by decarboxylation of compound (3).

A. Particularly when R ³ is a hydrogen atom, an alkali metal,
Alkaline earth metal, linear, branched or cyclic C _1-6 alkyl group, linear, branched or cyclic C _2-6 alkynyl group,
In the case of a phenyl group or a benzyl group, compound (4) can be obtained by heating compound (3) in a water-containing solvent in the air or under an inert gas atmosphere. At this time, the reaction may be performed by adding a salt.

At this time, the heating temperature is usually 50 to 25.
0 ° C, preferably 100 to 200 ° C.

The amount of water relative to compound (3) is usually 1.0 to 20 moles, and preferably 1.0 to 10 moles.
Times molar.

Examples of the salt include metal acetates such as lithium acetate, sodium acetate and potassium acetate; metal chlorides such as lithium chloride, sodium chloride, potassium chloride and calcium chloride; lithium bromide, sodium bromide, potassium bromide; Metal bromides such as calcium bromide, metal iodides such as lithium iodide, sodium iodide, and potassium iodide, or cyanides such as lithium cyanide, sodium cyanide, potassium cyanide, and calcium cyanide, sodium phosphate, and phosphoric acid Phosphates such as potassium and ammonium salts such as tetramethylammonium acetate are exemplified, and preferred are sodium chloride and sodium cyanide.

The amount of the salt relative to the compound (3) is usually 0 to 20 moles.

The reaction proceeds even without solvent, but it is usually preferable to use a solvent. Examples of the type of solvent include aromatic compounds such as benzene, toluene, xylene and chlorobenzene, and carbonized compounds such as hexane, heptane and cyclohexane. Hydrogens, chloroform, methylene chloride, halogenated hydrocarbons such as dichloroethane, ethylene glycol, alcohols such as diethylene glycol, dioxane, tetrahydrofuran, ethers such as dimethoxyethane,
Ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and isobutyronitrile, amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N'-dimethylimidazolinone, dimethyl sulfoxide And a mixture thereof, and preferably, N, N-dimethylformamide and dimethylsulfoxide.

The amount of the solvent used can be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

B. In particular, when R ³ is linear, branched or cyclic
In the case of a C _2-6 alkenyl group or a benzyl group, compound (4) is obtained by heating compound (3) in the presence of a metal catalyst and formic acid.

As the metal catalyst to be used, Pd / C, Pd (OA
c)_Two, Pd (OAc)_Two-PPh_Three , Pd_Two(dba)_Three(Dba: dibenzylide
Acetone), Pd_Two(dba)_Three-PPh_Three, PdCl_Two(PPh_Three)_Two, PdCl
_Two(CH_ThreeCN) _Two, PdCl_Two, Pd (PPh_Three)_FourSuch as palladium catalyst
No.

The amount of the metal catalyst to be used is usually 0.001 to 1.0 mole times with respect to the compound (3).

The amount of formic acid to be used may be the same as that of compound (3)
The molar ratio is usually 1.0 to 10 moles, preferably 1.0 to 5.0 moles.

The reaction can be carried out by further adding a phosphine ligand to the reaction system.

Examples of the phosphine ligand include triphenylphosphine, P (p-Tol) ₃ (p-Tol: paratolyl), dpp
aryl phosphines such as e (Ph ₂ P (CH ₂ ) ₂ PPh ₂ ) and dppb (Ph ₂ P (CH ₂ ) ₄ PPh ₂ ); and alkyl phosphines such as tri-normal butyl phosphine.

When the phosphine ligand is added, the amount used is usually in the range of 0.5 to 10 equivalents, preferably 1 to 5 equivalents, based on the amount of the metal catalyst used.

The reaction proceeds even without solvent, but it is usually preferable to use a solvent. Examples of the type of the solvent include aromatic compounds such as benzene, toluene, xylene and chlorobenzene, and carbonized compounds such as hexane, heptane and cyclohexane. Hydrogens, chloroform, methylene chloride, halogenated hydrocarbons such as dichloroethane, ethylene glycol, alcohols such as diethylene glycol, dioxane, tetrahydrofuran, ethers such as dimethoxyethane,
Ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and isobutyronitrile, amides such as N, N-dimethylformamide, N-methylpyrrolidone, N, N'-dimethylimidazolinone, dimethyl sulfoxide And mixtures thereof, preferably ethers, and more preferably tetrahydrofuran. The amount of the solvent to be used can be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction temperature is usually from 0 to 200 ° C, preferably from 20 to 150 ° C, more preferably from 25 to 70 ° C.

[Production of Compound (5) from Compound (4)]
Compound (5) can be produced by reducing compound (4).

The reduction methods include reagent reduction and catalytic hydrogenation.

A. Reagent Reduction As the reducing agent, for example, BH ₃ -THF, BH ₃ -SMe ₂ , LiAlH (O
_{Me) 3, LiAlH 4, AlH} 3, LiBEt 3 H, (i-Bu) 2 AlH, NaAlEt 2 H
_{2, NaBH 4 -ZnCl 2, NaBH} 4 -BF 3 OEt 2, NaBH 4 -TMSCl, NaBH 4 -
LiCl, NaBH ₄ -AlCl ₃ , NaBH ₄ -CoCl _{2 and the} like.

The amount of the reducing agent used is usually 1.0 to 20 moles per mole of the compound (4).

The reaction usually requires a solvent. Examples of the solvent include aromatic compounds such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, methanol, ethanol, t-butyl alcohol, and the like.
Examples include alcohols such as ethylene glycol and diethylene glycol, ethers such as dioxane, tetrahydrofuran, dimethoxyethane, and diglyme, and mixtures thereof.

The amount of the solvent to be used can be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used, preferably from -30 ° C to the boiling point of the solvent used.

When LiAlH ₄ is used as the reducing agent, the amount of LiAlH ₄ used is usually 1.
The molar amount is 0 to 20 times, preferably 1.0 to 2.0 times.

The reaction usually requires a solvent. Examples of the solvent include aromatic compounds such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, methanol, ethanol, t-butyl alcohol, and the like.
Ethylene glycol, alcohols such as diethylene glycol, dioxane, tetrahydrofuran, dimethoxyethane, ethers such as diglyme or mixtures thereof, preferably ethers,
More preferably, tetrahydrofuran is used.

The amount of the solvent to be used can be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used, preferably from -50 ° C to the boiling point of the solvent used, and more preferably from -20 ° C. The range of the boiling point of the solvent is mentioned.

B. Catalytic Hydrogenation Hydrogen is generally used in a molar amount of 4.0 to 100 times that of compound (4).

The catalyst is usually added to the compound (4) in an amount of 0.00
Use 1- to 1.0-fold molar.

Examples of the catalyst include platinum catalysts such as platinum (IV) oxide, platinum black, platinum carbon powder and platinum carbon sulfide powder; palladium catalysts such as palladium carbon, palladium alumina, palladium black and palladium oxide; and osmium catalysts such as osmium carbon. And rhenium catalysts such as rhenium carbon, and nickel catalysts such as Raney nickel.

In the reaction system, an acid such as sulfuric acid, hydrochloric acid, phosphoric acid or perchloric acid, or a base such as ammonia, pyridine, triethylamine, sodium hydroxide or potassium hydroxide can be added for the reaction.

The reaction usually requires a solvent, such as water, organic acids such as formic acid and acetic acid, esters such as ethyl acetate and butyl acetate, aromatic compounds such as benzene, toluene and xylene, hexane, heptane and cyclohexane. And hydrocarbons such as methanol, ethanol, t-butyl alcohol, ethylene glycol and diethylene glycol, ethers such as dioxane, tetrahydrofuran, dimethoxyethane and diglyme, and mixtures thereof.

The amount of the solvent used can be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used, preferably from 25 ° C to the boiling point of the solvent used.

The reaction pressure is usually from normal pressure to 20 MPa. [Production of Compound (6) from Compound (5)] Compound (5)
Compound (6) can be produced by protecting the hydroxyl group of

Examples of the protecting group for a hydroxyl group include the above-mentioned protecting groups, and the introduction and removal of these protecting groups can be carried out by appropriately employing the methods described in the literature (Green, TW; W
uts, PGM “Protective Groups in Organic Synthesi
s ”, 2nd Ed., Wiley Interscience Publication, John
-Weiley & Sons, New York, 1991, pp 14-118).

For example, when a bulky trisubstituted silyl group such as a t-butyldimethylsilyl group or a t-butyldiphenylsilyl group is used as a protecting group for a hydroxyl group, the reaction is carried out using t-butyldimethylsilyl chloride, Trisubstituted silyl halides such as butyldiphenylsilyl chloride or trisubstituted silyltrifluoromethanesulfonates such as t-butyldimethylsilyltrifluoromethanesulfonate and t-butyldiphenylsilyltrifluoromethanesulfonate can be used in the presence of a base such as imidazole or 2,6-lutidine. The reaction can be carried out by reacting with compound (5) below.

When an acyl group such as an acetyl group, a trifluoroacetyl group or a benzoyl group is used as a protecting group for a hydroxyl group, for example, the reaction is carried out with a carboxylic acid anhydride such as acetic anhydride, trifluoroacetic anhydride or a chloride. The reaction can be carried out by reacting a carboxylic acid halide such as benzoyl with a compound (5) in the presence of a base such as pyridine or triethylamine. In addition, as a protecting group for a hydroxyl group, an alkoxy group such as a methoxycarbonyl group or an ethoxycarbonyl group can be used. When a carbonyl group is used as a protecting group, the reaction can be carried out by reacting a chlorocarbonate such as methyl chlorocarbonate or ethyl chlorocarbonate with compound (5) in the presence of a base such as pyridine or triethylamine.

Further, for example, as a protective group for a hydroxyl group, a 2-hydroxy group such as a tetrahydrofuranyl group or a tetrahydropyranyl group may be used.
When using an oxacycloalkyl group as a protecting group, the reaction is as follows:
The reaction can be carried out by reacting an unsaturated cyclic ether such as 2,3-dihydrofuran or 2,3-dihydropyran with the compound (5) in the presence of an acid.

Examples of the acid used include mineral acids such as hydrochloric acid and sulfuric acid, carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, mandelic acid, and tartaric acid; methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and the like.
Sulfonic acids such as trifluoromethanesulfonic acid and camphorsulfonic acid, phosphorus oxychloride, Amberlite IR-1
20 (H type).

The amount of the acid to the compound (5) is usually 0.001 to 2.0 moles.

The amount of the unsaturated cyclic ether based on the compound (5) is 0.8 to 10 moles.

The reaction proceeds without solvent, but a solvent may be used. Examples of the solvent include benzene, toluene,
Xylene, aromatic compounds such as chlorobenzene, hexane, heptane, hydrocarbons such as cyclohexane, chloroform, methylene chloride, halogenated hydrocarbons such as dichloroethane, dioxane, tetrahydrofuran, ethers such as dimethoxyethane, acetone, methyl ethyl ketone, Ketones such as methyl isobutyl ketone, nitriles such as acetonitrile and isobutyronitrile, N, N-dimethylformamide, N-methylpyrrolidone, N, N'-
Examples thereof include amides such as dimethylimidazolinone, dimethyl sulfoxide and mixtures thereof, and preferably include halogenated hydrocarbons and ethers.

The amount of the solvent to be used may be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction is usually carried out at a temperature of from -80 to 200 ° C., preferably from -30 ° C. to the boiling point of the solvent used.

[Production of compound (7) from compound (4)]
Compound (7) can be produced by reducing compound (4).

The reduction method includes reagent reduction and catalytic hydrogenation.

A. Reagent Reduction As the reducing agent, for example, BH ₃ -THF, BH ₃ -SMe ₂ , LiAlH (O
_{Me) 3, LiAlH 4, AlH} 3, NaBH (OMe) 3, LiBEt 3 H, (i-Bu) 2 Al
H, NaAlEt ₂ H ₂ , NaBH ₄ -ZnCl ₂ , NaBH ₄ -BF ₃ OEt ₂ , NaBH ₄ -TM
_{SCl, NaBH 4 -LiCl, NaBH 4} -AlCl 3, NaBH 4 -CoCl 2, NaBH 4 -H
SCH ₂ CH ₂ SH and the like.

The amount of the reducing agent to be used is usually 0.5 to 20 moles per mole of Compound (4).

The reaction usually requires a solvent. Examples of the solvent include aromatic compounds such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, methanol, ethanol, t-butyl alcohol, and the like.
Examples include alcohols such as ethylene glycol and diethylene glycol, ethers such as dioxane, tetrahydrofuran, dimethoxyethane, and diglyme, and mixtures thereof.

The amount of the solvent to be used can be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used, preferably from -30 ° C to the boiling point of the solvent used.

[0152] When using the LiAlH ₄ as a reducing agent, the amount of LiAlH ₄ used, usually 0 to the compound (4).
5 to 1.0 times mol.

The reaction usually requires a solvent. Examples of the solvent include aromatic compounds such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, methanol, ethanol, t-butyl alcohol, and the like.
Ethylene glycol, alcohols such as diethylene glycol, dioxane, tetrahydrofuran, dimethoxyethane, ethers such as diglyme or mixtures thereof, preferably ethers,
More preferably, tetrahydrofuran is used.

The amount of the solvent to be used may be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used, preferably from -50 ° C to the boiling point of the solvent used, more preferably from -20 ° C. The range of the boiling point of the solvent is mentioned.

B. Catalytic hydrogenation Hydrogen is usually used in a molar amount of 2.0 to 100 times that of compound (4).

The catalyst is usually added to the compound (4) in an amount of 0.00
Use 1- to 1.0-fold molar.

Examples of the catalyst include platinum catalysts such as platinum (IV) oxide, platinum black, platinum carbon powder and platinum carbon sulfide powder, palladium catalysts such as palladium carbon, palladium alumina, palladium black and palladium oxide, and osmium catalysts such as osmium carbon. And rhenium catalysts such as rhenium carbon, and nickel catalysts such as Raney nickel.

In the reaction system, an acid such as sulfuric acid, hydrochloric acid, phosphoric acid or perchloric acid, or a base such as ammonia, pyridine, triethylamine, sodium hydroxide or potassium hydroxide can be added for the reaction.

The reaction usually requires a solvent, such as water, organic acids such as formic acid and acetic acid, esters such as ethyl acetate and butyl acetate, aromatic compounds such as benzene, toluene and xylene, hexane, heptane and cyclohexane. And hydrocarbons such as methanol, ethanol, t-butyl alcohol, ethylene glycol and diethylene glycol, ethers such as dioxane, tetrahydrofuran, dimethoxyethane and diglyme, and mixtures thereof.

The amount of the solvent to be used may be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used, preferably from 25 ° C to the boiling point of the solvent used.

The reaction pressure is usually from normal pressure to 20 MPa.

[Production of Compound (5) from Compound (7)]
Compound (5) can be produced by reducing compound (7).

The reduction method includes reagent reduction and catalytic hydrogenation.

A. Reagent Reduction As the reducing agent, for example, BH ₃ -THF, BH ₃ -SMe ₂ , LiAlH (O
_{Me) 3, LiAlH 4, AlH} 3, LiBEt 3 H, (i-Bu) 2 AlH, NaAlEt 2 H
_{2, NaBH 4 -ZnCl 2, NaBH} 4 -BF 3 OEt 2, NaBH 4 -TMSCl, NaBH 4 -
LiCl, NaBH ₄ -AlCl ₃ , NaBH ₄ -CoCl _{2 and the} like.

The amount of the reducing agent used is usually 1.0 to 20 moles per mole of the compound (7).

The reaction usually requires a solvent. Examples of the solvent include aromatic compounds such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, methanol, ethanol, t-butyl alcohol, and the like.
Examples include alcohols such as ethylene glycol and diethylene glycol, ethers such as dioxane, tetrahydrofuran, dimethoxyethane, and diglyme, and mixtures thereof.

The amount of the solvent to be used may be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used, preferably from -30 ° C to the boiling point of the solvent used.

When LiAlH ₄ is used as the reducing agent, the amount of LiAlH ₄ used is usually 1.
The molar amount is 0 to 20 times, preferably 0.5 to 1.3 times.

The reaction usually requires a solvent. Examples of the solvent include aromatic compounds such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, methanol, ethanol, t-butyl alcohol, and the like.
Ethylene glycol, alcohols such as diethylene glycol, dioxane, tetrahydrofuran, dimethoxyethane, ethers such as diglyme or mixtures thereof, preferably ethers,
More preferably, tetrahydrofuran is used.

The amount of the solvent to be used can be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used, preferably from -50 ° C to the boiling point of the solvent used, more preferably from -20 ° C. The range of the boiling point of the solvent is mentioned.

B. Catalytic hydrogenation Hydrogen is usually used in a molar amount of 2.0 to 100 times that of compound (7).

The catalyst is usually added to the compound (7) in an amount of 0.00
Use 1- to 1.0-fold molar.

Examples of the catalyst include platinum catalysts such as platinum (IV) oxide, platinum black, platinum carbon powder and platinum carbon sulfide powder; palladium catalysts such as palladium carbon, palladium alumina, palladium black and palladium oxide; and osmium catalysts such as osmium carbon. And rhenium catalysts such as rhenium carbon, and nickel catalysts such as Raney nickel.

In the reaction system, an acid such as sulfuric acid, hydrochloric acid, phosphoric acid or perchloric acid, or a base such as ammonia, pyridine, triethylamine, sodium hydroxide or potassium hydroxide can be added for the reaction.

The reaction usually requires a solvent, such as water, organic acids such as formic acid and acetic acid, esters such as ethyl acetate and butyl acetate, aromatic compounds such as benzene, toluene and xylene, hexane, heptane and cyclohexane. And hydrocarbons such as methanol, ethanol, t-butyl alcohol, ethylene glycol and diethylene glycol, ethers such as dioxane, tetrahydrofuran, dimethoxyethane and diglyme, and mixtures thereof.

The amount of the solvent used can be usually 0.1 to 30 times by mass, preferably 1.0 to 20 times by mass, based on the reaction substrate.

The reaction temperature is usually from -80 ° C to the boiling point of the solvent used, preferably from 25 ° C to the boiling point of the solvent used.

The reaction pressure is usually from normal pressure to 20 MPa.

[Production of Compound (8) from Compound (7)]
Compound (8) can be produced by protecting the hydroxyl group of compound (7). The method for producing compound (8) by protecting the hydroxyl group can be carried out under the same conditions as the method for producing compound (6) from compound (5).

[Production of Compound (6) from Compound (8)]
Compound (6) can be produced by reducing compound (8). The method for producing compound (6) by reduction can be performed under the same conditions as the method for producing compound (5) from compound (7).

[0185]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. In addition, ethyl (R) -2-chloropropionate (1
-a) was obtained from a commercially available optically active (S) -ethyl lactate using the literature (Journal of Medicinal Chemistry).
(J. Med. Chem.) Vol. 29, paragraphs 1183-1188 (1986). ), And a commercially available reagent was used as ethyl (S) -2-chloropropionate (1-b).

The optical purity of the compound was determined by the following method.

Compound (3-c) Analytical equipment: HPLC (high performance liquid chromatography) Analytical conditions: Column: CHIRALPAC AD-H (4.6 mm × 250 mm)
Directly, moving bed: hexane / 2-propanol /
Ethanol = 9: 1: 0.1, flow rate: 1.0 mL / min., Detection wavelength: 230 nm, column temperature: 7 ° C

Compounds (4-a) and (4-b) Analytical equipment: HPLC (high performance liquid chromatography) Analytical conditions: Column: CHIRAL RU-2 (manufactured by Shiseido Co., Ltd.)
Column size: 4.6 mm ID × 250 mm, moving bed: methyl alcohol, flow rate: 0.5 mL / min, measurement wavelength: 220 n
m, column temperature: 30 ° C

Compound (5-a) pretreatment: Compound (5-a) (50 mg) in dichloromethane (3 m
L) The solution was added with triethylamine (147 mg) and then with benzoyl chloride (205 mg), and then stirred at room temperature for 1 hour. A solution obtained by diluting 0.1 mL of the reaction solution with dichloromethane (1 mL) was used for analysis. Analytical instrument: HPLC (High Performance Liquid Chromatography) Analysis conditions: Column: CHIRALCEL OD-H (4.6 mm × 250 m
m), mobile phase: hexane / 2-propanol / ethanol
= 90: 9: 1, flow rate: 1 mL / min., Detection wavelength: 254 n
m, column temperature: 35 ° C

Compound (7-a) Analytical instrument: GC (gas chromatography) Analytical conditions: Column: SUPELCO γ-CD (30.0 mx 250 μm x 0.2
5 ° C), 80 ° C (20 min. Hold), 5 ° C / min. (Heating), 200 ° C (10 min. Hold), pressure 68.8 kPa, column flow rate 0.7 mL / min., Column average linear velocity 20 cm / se
c, split ratio 100: 1, inlet temperature 200 ° C, detector temperature 250 ° C

Compound (6-a) was pretreated by adding triethylamine and benzoyl chloride to an acetonitrile solution of (6-a), left at room temperature for about 10 minutes, and then measured by HPLC.

Example 1 (3R) -1-allyl 4-ethyl 2-cyano-3-
Synthesis of methyl butane diate (3-a)

[0193]

Embedded image

Under a nitrogen atmosphere, in a 300 mL reaction flask
N, N-dimethylformamide (80 mL) was added, and 2.23 g (55.7 mmol) of 60% sodium hydride was weighed and brought to 0 to 5 ° C. At the same temperature, allyl cyanoacetate (2-a) (7.33 g, 59 mmol) was added dropwise with vigorous stirring, followed by stirring at 25 ° C. for 15 minutes to completely react sodium hydride. The reaction solution is brought to 0 to 5 ° C,
Ethyl (R) -2-chloropropionate (1-a) (4.0 g,
After dropwise addition of 29.3 mmol), the mixture was stirred at 25 ° C for 18 hours. The reaction solution was poured into ice water, and diluted hydrochloric acid was added to adjust the pH to neutral to acidic. Ethyl acetate was added for extraction, followed by washing with brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound as a crude product. This was distilled to remove impurities having a low boiling point by distillation, and purified by silica gel column chromatography to give the title compound (3R) -1-allyl 4-ethyl 2-cyano-3-methylbutanediate (3-a).
(5.8 g, yield 88%) was obtained.

Example 2 (3S) -1-allyl 4-ethyl 2-cyano-3-
Synthesis of methyl butane diate (3-b)

[0196]

Embedded image

Under a nitrogen atmosphere, in a 300 mL reaction flask
N, N-dimethylformamide (80 mL) was added, and 2.34 g (59 mmol) of 60% sodium hydride was weighed and brought to 0 to 5 ° C. At the same temperature, allyl cyanoacetate (2-a) (7.33 g, 59 mmol) was added dropwise with vigorous stirring, followed by stirring at 25 ° C. for 15 minutes to completely react sodium hydride. The temperature of this reaction solution was adjusted to 0 to 5 ° C, and optically active ethyl (S) -2-chloropropionate (1-b) (4.0
g, 29.3 mmol), and the mixture was stirred at 25 ° C. for 18 hours. The reaction solution was poured into ice water, and diluted hydrochloric acid was added to adjust the pH to neutral to acidic. Ethyl acetate was added for extraction, followed by washing with brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound (3-b) as a crude product.

Example 3 (3R) -1-methyl 4-ethyl 2-cyano-3-
Synthesis of methyl butane diate (3-c)

[0199]

Embedded image

Under a nitrogen atmosphere, in a 300 mL reaction flask
N, N-dimethylformamide (80 mL) was added, and 2.23 g (55.7 mmol) of 60% sodium hydride was weighed and brought to 0 to 5 ° C. Methyl cyanoacetate (2-b) (5.80 g, 58.6 mmol) with vigorous stirring at the same temperature.
After dropwise addition, the mixture was stirred at 25 ° C. for 15 minutes to completely react sodium hydride. The reaction solution is brought to 0 to 5 ° C,
Ethyl (R) -2-chloropropionate (1-a) (4.0 g,
After dropwise addition of 29.3 mmol), the mixture was stirred at 25 ° C for 18 hours. The reaction solution was poured into ice water, and diluted hydrochloric acid was added to adjust the pH to neutral to acidic. Ethyl acetate was added for extraction, followed by washing with brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound as a crude product. This was distilled to remove impurities having a low boiling point by distillation, and purified by silica gel column chromatography to give the title compound (3R) -1-methyl 4-ethyl 2-
Cyano-3-methylbutanediate (3-c) (4.96)
g, 85% yield).

Example 4 (3R) -1-methyl 4-ethyl 2-cyano-3-
Synthesis of methyl butane diate (3-c) (using potassium carbonate as a base) Under a nitrogen atmosphere, N, N-dimethylformamide (40 mL) was added to a 100 mL reaction flask, and (R) -2-chloropropion was added thereto. Ethyl acid (1-a) (2.0 g, 14.7 mmol)
l) and methyl cyanoacetate (2-b) (2.9 g, 29.3 mmol)
l) was measured. Then, while stirring vigorously, 4.05 g (29.3 mmol) of potassium carbonate was added.
Stirred at C for 16 hours. The reaction solution was poured into water, and the pH was adjusted to neutral to acidic by adding dilute hydrochloric acid. Ethyl acetate was added for extraction, followed by washing with brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound as a crude product. The low boiling impurities were distilled off by distillation, and the residue was purified by silica gel column chromatography to give the title compound (3R) -1-methyl 4-ethyl 2-cyano-3-methylbutanediate (3-c) ( 2.33 g, a yield of 80%, and an optical purity of 95% ee at the third position were obtained. Note that the optical purity of the title compound was determined by analyzing with an optically active column.

Example 5 (3R) -1-methyl 4-ethyl 2-cyano-3-
Synthesis of methyl butanediate (3-c) (using cesium carbonate as base) N, N-dimethylformamide (40 mL) was added to a 100 mL reaction flask under a nitrogen atmosphere, and (R) -2-chloropropion was added thereto. Ethyl acid (1-a) (4.0 g, 29.3 mmol)
l) and methyl cyanoacetate (2-b) (3.05 g, 30.8 mmol)
l) was measured. Then, with vigorous stirring, 10.0 g (30.7 mmol) of cesium carbonate was added.
Stirred at C for 6 hours. The reaction solution was poured into water, and the pH was adjusted to neutral to acidic by adding dilute hydrochloric acid. Ethyl acetate was added for extraction, followed by washing with brine.

After drying the organic layer over anhydrous magnesium sulfate,
Evaporation of the solvent gave the title compound as a crude product. This was distilled to remove impurities having a low boiling point by distillation, and purified by silica gel column chromatography to give the title compound (3R) -1-methyl 4-ethyl 2-
Cyano-3-methylbutanediate (3-c) (4.3 g,
A yield of 74% and an optical purity of the third position of 93% ee) were obtained.
Note that the optical purity of the title compound was determined by analyzing with an optically active column.

Example 6 (3R) -1-t-butyl 4-ethyl 2-cyano-3
-Methylbutane diate (3-d) synthesis

[0205]

Embedded image

Under a nitrogen atmosphere, in a 300 mL reaction flask
N, N-dimethylformamide (80 mL) was added, and 2.11 g (52.8 mmol) of 60% sodium hydride was weighed and brought to 0 to 5 ° C. While vigorously stirring at the same temperature, t-butyl cyanoacetate (2-c) (8.274 g, 58.6 m)
mol) was added dropwise, followed by stirring at 25 ° C. for 15 minutes to completely react sodium hydride. This reaction solution is 0 to 5 ° C.
And ethyl (R) -2-chloropropionate (1-a)
(4.0 g, 29.3 mmol) was added dropwise, followed by stirring at 25 ° C. for 18 hours. Pour the reaction solution into ice water and add dilute hydrochloric acid
The pH was made neutral to acidic. Add ethyl acetate and extract,
Further, it was washed with saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound as a crude product. The low-boiling impurities were distilled off by distillation, and the residue was purified by silica gel column chromatography to give the title compound (3R) -1-t-butyl4.
-Ethyl 2-cyano-3-methylbutanediate (3-d) (6.01 g, 85% yield) was obtained.

Example 7 Ethyl (R) -2-methyl-3-cyanopropionate (4
Synthesis of -a)

[0208]

Embedded image

Under a nitrogen atmosphere, tetrahydrofuran (10 mL) was added to a 100 mL reaction flask, and palladium acetate (0.050 g, 0.22 mmol), triphenylphosphine (0.117 g, 0.45 mmol), and formic acid (1.02 g) were added thereto. ,
22 mmol) and stirred at room temperature for 10 minutes.
The (3R) -1-allyl 4- obtained in Example 1
Ethyl 2-cyano-3-methylbutanediate (3-
a) (1.0 g, 4.4 mmol) of tetrahydrofuran (20
mL) solution and heated to reflux for 2 hours. After the reaction solution was brought to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and ethyl acetate was added for extraction, followed by washing with brine. After the organic layer was dried over magnesium sulfate, the solvent was distilled off to obtain the title compound as a crude product. This was distilled (120 ° C / 1.3-2.6 kP
a) to give the title compound (R) -2-methyl-3-
Ethyl cyanopropionate (4-a) (0.561 g, 90% yield, 96% ee) was obtained.

Example 8 Ethyl (S) -2-methyl-3-cyanopropionate (4
-b) Synthesis

[0211]

Embedded image

Under a nitrogen atmosphere, tetrahydrofuran (60 mL) was added to a 300 mL reaction flask, and palladium acetate (0.329 g, 1.47 mmol), triphenylphosphine (0.769 g, 2.93 mmol) and formic acid (6.74 g) were added thereto. ,
146 mmol) and stirred at room temperature for 10 minutes. About 11 g of crude product (3S) -1-allyl 4-ethyl 2-cyano-3-obtained in Example 2
A solution of methylbutanediate (3-b) in tetrahydrofuran (120 mL) was added, and the mixture was heated under reflux for 2 hours. After the reaction solution was brought to room temperature, a saturated aqueous sodium hydrogen carbonate solution was added, and ethyl acetate was added for extraction, followed by washing with brine. After the organic layer was dried over magnesium sulfate, the solvent was distilled off to obtain the title compound as a crude product. This was purified by silica gel column chromatography to give the title compound (S)-
Ethyl 2-methyl-3-cyanopropionate (4-b)
(3.62 g, 88% yield from (1-b), 96% ee) was obtained. Note that the optical purity of the title compound was determined by analyzing with an optically active column.

Example 9 Ethyl (R) -2-methyl-3-cyanopropionate (4
Synthesis of -a)

[0214]

Embedded image

The (3R) -1-methyl 4-ethyl 2-cyano-3 obtained in Example 3 was placed in a 50 mL reaction flask.
-Methylbutane diate (3-c) (1 g, 5.03 mmol)
l), dimethyl sulfoxide (5 mL), water (0.15 mL,
8.33 mmol) under nitrogen atmosphere for 2 hours.
The mixture was heated and stirred at 180 ° C. The reaction solution was cooled to room temperature, extracted with ethyl acetate and water, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain the title compound as a crude product. This is distilled (120-13)
(0 ° C./1.3-2.6 kPa) to give the title ethyl (R) -2-methyl-3-cyanopropionate (4.
-a) (0.58 g, yield 82%, optical yield 95% ee) was obtained. Note that the optical purity of the title compound was determined by analyzing with an optically active column.

Example 10 (R) -3-methyl-4-hydroxy-butylamine (5
Synthesis of -a)

[0219]

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Ethyl (R) -2-methyl-3-cyanopropionate (4-a) (0.50 g, 3.55 mmol) obtained in Example 7 was weighed into a 100 mL reaction flask, and tetrahydrofuran (5 mL) was added. ) Was added under a nitrogen atmosphere. LiAlH ₄ (0.242g, 6.38mmo) was added to this at 0 ° C.
l) and stirred for 1 hour, water (0.6 mL) was added at 0 ° C, and then a 15% aqueous sodium hydroxide solution (0.2 mL).
L) was added and stirred for 30 minutes. The precipitate was filtered through celite, washed with ethyl acetate, and the filtrate was dried over anhydrous magnesium sulfate and concentrated to give the title compound as a crude product. This is distilled (80-130 ° C / 1.1-1.4).
kPa) to give the title compound (R) -3-methyl-4
-Hydroxy-butylamine (5-a) (0.306 g, 84% yield) was obtained.

Example 11 Synthesis of (R) -3-methyl-4-hydroxy-butyronitrile (7-a)

[0220]

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In a 100 mL reaction flask under a nitrogen atmosphere,
Ethyl (R) -2-methyl-3-cyanopropionate (4-a) (1.0 g, 7.09 mmol) obtained in Example 7 was weighed, tetrahydrofuran (8 mL) was added, and the mixture was added at 0 ° C.
And LiAlH ₄ (0.215 g, 5.67 mmol)
Was added and stirred at the same temperature for 30 minutes. Water (1 mL) is added, followed by a 15% aqueous sodium hydroxide solution (0.2 mL)
Was added, and the mixture was stirred at room temperature for 30 minutes. The precipitate was filtered through celite, washed with ethyl acetate, and the filtrate was dried over anhydrous magnesium sulfate and concentrated to obtain the title crude product. This was distilled (130 ° C./0.53 kPa) to give the title compound (R) -3-methyl-4-hydroxy-butyronitrile (7-a) (0.52 g, yield 74%).

Example 12 Synthesis of (R) -3-methyl-4-hydroxy-butyronitrile (7-a) Under a nitrogen atmosphere, dimethoxyethane (30 mL) was added to a 100 mL reaction flask, and the mixture was stirred. LiAlH
₄ (0.74 g, 19.1 mmol) was added to -10 ° C.
A solution of ethyl (R) -2-methyl-3-cyanopropionate (4-a) (5.0 g, 35.4 mmol, 94% ee) in dimethoxyethane (30 mL) was added thereto at the same temperature for 40 minutes. After the dropwise addition, the mixture was stirred for 2 hours. Add water, then 2
0% hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain the title crude product. This is distilled (130 ° C / 0.53 kP
a) to give the title compound (R) -3-methyl-4-hydroxy-butyronitrile (7-a) (2.8 g, 80% yield,
94% ee). Note that the optical purity of the title compound was determined by analyzing with an optically active column.

Example 13 (R) -3-methyl-4-hydroxy-butylamine (5
Synthesis of -a)

[0224]

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Under a nitrogen atmosphere, (R) -3-methyl-4-hydroxy-butyronitrile (7-a) (0.1 g, 1.01 mmol) obtained in Example 11 was weighed into a 50 mL reaction flask, Add tetrahydrofuran (1 mL) and add 0
° C. Add LiAlH ₄ (0.047g, 1.25mmo)
After l) was added, the mixture was stirred at room temperature for 1 hour. At 0 ° C., water (0.1 mL) was added, and then a 15% aqueous sodium hydroxide solution (0.1 mL) was added, followed by stirring at room temperature for 30 minutes. The precipitate was filtered through celite, washed with ethyl acetate,
The filtrate was dried over anhydrous magnesium sulfate and concentrated to give the title compound as a crude product. This is distilled (80
(130 ° C./1.1-1.4 kPa) to give the title compound (R) -3-methyl-4-hydroxy-butylamine (5-a) (0.075 g, 72% yield, 94% ee). was gotten. Note that the optical purity of the title compound was determined by analyzing with an optically active column.

Example 14 (R) -3-Methyl-4-hydroxy-butylamine (5
Synthesis of (R) -3-methyl-4-hydroxy-butyronitrile (7-a) (1.01 g, 10 mmol) in ethanol (10 m
L) PtO ₂ (0.05 g) and 35% hydrochloric acid (2.0 g) were added to the solution, and the mixture was stirred under hydrogen pressure (0.7 MPa) at 50 ° C. for 4 hours. After filtration, the catalyst was concentrated, a 20% aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (R) -3-methyl-4-hydroxy-butylamine (5
-a) (0.95 g, yield 90%, 94% ee) was obtained.
Note that the optical purity of the title compound was determined by analyzing with an optically active column.

Example 15 (R) -3-methyl-4-hydroxy-butylamine (5
Synthesis of (R) -3-methyl-4-hydroxy-butyronitrile (7-a) (1.01 g, 10 mmol) in ethanol (10 m
L) A solution containing 2% Pt-C and 50% water (0.2 g) and 35% hydrochloric acid (2.0 g) were added to the solution, and the mixture was stirred at 50 ° C for 4 hours under a hydrogen pressure (0.7 MPa). After filtration, the catalyst was concentrated, a 20% aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform.
The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (R) -3-methyl-4-hydroxy-butylamine (5-a) (0.78 g, yield 74%).

Example 16 Synthesis of (R) -3-methyl-4- (2-tetrahydropyranyloxy) butylamine (6-a)

[0229]

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(R) -3-Methyl-4-hydroxy-butylamine (5-a) (0.50 g, 4.85 mmol) obtained in Example 10 was weighed into a 100 mL reaction flask.
Tetrahydrofuran (5 mL) was added and 3,4-dihydropyran (0.61 g, 7.25 mmol) was added to bring the temperature to 0 ° C. While stirring at the same temperature, 35% hydrochloric acid (0.561 g,
(5.38 mmol) was added dropwise, followed by stirring at room temperature for 5 hours. A 15% aqueous sodium hydroxide solution was added to the reaction solution to make the pH neutral to alkaline, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound as a crude product. This was purified by distillation (80-100 ° C./0.8-1.2 kPa) to give the title compound (R) -3-methyl-4- (2-tetrahydropyranyloxy) butylamine (6-a) (0.8%). 73
g, a yield of 80%, and an optical purity of 95% ee at the third position). Note that the optical purity of the title compound was determined by analyzing with an optically active column.

Example 17 Synthesis of (R) -3-methyl-4- (2-tetrahydropyranyloxy) butylamine (6-a) In a 500 mL reaction flask, (R) -3-methyl-4-hydroxy was added. -Butylamine (5-a) (25 g, 243 mmol)
And tetrahydrofuran (250 mL) was added, and 3,4-dihydropyran (24.5 g, 291 mmol) was added.
Was added. While stirring at 20 to 30 ° C, methanesulfonic acid (24.5 g, 255 mmol) was added dropwise, followed by stirring at room temperature for 1 hour. A 15% aqueous sodium hydroxide solution was added to the reaction solution to make the pH neutral to alkaline, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (R) -3-methyl-
4- (2-tetrahydropyranyloxy) butylamine (6-a) (43.1 g, yield 95%, optical purity 95 at the 3-position)
% Ee). Note that the optical purity of the title compound was determined by analyzing with an optically active column.

Example 18 Synthesis of (R) -3-methyl-4- (2-tetrahydropyranyloxy) butyronitrile (8-a)

[0233]

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In a 50 mL reaction flask, (R) -3-methyl-4-hydroxy-butyronitrile (7-a) (0.1 g, 1.01 mmol) obtained in Example 11 was weighed, and tetrahydrofuran (1 mL) was added. And 3,4-dihydropyran (0.127 g, 1.51 mmol) was added. While stirring at room temperature, p-toluenesulfonic acid (0.019 g,
(0.10 mmol) was added, followed by stirring at room temperature for 6 hours.
To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain the title crude product. This was purified by silica gel column chromatography to obtain the title compound (R) -3-methyl-4- (2-tetrahydropyranyloxy) butyronitrile (8-a) (0.106 g, yield 57%). Was.

Example 19 Synthesis of (R) -3-methyl-4- (2-tetrahydropyranyloxy) butylamine (6-a)

[0236]

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Under a nitrogen atmosphere, tetrahydrofuran (1 mL) was added to a 50 mL reaction flask, and the temperature was adjusted to 0 ° C. LiAlH ₄ (0.021 g, 0.553 mmol) was added thereto, and the mixture was stirred at the same temperature, and the (R) -3- obtained in Example 18 was obtained.
A solution of methyl-4- (2-tetrahydropyranyloxy) butyronitrile (8-a) (0.10 g, 0.546 mmol) in tetrahydrofuran (2 mL) was added. After stirring at room temperature for 2 hours, water (0.1 mL) was added at 0 ° C.
% Sodium hydroxide aqueous solution (0.1 mL) was added, and the mixture was stirred for 30 minutes. The precipitate was filtered through celite, washed with ethyl acetate, and the filtrate was dried over anhydrous magnesium sulfate and concentrated to give the title compound as a crude product. This was purified by distillation (80-100 ° C / 0.8-1.2 kPa) to give the title compound (R) -3-methyl-4- (2-tetrahydropyranyloxy) -butylamine (6-a) (0 .0
72 g, a yield of 70%, and an optical purity of 95% ee at the third position were obtained. Note that the optical purity of the title compound was determined by analyzing with an optically active column.

[0238]

According to the method of the present invention, optically active 3-substituted-4-substituted oxy-butylamines or their enantiomers can be produced efficiently and at low cost.

Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) C07D 309/12 C07D 309/12 // A61K 31/4375 A61K 31/4375 A61P 13/02 A61P 13/02 C07B 53/00 C07B 53/00 FG 61/00 300 61/00 300 C07D 487/04 147 C07D 487/04 147 C07M 7:00 C07M 7:00 (72) Inventor Kenichi Seki 722-1, Tsuboi-cho, Funabashi-shi, Chiba Nissan Chemical (72) Inventor Yasuo Kawamura 722 Tsuboi-cho, Funabashi-shi, Chiba F-term (reference) 4M050 AA01 BB07 CC07 EE02 FF01 GG07 HH01 4C062 AA20 4C086 AA04 CB09 ZA81 4H006 AA02 AC22 AC41 AC52 AC54 AC81 BA26 BA52 BA55 BA66 BE22 BN10 BU32 QN30 4H039 CA42 CA71 CB30 CF10

Claims (8)

[Claims] (1) Formula (4) (Wherein R ¹ is a linear, branched or cyclic C _1-6 alkyl group, a linear, branched or cyclic C _2-6 alkenyl group, a linear, branched or cyclic C _2-6 alkynyl) R ² represents a hydrogen atom, an alkali metal, an alkaline earth metal, a linear, branched or cyclic C _{1-6 group;}
Represents an alkyl group, a linear, branched or cyclic C _2-6 alkenyl group, a linear, branched or cyclic C _2-6 alkynyl group, a phenyl group or a benzyl group. ), Wherein the 2-substituted-3-cyanopropanoic acid ester or its enantiomer is reduced. (Wherein, R ¹ represents the same meaning as described above).
A process for producing 3-substituted-4-hydroxybutylamines or enantiomers thereof. 2. Formula (3) (Wherein, R ¹ and R ² represent the same meaning as described above;
³ is a hydrogen atom, an alkali metal, an alkaline earth metal, a linear, branched or cyclic C _1-6 alkyl group, a linear, branched or cyclic C _2-6 alkenyl group, a linear, branched or Represents a cyclic C _2-6 alkynyl group, phenyl group or benzyl group. Formula (4) which is produced by decarboxylation of a 3-substituted-2-cyanobutanedicarboxylic acid or an enantiomer thereof represented by the following formula: (Wherein, R ¹ and R ² have the same meanings as described above), and a 2-substituted-3-cyanopropanoic acid ester or an enantiomer thereof is used. A process for producing the 3-substituted-4-hydroxybutylamines or the enantiomers thereof as described above. 3. Formula (1) (Wherein, R ¹ and R ² represent the same meaning as described above, and X represents a halogen atom, a C _1-4 alkylsulfonyloxy group, a halogenated alkylsulfonyloxy group, or an arylsulfonyloxy group.) Optically active 2-substituted acetic acids or their enantiomers and formula (2) (Wherein, R ³ has the same meaning as described above), which is produced by reacting a cyanoacetic acid represented by the formula (3) in the presence of a base: (Wherein, R ¹ , R ² and R ³ have the same meanings as described above), wherein 3-substituted-2-cyanobutanedicarboxylic acids or their enantiomers are used. Item 3. A process for producing a 3-substituted-4-hydroxybutylamine or an enantiomer thereof according to Item 2. 4. A compound of the formula (5) obtained by the process for producing a 3-substituted-4-hydroxybutylamine or an enantiomer thereof according to claim 3. (Wherein, R ¹ represents the same meaning as described above).
Formula (6) wherein the hydroxyl group of the 3-substituted-4-hydroxybutylamine or its enantiomer is protected. (In the formula, R ⁴ represents a hydroxyl-protecting group.)
A process for producing 3-substituted-4-substituted oxy-butylamines or enantiomers thereof. 5. The formula (4) (Wherein, R ¹ and R ² have the same meanings as described above), and the 2-substituted-3-cyanopropanoic acid esters or their enantiomers are reduced to give a compound of the formula (7) ] (Wherein, R ¹ represents the same meaning as described above).
Formula (5), which is reduced to a 3-substituted-4-hydroxybutyronitrile or an enantiomer thereof, and then reduced. (Wherein, R ¹ represents the same meaning as described above).
A process for producing 3-substituted-4-hydroxybutylamines or enantiomers thereof. 6. A compound of formula (5) obtained by the process for producing a 3-substituted-4-hydroxybutylamine or an enantiomer thereof according to claim 5. (Wherein, R ¹ represents the same meaning as described above).
Formula (6) wherein the hydroxyl group of the 3-substituted-4-hydroxybutylamine or its enantiomer is protected. (In the formula, R ⁴ represents a hydroxyl-protecting group.)
A process for producing 3-substituted-4-substituted oxy-butylamines or enantiomers thereof. 7. Formula (4) (Wherein R ¹ and R ² represent the same meaning as described above), by reducing a 2-substituted-3-cyanopropanoic acid ester or an enantiomer thereof to obtain a compound represented by the formula (7): Embedded image (Wherein, R ¹ represents the same meaning as described above).
Formula (8), which is a 3-substituted-4-hydroxybutyronitrile or an enantiomer thereof, and then protects a hydroxyl group. (Wherein, R ¹ and R ⁴ have the same meanings as described above.) A method for producing a 3-substituted-4-substituted oxy-butyronitrile or an enantiomer thereof. 8. A compound of the formula (8) obtained by the process for producing a 3-substituted-4-substituted oxy-butyronitrile or an enantiomer thereof according to claim 7. (Wherein R ¹ and R ⁴ represent the same meaning as described above), characterized by reducing a 3-substituted-4-substituted oxy-butyronitrile or an enantiomer thereof. ) (In the formula, R ⁴ represents a hydroxyl-protecting group.)
A process for producing 3-substituted-4-substituted oxy-butylamines or enantiomers thereof.