JP2003267923A - Method for producing optically active 3-halogenocarboxylic acid ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method of producing a desired optically active 3- halogenocarboxylic acid ester with high optical purity in high yield in no use of heavy metal. <P>SOLUTION: The optically active 3-hydroxycarboxylic acid ester is allowed to react with thionyl halide in the presence of a basic catalyst in an organic solvent to produce the optically active 3-halogenocarboxylic ester. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active 3-halogenocarboxylic acid ester useful as a pharmaceutical intermediate, a liquid crystal material and the like.

[0002]

2. Description of the Related Art Recently, optically active compounds are widely used, and they are used as pharmaceuticals, agricultural chemicals, liquid crystal materials, etc. One of such optically active compounds is an optical compound in which the β-position of carboxylic acid is halogenated. Active 3-chlorocarboxylic acid derivatives are known. As a method for producing an optically active 3-chlorocarboxylic acid derivative in which the β-position of a carboxylic acid is halogenated, conventionally, α,
A method for producing an optically active 3-chlorocarboxylic acid by subjecting a β-unsaturated carboxylic acid to an addition reaction with hydrogen chloride [J. Or
g. Chem., 55, 564 (1990)], (2) Optically active 3-hydroxycarboxylic acid ester and thionyl chloride are reacted in the presence of a catalytic amount of zinc chloride to produce an optically active 3-chlorocarboxylic acid ester. A method (Japanese Patent Laid-Open No. 63-222148; especially Example 4) and the like are known.

However, the above-mentioned production method (1) has the problems that the reaction requires a long time, the yield is low, and the optical yield of the optically active 3-chlorocarboxylic acid obtained is low. There is. Further, in the production method (2), it is necessary to use an excess amount of thionyl chloride, the reaction takes a long time, the yield is low, and it is necessary to use a heavy metal salt as a catalyst, which causes various problems. Have Moreover, in the case of the production method of the above (2), there is no guarantee that an optically active 3-chlorocarboxylic acid ester with high optical purity can be obtained.

Further, the invention described in JP-A No. 11-246472 uses an optically active α-substituted carboxylic acid ester as a starting compound, and uses the optically active α-substituted carboxylic acid ester in the presence of an inorganic acid catalyst. The present invention relates to a method for producing an optically active α-substituted carboxylic acid by bringing it into contact with an organic acid. In Example 1 of this publication, L-methyl lactate and thionyl chloride are used as a solvent in the presence of a catalytic amount of pyridine. To produce D- corresponding to one of the optically active α-substituted carboxylic acid ester as a raw material compound.
A method for making methyl 2-chloropropionate is described. However, according to the method described in Example 1 of this publication, methyl D-2-chloropropionate cannot be obtained in a high yield. Also,
The inventors of the present invention applied the method described in Example 1 of this publication to the production of an optically active 3-chlorocarboxylic acid ester, and tried an experiment for producing an optically active 3-chlorocarboxylic acid ester. However, the desired optical activity 3-
The yield of halogenocarboxylic acid ester was low, and an optically active 3-halogenocarboxylic acid ester with high optical purity could not be produced with high yield and high productivity.

[0005]

The object of the present invention is to efficiently produce an optically active 3-halogenocarboxylic acid ester having a high optical purity in a short reaction time and in a high yield without using a heavy metal salt catalyst or the like. It is to provide a method that can be manufactured well.

[0006]

[Means for Solving the Problems] The present inventors have conducted extensive studies to achieve the above object. As a result, when an optically active 3-hydroxycarboxylic acid ester and a thionyl halide are reacted in an organic solvent in the presence of a basic substance, an optically active 3-halogenocarboxylic acid ester having a high optical purity is reacted with a short reaction time. The present invention has been completed by finding that it can be produced at a high yield.

That is, the present invention includes (1) the following general formula (I);

[0008]

[Chemical 4] (Wherein R ¹ represents an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, R ² represents a lower alkyl group, and * represents an asymmetric carbon). 3-hydroxycarboxylic acid ester and thionyl halide are reacted in an organic solvent in the presence of a basic substance, represented by the following general formula (II);

[0009]

[Chemical 5] (In the formula, X represents a halogen atom, and R ¹ , R ² and * are the same as the above.) The method for producing an optically active 3-halogenocarboxylic acid ester.

The present invention (2) uses thionyl chloride as the thionyl halide and has the following general formula (II
a);

[0011]

[Chemical 6] (In the formula, R ¹ , R ² and * are the same as above.) The production method of (1) above for producing the optically active 3-chlorocarboxylic acid ester; and (3) the basic substance is an amine. The method for producing (1) or (2), which is a class;

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The optically active 3-hydroxycarboxylic acid ester represented by the above general formula (I) used as a raw material compound in the production method of the present invention [hereinafter, this may be referred to as "optically active 3-hydroxycarboxylic acid ester (I)". ], R ¹ is an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, and R ² is a lower alkyl group.

When R ¹ is an alkyl group, the alkyl group may be a linear, branched or cyclic alkyl group, for example, a linear alkyl group having 1 to 10 carbon atoms, a branched alkyl group or A cyclic alkyl group can be mentioned. Specific examples of the case where R ¹ is an alkyl group include:
Methyl group, ethyl group, n-propyl group, 2-propyl group, n-butyl group, 2-butyl group, t-butyl group, n-
Pentyl group, 2-pentyl group, t-pentyl group, n-hexyl group, 2-hexyl group, 3-hexyl group, t-hexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, Examples thereof include cyclopropyl group and cyclohexyl group.

When R ¹ is a substituted alkyl group, an alkyl group in which at least one hydrogen atom of the above-mentioned alkyl group is substituted with a substituent is mentioned, and examples of the substituent in this case include alkoxy. A group etc. can be mentioned. The alkoxy group forming the substituent may be either a linear alkoxy group or a branched alkoxy group, and examples thereof include a linear alkoxy group having 1 to 10 carbon atoms or a branched alkoxy group. When R ¹ is a substituted alkyl group, specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group,
A straight chain having 1 to 10 carbon atoms substituted with an alkoxy group such as a hexyloxy group, a heptyloxy group, an octyloxy group, a nonyloxy group, a decyloxy group, a 2-propoxy group, a t-butoxy group and a 2-ethylhexyloxy group. An alkyl group or a branched alkyl group can be mentioned.

R¹Is a aralkyl group, methyl
Group, ethyl group, n-propyl group, 2-propyl group, n-
Carbon number 1 such as butyl group, 2-butyl group, t-butyl group
At least one hydrogen atom in the lower alkyl group of
An aralkyl group substituted with an aryl group can be mentioned.
Wear. At this time, the aryl group forming a substituent includes
C6-C14 aryl such as phenyl group and naphthyl group
Group. R ¹When is an aralkyl group
Examples of the body include benzyl group, phenethyl group, 3-
Examples include phenylpropyl group and 4-phenylbutyl group
You can

When R ¹ is a substituted aralkyl group, a group in which at least one hydrogen atom of the aryl group in the above aralkyl group is substituted with a substituent can be mentioned. Examples of the substituent at that time include a methyl group, an ethyl group, and n-
Propyl group, 2-propyl group, n-butyl group, 2-butyl group, t-butyl group or other linear or branched alkyl group having 1 to 4 carbon atoms, methoxy group, ethoxy group, propoxy group, 2 -A linear or branched alkoxy group having 1 to 4 carbon atoms such as a propoxy group and a butoxy group, and a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. When R ¹ is a substituted aralkyl group, specific examples thereof include a methylbenzyl group, a methylphenethyl group, a methoxybenzyl group, a methoxyphenethyl group,
Examples thereof include a chlorobenzyl group and a chlorophenethyl group.

The lower alkyl group represented by R ² may be linear or branched, and examples thereof include an alkyl group having 1 to 4 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, Examples thereof include 2-propyl group, n-butyl group, 2-butyl group, t-butyl group and the like.

Specific examples of the optically active 3-hydroxycarboxylic acid ester (I) used as the raw material compound are 3
-Hydroxybutanoic acid, 3-hydroxypentanoic acid, 3
-Hydroxy-4-methylpentanoic acid, 3-hydroxy-4,4-dimethylpentanoic acid, 3-hydroxyhexanoic acid, 3-hydroxy-4-methylhexanoic acid, 3-hydroxy-5-methylhexanoic acid, 3-hydroxy-
5,5-dimethylhexanoic acid, 3-hydroxy-4,
4,5-Trimethylhexanoic acid, 3-hydroxyheptanoic acid, 3-hydroxy-4-methylheptanoic acid, 3-hydroxy-6-methylheptanoic acid, 3-hydroxy-
6,6-Dimethylheptanoic acid, 3-hydroxyoctanoic acid, 3-hydroxy-7-methyloctanoic acid, 3-hydroxynonanoic acid, 3-hydroxy-8-methylnonanoic acid, 3-hydroxydecanoic acid, 3-hydroxy-9 -Methyldecanoic acid, 3-hydroxyundecanoic acid, 3-hydroxy-10-methylundecanoic acid, 3-hydroxy-
11-methyldodecanoic acid, 3-hydroxy-12-methyltridecanoic acid, 3-hydroxy-4-phenylbutanoic acid, 3-hydroxy-5-phenylpentanoic acid, 3-hydroxy-6-phenylhexanoic acid, 3-hydroxy −
7-phenylheptanoic acid, 3-hydroxy-4- (p-
Methylphenyl) butanoic acid, 3-hydroxy-5- (p
-Methylphenyl) pentanoic acid, 3-hydroxy-4-
(P-Methoxyphenyl) butanoic acid, 3-hydroxy-
Carboxylic acids in which R ¹ is a substituted aralkyl group, such as 5- (p-methoxyphenyl) pentanoic acid, 3-hydroxy-4- (p-chlorophenyl) butanoic acid, and 3-hydroxy-5- (p-chlorophenyl) pentanoic acid. Examples thereof include esters such as methyl ester, ethyl ester, n-propyl ester, 2-propyl ester, n-butyl ester, 2-butyl ester and t-butyl ester.

The above-mentioned optically active 3-hydroxycarboxylic acid ester (I) used in the present invention has a (3S) form and a (3R) form, and unless it is a racemic form,
It may be either a (3S) form or a (3R) form.
When the (3R) form is used as the optically active 3-hydroxycarboxylic acid ester (I) which is the raw material compound, the optically active 3-halogenocarboxylic acid ester (II) obtained by the reaction with thionyl halide is the (3S) form. is there. Further, when the (3S) form is used as the optically active 3-hydroxycarboxylic acid ester (I) which is a raw material compound, the optically active 3-halogenocarboxylic acid ester (II) obtained by the reaction with thionyl halide is (3R). It is the body.

The optically active 3-hydroxycarboxylic acid ester (I) used as a raw material compound in the present invention is a known compound, and is described in, for example, J. Am. Chem. Soc., 110,
629 (1988) and Tetrahedron Lett., 39,
It can be easily manufactured by the method described in 4441 (1998) and the like. More specifically, the optically active 3-hydroxycarboxylic acid ester (I) has, for example, the following general formula (III);

[0021]

[Chemical 7] (In the formula, R ¹ and R ² are the same as the above.) 3-
The oxocarboxylic acid ester can be produced with good optical purity by subjecting it to a hydrogenation reaction in the presence of an asymmetric hydrogenation catalyst.

In the production method of the present invention, the optically active 3-
The thionyl halide to be reacted with the hydroxycarboxylic acid ester (I) is represented by the general formula: SOX ₂ (in the formula, X
Is a halogen atom) and a compound represented by
Specific examples thereof include thionyl chloride and thionyl bromide. Among them, thionyl chloride is preferably used because it is inexpensive and easy to handle.

The amount of thionyl halide used is usually preferably 1 to 1.5 mol ratio, based on 1 mol of the optically active 3-hydroxycarboxylic acid ester (I).
It is more preferably 1.1 mol. If the amount of thionyl halide used is less than 1 mol with respect to 1 mol of the optically active 3-hydroxycarboxylic acid ester (I), the optically active compound 3 represented by the above general formula (II) is a target compound.
-Halogenocarboxylic acid ester [hereinafter, this may be referred to as "optically active 3-halogenocarboxylic acid ester (II)"] is difficult to obtain smoothly. On the other hand, when it exceeds 1.5 mol, the reaction rate increases, but excess It is necessary to neutralize the thionyl halide for a minute, which is costly and troublesome.

In the production method of the present invention, the reaction of the optically active 3-hydroxycarboxylic acid ester (I) and thionyl halide is carried out in the presence of a basic substance. The basic substance is
Optically active 3-hydroxycarboxylic acid ester (I) 3
It acts as a catalyst for converting the hydroxyl group in position to a halogen atom by reaction with thionyl halide. Amines are preferably used as the basic substance forming the catalyst. The amines preferably used as the catalyst may be any of primary amine, secondary amine and tertiary amine,
Specific examples include triethylamine, diisopropylethylamine, tripropylamine, tributylamine,
Aliphatic tertiary amines such as N-methylpiperidine and N-methylmorpholine; diethylamine, dipropylamine,
Aliphatic 2 such as diisopropylamine and dibutylamine
Examples thereof include aliphatic amines such as primary amines, aromatic amines such as pyridine, lutidine, picoline and quinoline. These amines can be used alone or
You may use it, combining two or more types suitably. Among them, the aliphatic amines are more preferably used from the viewpoints that the optically active 3-halogenocarboxylic acid ester (II) which is the target compound can be obtained in a higher yield, the cost, etc., and triethylamine, diisopropylethylamine, tripropyl are used. Aliphatic tertiary amines such as amine, tributylamine, N-methylpiperidine and N-methylmorpholine are more preferably used.

The amount of the basic substance used may be a catalytic amount, and is generally 0.005 to 1 mol with respect to 1 mol of the optically active 3-hydroxycarboxylic acid ester (I).
0.5 mol, more preferably 0.005-0.2 mol,
More preferably, it is used in a proportion of 0.01 to 0.05 mol.

Further, in the production method of the present invention, the optically active 3-halogenocarboxylic acid ester (I
In order to obtain I) in high yield, it is necessary to carry out the reaction of the optically active 3-hydroxycarboxylic acid ester (I) with thionyl halide in the presence of a basic substance in an organic solvent. When the reaction of the optically active 3-hydroxycarboxylic acid ester (I) and thionyl halide is carried out in the absence of a solvent, the objective compound, the optically active 3-halogenocarboxylic acid ester (II), cannot be obtained in a high yield. Specific examples of the organic solvent used in the present invention include aliphatic hydrocarbons such as pentane, hexane and heptane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dioxolane, dimethoxyethane. And ethers; methyl acetate, ethyl acetate, butyl acetate, methyl propionate, and other esters; and dichloromethane, chloroform, dichloroethane, carbon tetrachloride, and other halogenated hydrocarbons. These organic solvents may be used alone or in appropriate combination of two or more kinds. Among these organic solvents, the yield of the desired optically active 3-halogenocarboxylic acid ester (II),
From the viewpoint of operability, aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene and toluene; ethers such as diethyl ether and diisopropyl ether are preferably used, and such as diethyl ether and diisopropyl ether. Ethers are more preferably used.

The amount of the organic solvent used depends on the yield of the desired optically active 3-halogenocarboxylic acid ester (II), industrial efficiency such as reduction of the time required for removing the organic solvent after the reaction, and the like. In consideration of 100 g of the optically active 3-hydroxycarboxylic acid ester (I),
It is preferably about 500 ml, 100 to 200
More preferably, it is about ml.

The reaction of the optically active 3-hydroxycarboxylic acid ester (I) with thionyl halide in an organic solvent in the presence of a basic substance allows the reaction to proceed smoothly to give the desired optically active 3-halogeno Carboxylic acid ester (II)
In order to obtain a high yield, it is preferable to carry out at a temperature of usually -15 ° C to 110 ° C, especially 20 to 110 ° C. In the above reaction, if necessary, the optically active 3-hydroxycarboxylic acid ester (I) and thionyl halide may be mixed under cooling and then heated to the reaction temperature to react. The reaction time is usually 2 to 15 hours, preferably 4
It is appropriately selected from the range of 9 hours. The method for recovering the produced optically active 3-halogenocarboxylic acid ester (II) from the reaction system, the method for purifying it, etc. are not particularly limited, and the same operation as normally performed can be adopted. Although not limited in any way, for example, after the reaction,
Water is added to the reaction system to separate it into an organic phase and an aqueous phase, and the organic phase is recovered. The organic phase is washed with an alkali such as an aqueous solution of sodium hydrogen carbonate, an acid such as hydrochloric acid or citric acid, or a saturated saline solution. After that, the organic solvent is removed, distillation under reduced pressure, and the like are sequentially performed to obtain the optically active 3-halogenocarboxylic acid ester (II) as a target compound with high optical purity and high yield.

By carrying out the above-mentioned production method of the present invention, racemization of the objective optically active 3-halogenocarboxylic acid ester (II) can be carried out by a simple operation without using a heavy metal salt catalyst or the like. And can be smoothly obtained with high yield and high optical purity.

In the present invention, the optically active 3 used as a raw material is used.
An optically active 3-halogenocarboxylic acid ester (II) represented by the above general formula (II) corresponding to the types of the hydroxycarboxylic acid ester (I) and the thionyl halide.
Can be manufactured. Specific examples of the optically active 3-halogenocarboxylic acid ester (II) obtained by the production method of the present invention include 3-chlorobutanoic acid, 3-chloropentanoic acid, 3-chloro-4-methylpentanoic acid and 3-chloro- 4,4-dimethylpentanoic acid, 3-chlorohexanoic acid, 3-chloro-4-methylhexanoic acid, 3-chloro-
5-methylhexanoic acid, 3-chloro-5,5-dimethylhexanoic acid, 3-chloro-4,4,5-trimethylhexanoic acid, 3-chloroheptanoic acid, 3-chloro-4-methylheptanoic acid , 3-chloro-6-methylheptanoic acid, 3
-Chloro-6,6-dimethylheptanoic acid, 3-chlorooctanoic acid, 3-chloro-7-methyloctanoic acid, 3-chlorononanoic acid, 3-chloro-8-methylnonanoic acid, 3-
Chlorodecanoic acid, 3-chloro-9-methyldecanoic acid, 3
-Chloroundecanoic acid, 3-chloro-10-methylundecanoic acid, 3-chloro-11-methyldodecanoic acid, 3-
Chloro-12-methyltridecanoic acid, 3-chloro-4-
Phenylbutanoic acid, 3-chloro-5-phenylpentanoic acid, 3-chloro-6-phenylhexanoic acid, 3-chloro-7-phenylheptanoic acid, 3-chloro-4- (p-methylphenyl) butanoic acid, 3 -Chloro-5- (p-methylphenyl) pentanoic acid, 3-chloro-4- (p-methoxyphenyl) butanoic acid, 3-chloro-5- (p-methoxyphenyl) pentanoic acid, 3-chloro-4- (P-chlorophenyl) butanoic acid, 3-chloro-5- (p-chlorophenyl) pentanoic acid, 3-bromobutanoic acid, 3-bromopentanoic acid, 3-bromo-4-methylpentanoic acid,
3-bromo-4,4-dimethylpentanoic acid, 3-bromohexanoic acid, 3-bromo-4-methylhexanoic acid, 3-
Bromo-5-methylhexanoic acid, 3-bromo-5,5-
Dimethylhexanoic acid, 3-bromo-4,5,5-trimethylhexanoic acid, 3-bromoheptanoic acid, 3-bromo-
4-methylheptanoic acid, 3-bromo-6-methylheptanoic acid, 3-bromo-6,6-dimethylheptanoic acid, 3-
Bromooctanoic acid, 3-bromo-7-methyloctanoic acid, 3-bromononanoic acid, 3-bromo-8-methylnonanoic acid, 3-bromodecanoic acid, 3-bromo-9-methyldecanoic acid, 3-bromoundecanoic acid, 3- Bromo-10-
Methylundecanoic acid, 3-bromo-11-methyldodecanoic acid, 3-bromo-12-methyltridecanoic acid, 3-bromo-4-phenylbutanoic acid, 3-bromo-5-phenylpentanoic acid, 3-bromo-6 -Phenylhexanoic acid,
3-Bromo-7-phenylheptanoic acid, 3-bromo-4
-(P-methylphenyl) butanoic acid, 3-bromo-5-
(P-Methylphenyl) pentanoic acid, 3-bromo-4-
(P-Methoxyphenyl) butanoic acid, 3-bromo-5-
(P-Methoxyphenyl) pentanoic acid, 3-bromo-4
-(P-chlorophenyl) butanoic acid, 3-bromo-5-
Methyl ester, ethyl ester, n-propyl ester, 2-propyl ester, n-butyl ester, 2- of carboxylic acid such as (p-chlorophenyl) pentanoic acid
Examples thereof include butyl ester and t-butyl ester.

Optical activity 3 produced by the method of the present invention
-The halogenocarboxylic acid ester (II) is in an optically active form of either (3S) form or (3R) form.
As described above, when the optically active 3-hydroxycarboxylic acid ester (I) of the (3R) form is used as the raw material compound, the optically active 3-halogenocarboxylic acid ester (II) of the (3S) form is obtained. , The optically active 3-hydroxycarboxylic acid ester (I) of the (3S) form is used to obtain the optically active 3-halogenocarboxylic acid ester (II) of the (3R) form. Generally, the optically active 3- (3S) form 3-
The halogenocarboxylic acid ester (II) is useful for applications such as pharmaceutical intermediates, and the (3R) optically active 3-halogenocarboxylic acid ester (II) is useful for applications such as liquid crystal materials.

Optical activity obtained by the production method of the present invention 3-
Among the halogenocarboxylic acid esters (II), the following general formula (IIa);

[0033]

[Chemical 8] (In the formula, R ¹ , R ² and * are the same as above.) The optically active 3-chlorocarboxylic acid ester can be effectively used for applications such as pharmaceutical intermediates and liquid crystal materials, and is further manufactured. It is particularly useful in terms of cost.

[0034]

EXAMPLES The present invention will be specifically described below with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. In the following Examples and Comparative Examples, the reaction conversion rate, the product compound [(3S)-
Optical rotation of [chlorocarboxylic acid methyl esters] ([α]
_D ^20), nuclear magnetic resonance ⁽¹ H-NMR), mass spectral (MS), chemical purity and optical purity were determined in the following manner.

(1) Conversion of reaction: Gas chromatography (GC) (Agilent Technology)
The conversion rate of the reaction was determined from the peak area ratio using "6890A" manufactured by es.

(2) Optical rotation ([α] _D ²⁰ ) of the produced compound: "DIP-36" manufactured by JASCO Corporation
It was measured using "0".

(3) Nuclear magnetic resonance spectrum ( ¹ H-NMR) of the produced compound: Using a nuclear magnetic resonance measuring apparatus "DRX-500" (200 MHz) manufactured by BRUKER.
The ¹ H-NMR of the produced compound was measured.

(4) Mass spectrum (M
S): The mass spectrum (MS) of the produced compound was measured using "M2000A" manufactured by Hitachi, Ltd.

(5) Chemical purity of product compound: Gas chromatography ("TC-WA" manufactured by GL SCIENCE)
X ") is used to measure an initial temperature of 100 ° C to 150 ° C.
The chemical purity (%) of the produced compound was measured by performing the measurement under the conditions of ℃, temperature rising rate 3 ℃ / min, inlet temperature 220 ℃, detector temperature 250 ℃.

(6) Optical purity of produced compound: Gas chromatography ("CHIRAL DEX" manufactured by ASTEC)
B-TA ”) at a constant temperature of 90 ° C. under the conditions of an inlet temperature of 200 ° C. and a detector temperature of 200 ° C. to measure the optical purity (%) of the produced compound. .

Example 1 [Production of methyl (3S) -chlorobutanoate] (1) Methyl (3R) -hydroxybutanoate 13
2.55 g (1.122 mol) (optical purity 99.5%
ee), 265 ml of diisopropyl ether and 7.8 ml (0.056 mol) of triethylamine were mixed, and then the resulting mixed solution was cooled to −15 ° C., and then 40.5 ml of thionyl chloride (0.561 mo)
l) was added dropwise. After completion of dropping, the liquid temperature was raised to room temperature, and 40.5 ml (0.561 mol) of thionyl chloride was further added dropwise. After completion of the dropping, the mixture was gradually heated to 75 ° C. for 6 hours and then reacted at 75 ° C. for 10 minutes (reaction conversion rate 99.4%). (2) After completion of the reaction in (1) above, the reaction solution was cooled to 10 ° C. or lower, 80 ml of water was added to separate the solution into an organic phase and an aqueous phase, and the recovered organic phase was diluted with 5% sodium hydrogen carbonate aqueous solution 1
It was washed successively with 60 ml and saturated saline 160 ml.
After the solvent was distilled off, the residue was purified by distillation under reduced pressure to obtain 131.90 g (yield 86.1%) of the target methyl (3S) -chlorobutanoate. The obtained methyl (3S) -chlorobutanoate has an optical purity of 99.1% ee and a boiling point of 70.
It was ˜72 ° C./4666 Pa (35 mmHg). (3) In addition, methyl (3S) -obtained in the above (2)
Optical rotation of chlorobutanoate ([α] _D ²⁰ ), ¹ H-NM
The measurement results of R and MS were as follows.・ [Α] _D ²⁰ = + 35.0 ° (c = 1.01, CHC
l ₃ ) ・ [α] _D ²⁰ = + 41.47 ° (c = 1.01, CH ₃ O
H). ¹ H-NMR (CDCl ₃ ): δ = 1.56 (3H, d,
J = 6.6 Hz), 2.74 (2H, dd, J = 6.
5, 16.1 Hz), 3.71 (3H, s), 4.3-
4.5 (1H, m) MS: m / z 137 (M ⁺ +1)

Examples 2 to 5 [Production of methyl (3S) -chlorobutanoate] (1) Methyl (3R) -hydroxybutanoate 2
0.00 g (0.169 mol) (optical purity 99.5%
ee), each solvent shown in Table 1 below (40 ml)
And triethylamine 1.2 ml (8.5 mmol)
And then mix the resulting mixed solution with -15
After cooling to ℃, 6.1 ml of thionyl chloride (0.085
(mol) was added dropwise. After the dropping was completed, the liquid temperature was raised to room temperature, and 6.1 ml (0.085 mol) of thionyl chloride was further added dropwise. After completion of the dropping, the mixture was gradually heated to around 75 ° C over 6 to 7 hours, and then reacted at 75 ° C for 10 minutes. (2) After completion of the reaction in (1) above, the reaction solution was cooled to 10 ° C. or lower, water was added to separate the solution into an organic phase and an aqueous phase, and the recovered organic phase was diluted with 5% aqueous sodium hydrogen carbonate solution and saturated sodium chloride. It was washed successively with water. After the solvent was distilled off, the residue was purified by distillation under reduced pressure to obtain the desired methyl (3S) -chlorobutanoate. The yield, yield, reaction conversion rate and optical purity were as shown in Table 1 below.

[0043]

[Table 1]

Comparative Example 1 [Production of Methyl (3S) -chlorobutanoate] Methyl (3R) -hydroxybutanoate 11.80 g
(0.10 mol) and thionyl chloride 13.09 g
(0.10 mol) were mixed, and the mixture was stirred at room temperature for 20 hours and then refluxed for 30 minutes. The reaction solution was cooled to room temperature, 10 ml of water was added, and 20 m of diisopropyl ether was added.
It was extracted with 1. The organic phase was washed successively with 15 ml of 5% aqueous sodium hydrogen carbonate solution and 15 ml of saturated saline. After the solvent was distilled off, the residue was measured by gas chromatography. As a result, the production of the target methyl (3S) -chlorobutanoate was not confirmed. As is clear from the results of Comparative Example 1, even if the optically active 3-hydroxycarboxylic acid ester (I) and thionyl halide are directly reacted without using a basic substance and an organic solvent,
The desired optically active 3-hydroxycarboxylic acid ester (I) cannot be obtained.

Comparative Example 2 [Production of Methyl (3S) -chlorobutanoate] Methyl (3R) -hydroxybutanoate 10.00 g
(0.085 mol), 11.10 g of thionyl chloride
(0.093 mol) and pyridine 0.04 g (0.
56 mmol) and mixed at 60 ° C. for 3 hours,
The mixture was refluxed at 75 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, 10 ml of water was added, and the mixture was extracted with 20 ml of diisopropyl ether. The organic phase was washed successively with 15 ml of 5% aqueous sodium hydrogen carbonate solution and 15 ml of saturated saline. After distilling off the solvent, the residue was purified by distillation under reduced pressure to obtain the desired methyl (3S) -chlorobutanoate 6.25.
g (54% yield) was obtained. The optical purity of the obtained methyl (3S) -chlorobutanoate was 97.8% ee, and the boiling point was 70 ° C./4800 Pa (36 mmHg). As is clear from the results of Comparative Example 2, even when the optically active 3-hydroxycarboxylic acid ester (I) is reacted with thionyl halide in the presence of a basic substance, the reaction is performed in an organic solvent. Otherwise, the desired optical activity 3-
The yield of the hydroxycarboxylic acid ester (I) is significantly reduced, and the optical purity of the optically active 3-hydroxycarboxylic acid ester (I) is also lower than that when an organic solvent is used.

Comparative Example 3 [Production of Methyl (3S) -chlorobutanoate] Methyl (3R) -hydroxybutanoate 10.00 g
(0.085 mol), 11.10 g of thionyl chloride
(0.093 mol) and triethylamine 0.05
g (0.50 mmol) were mixed, stirred at 60 ° C. for 3 hours, and then refluxed at 75 ° C. for 1 hour. After the reaction,
The reaction solution was cooled to room temperature, 10 ml of water was added, and the mixture was extracted with 20 ml of diisopropyl ether. The organic phase was washed successively with 15 ml of 5% aqueous sodium hydrogen carbonate solution and 15 ml of saturated saline. After distilling off the solvent, the residue was purified by distillation under reduced pressure to obtain 1.34 g of the target methyl (3S) -chlorobutanoate (yield 10.0%). Optical purity 96.
0% ee. Also from the results of Comparative Example 3, even when the optically active 3-hydroxycarboxylic acid ester (I) is reacted with thionyl halide in the presence of a basic substance, the reaction must be performed in an organic solvent. The yield of the target optically active 3-hydroxycarboxylic acid ester (I) is significantly reduced, and the optical purity of the optically active 3-hydroxycarboxylic acid ester (I) is lower than that when an organic solvent is used. You can see.

Example 5 [Production of Methyl (3S) -chloropentanoate] (1) Methyl (3R) -hydroxypentanoate 1
41.85 g (1.073 mol) (optical purity 99.4
% Ee), 284 ml of diisopropyl ether and 7.5 ml (0.054 mol) of triethylamine, and then the mixed solution thus obtained was cooled to −15 ° C., and then 38.7 ml (0.537 mo of thionyl chloride).
l) was added dropwise. After the dropping was completed, the liquid temperature was raised to room temperature, and thionyl chloride (38.7 ml, 0.537 mol) was further added dropwise. After the dropping was completed, the mixture was gradually heated to around 75 ° C. over 6 hours and then reacted at 75 ° C. for 30 minutes. (2) After completion of the reaction of (1) above, the mixture was cooled to 10 ° C. or lower, 80 ml of water was added to separate into an organic phase and an aqueous phase, and the recovered organic phase was 160 ml of a 5% sodium hydrogen carbonate aqueous solution.
And it wash | cleaned one by one by 160 ml of saturated salt solutions. After distilling off the solvent, the residue was purified by vacuum distillation to obtain the desired methyl (3
122.97 g (S) -chloropentanoate (yield 7
6.0%) was obtained. The obtained methyl (3S) -chloropentanoate has an optical purity of 99.2% ee and a boiling point of 69.
It was −70 ° C./2400 Pa (18 mmHg). (3) In addition, methyl (3S) -obtained in the above (2)
Optical rotation of chloropentanoate ([α] _D ²⁰ ), ¹ H-N
The measurement results of MR and MS were as follows.・ [Α] _D ²⁰ = + 18.3 ° (c = 1.01, CHC
l ₃ ) · ¹ H-NMR (CDCl ₃ ): δ = 1.04 (3 H, t,
J = 7.3 Hz), 1.6-1.9 (2H, m), 2.7
4 (2H, d, J = 6.6Hz), 3.71 (3H,
s), 4.1-4.3 (1H, m) MS: m / z 151 (M ⁺ +1)

Example 6 [Production of methyl (3S) -chloroheptanoate] (1) Methyl (3R) -hydroxyheptanoate 1
40.85 g (0.879 mol) (optical purity 99.6
% Ee), 280 ml of diisopropyl ether and 6.1 ml (0.044 mol) of triethylamine were mixed, and then the mixed solution thus obtained was cooled to -15 ° C, and then 31.7 ml (0.440mo of thionyl chloride).
l) was added dropwise. After the dropping was completed, the liquid temperature was raised to room temperature, and 31.7 ml (0.440 mol) of thionyl chloride was further added dropwise. After the dropping was completed, the mixture was gradually heated to around 75 ° C. over 7 hours and then reacted at 75 ° C. for 10 minutes. (2) After completion of the reaction in (1) above, the mixture was cooled to 10 ° C. or lower and 80 ml of water was added to separate into an organic phase and an aqueous phase. The recovered organic phase was 160 ml of 5% aqueous sodium hydrogen carbonate solution and 160 ml of saturated saline. Washed sequentially. After distilling off the solvent, the residue was purified by vacuum distillation to obtain the desired methyl (3
S) -chloroheptanoate 123.02 g (yield 7
8.3%). The obtained methyl (3S) -chloroheptanoate has an optical purity of 99.2% ee and a boiling point of 65.
C./533.3 Pa (4 mmHg). (3) In addition, methyl (3S) -obtained in the above (2)
Optical rotation of chloroheptanoate ([α] _D ²⁰ ), ¹ H-N
The measurement results of MR and MS were as follows.・ [Α] _D ²⁰ = −0.39 ° (c = 1.02, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ): δ = 0.90 (3 H, t,
J = 7.1 Hz), 1.2-1.5 (4H, m), 1.6
5-1.85 (2H, m), 2.74 (2H, d, J =
7.0 Hz), 3.71 (3H, s), 4.2-4.4
(1H, m) MS: m / z 179 (M ⁺ +1)

Example 7 [Production of methyl (3S) -chlorooctanoate] (1) Methyl (3R) -hydroxyoctanoate 1
45.00 g (0.832 mol) (optical purity 99.6
% Ee), 290 ml of diisopropyl ether and 5.8 ml (0.042 mol) of triethylamine, and then the mixed solution thus obtained was cooled to -15 ° C, and then 30.0 ml (0.416mo of thionyl chloride).
l) was added dropwise. After completion of the dropping, the liquid temperature was raised to room temperature, and thionyl chloride (30.0 ml, 0.416 mol) was further added dropwise. After the dropping was completed, the mixture was gradually heated to around 75 ° C. over 7 hours and then reacted at 75 ° C. for 10 minutes. (2) After completion of the reaction in (1) above, the mixture was cooled to 10 ° C. or lower and 80 ml of water was added to separate into an organic phase and an aqueous phase. The recovered organic phase was 160 ml of 5% aqueous sodium hydrogen carbonate solution and 160 ml of saturated saline. Washed sequentially. After distilling off the solvent, the residue was purified by vacuum distillation to obtain the desired methyl (3
S) -chlorooctanoate 126.34 g (yield 7
8.8%) was obtained. The obtained methyl (3S) -chlorooctanoate has an optical purity of 99.0% ee and a boiling point of 53.
It was −55 ° C./41.3 Pa (0.31 mmHg). (3) In addition, methyl (3S) -obtained in the above (2)
Optical rotation of chlorooctanoate ([α] _D ²⁰ ), ¹ H-N
The measurement results of MR and MS were as follows.・ [Α] _D ²⁰ = −3.70 ° (c = 1.00, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ): δ = 0.89 (3 H, t,
J = 6.6 Hz), 1.2-1.6 (6H, m), 1.
65-1.8 (2H, m), 2.74 (2H, d, J =
6.0 Hz), 3.71 (3H, s), 4.2-4.4
(1H, m) MS: m / z 193 (M ⁺ +1)

<Example 8> [Production of methyl (3S) -chlorononanoate] (1) Methyl (3R) -hydroxynonanoate 14
0.00 g (0.744 mol) (optical purity 99.7%
ee), 280 ml of diisopropyl ether and 5.2 ml (0.037 mol) of triethylamine were mixed, and then the mixed solution thus obtained was cooled to -15 ° C, and then 26.8 ml (0.372mo of thionyl chloride).
l) was added dropwise. After the completion of the dropping, the liquid temperature was raised to room temperature, and 26.8 ml (0.372 mol) of thionyl chloride was further added dropwise. After the dropping was completed, the mixture was gradually heated to around 75 ° C. over 7 hours and then reacted at 75 ° C. for 10 minutes. (2) After completion of the reaction in (1) above, the mixture was cooled to 10 ° C. or lower and 80 ml of water was added to separate into an organic phase and an aqueous phase. Washed sequentially. After distilling off the solvent, the residue was purified by vacuum distillation to obtain the desired methyl (3
S) -Chlononanoate 117.24 g (yield 76.
3%) was obtained. The obtained methyl (3S) -chlorononanoate has an optical purity of 99.3% ee and a boiling point of 65 ° C / 2.
It was 9.3 Pa (0.22 mmHg). (3) In addition, methyl (3S) -obtained in the above (2)
Optical rotation of chlorooctanoate ([α] _D ²⁰ ), ¹ H-N
The measurement results of MR and MS were as follows. -[Α] _D ²⁰ = -4.01 ° (c = 1.02, CHC
l ₃ ) · ¹ H-NMR (CDCl ₃ ): δ = 0.88 (3H, t,
J = 6.6 Hz), 1.2-1.6 (8H, m), 1.
65-1.8 (2H, m), 2.75 (2H, d, J =
7.0 Hz), 3.72 (3H, s), 4.2-4.4
(1H, m) MS: m / z 207 (M ⁺ +1)

Example 9 [Methyl (3S) -chloro-
Production of 5-Methylhexanoate] (1) Methyl (3R) -hydroxy-5-methylhexanoate 140.00 g (0.874 mol) (optical purity 99.6% ee), diisopropyl ether 280
ml and triethylamine 6.1 ml (0.044 m
ol), and then the mixed solution thus obtained was cooled to −15 ° C., and then 31.5 ml of thionyl chloride was mixed.
(0.437 mol) was added dropwise. After the dropping was completed, the liquid temperature was raised to room temperature and thionyl chloride (31.5 ml, 0.437) was added.
(mol) was further added dropwise. 7 hours after the end of dropping
After gradually heating to around 5 ° C, the mixture was reacted at 75 ° C for 10 minutes. (2) After the reaction of the above (1) is completed, the liquid temperature is cooled to 10 ° C. or lower, 80 ml of water is added to separate into an organic phase and an aqueous phase,
The recovered organic phase was treated with a 5% aqueous sodium hydrogen carbonate solution 160
ml and saturated saline (160 ml) successively. After distilling off the solvent, the residue was purified by distillation under reduced pressure to obtain the desired methyl (3S) -chloro-5-methylhexanoate 108.
86 g (yield 69.8%) was obtained. Obtained methyl (3
The optical purity of (S) -chloro-5-methylhexanoate is 99.0% ee, and the boiling point is 44 ° C / 73.3 Pa (0.5
It was 5 mmHg). (3) In addition, methyl (3S) -obtained in the above (2)
Optical rotation of chlorohexanoate ([α] _D ²⁰ ), ¹ H-N
The measurement results of MR and MS were as follows. -[Α] _D ²⁰ = -18.8 ° (c = 1.02, CHC
l ₃ ). ¹ H-NMR (CDCl ₃ ): δ = 0.92 (3 H, d,
J = 6.6 Hz), 0.93 (3H, d, J = 6.6H)
z), 1.4-1.8 (2H, m), 1.8-2.0
(1H, m), 2.73 (2H, d, J = 7.4Hz),
3.72 (3H, s), 4.25-4.41 (1H,
m) MS: m / z 179 (M ⁺ +1)

Example 10 [Production of methyl (3S) -chlorobutanoate] (1) Methyl (3R) -hydroxybutanoate 1
0.0 g (0.085 mol) (optical purity 99.5% e
e), 20 ml of diisopropyl ether, 11.1 g (0.093 mol) of thionyl chloride and 0.0 of pyridine
4 g (0.56 mmol) were mixed, and the mixed solution thus obtained was stirred at 60 ° C. for 3 hours and then refluxed at 75 ° C. for 1 hour. (2) After completion of the reaction in (1) above, the reaction solution was cooled to room temperature, and 10 ml of water was added to separate the solution into an organic phase and an aqueous phase.
The recovered organic phase was treated with a 5% aqueous sodium hydrogen carbonate solution 160
ml and saturated saline (160 ml) successively. After distilling off the solvent, the residue was purified by distillation under reduced pressure to obtain 8.91 g of the target methyl (3S) -chlorobutanoate (yield 72.
9%) was obtained. The obtained methyl (3S) -chlorobutanoate had an optical purity of 99.5% ee and a boiling point of 70 ° C / 4.
It was 800 Pa (36 mmHg).

[0053]

INDUSTRIAL APPLICABILITY According to the production method of the present invention, the desired optically active 3-halogenocarboxylic acid ester (II) can be obtained without racemization without using a heavy metal salt catalyst, with high yield and high optical activity. It can be manufactured smoothly with high purity. Optical activity 3 obtained by the production method of the present invention
-The halogenocarboxylic acid ester (II) is extremely useful for pharmaceutical intermediates, liquid crystal materials and the like.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Takashi Miura             Takasago incense, 5-37-1 Kamata, Ota-ku, Tokyo             Ryo Kogyo Co., Ltd. F-term (reference) 4H006 AA02 AC30 AC81 BA51 BM10                       BM72 KA31                 4H039 CA52 CD30

Claims (3)

[Claims] 1. The following general formula (I): (Wherein R ¹ represents an alkyl group, a substituted alkyl group, an aralkyl group or a substituted aralkyl group, R ² represents a lower alkyl group, and * represents an asymmetric carbon). 3-hydroxycarboxylic acid ester and thionyl halide are reacted in an organic solvent in the presence of a basic substance, represented by the following general formula (II); (In the formula, X represents a halogen atom, and R ¹ , R ² and * are the same as the above.) The method for producing an optically active 3-halogenocarboxylic acid ester. 2. Using thionyl chloride as the thionyl halide, the following general formula (IIa); The production method according to claim 1, wherein the optically active 3-chlorocarboxylic acid ester represented by the formula (wherein R ¹ , R ² and * are the same as above). 3. The method according to claim 1, wherein the basic substance is an amine.