JP2003064023A - Method of producing optically active hydroxybutyric acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of producing optically active 4-halo-3- hydroxybutyric acid derivative and 3,4-epoxybutyric acid from optically active 4-halo-3-hydroxybutyric ester through simple operations. SOLUTION: An optically active 4-halo-3-hydroxybutyric ester is treated with an acid in a solvent, for example, water, formic acid or acetic acid to give an optically active 4-halo-3-hydroxy-butyric acid derivative. An optically active 3,4-epoxybutyric acid is produced by treating the obtained optically active 4-halo-3-hydroxybutyric acid derivative with a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an optically active 4-halo-3-hydroxybutyric acid derivative and an optically active 3,4-epoxybutyric acid, which are useful as intermediates for agricultural chemicals and pharmaceuticals. An optically active 4-halo-3-hydroxybutyric acid derivative and an optically active 3,4-epoxybutyric acid are useful as an intermediate of a hyperlipidemic drug, a 4-cyano-3-hydroxybutyric acid derivative (WO00 / 46186, Tetrahedr.
on Letters, Vol. 33, 2279, 1992).
And 4-dimethylamino-3-hydroxybutyric acid (carnitine) (Japanese Patent Application Laid-Open No. 2-279995).

[0002]

2. Description of the Related Art As a method for producing an optically active 4-halo-3-hydroxybutyric acid derivative, (1) a method of reacting optically active 3-hydroxybutyrolactone with hydrobromic acid / acetic acid (WO00 / 4618)
6), (2) Method of hydrolyzing optically active 4-halo-3-hydroxybutyronitrile with an enzyme or an acid (JP-A-4-36)
0689, JP-A-4-124157), (3) A method of hydrolyzing an optically active 4-halo-3-hydroxybutyric acid ester with an enzyme (JP-A-61-117).
3788), etc. are known. The racemic 4-
As a method for producing chloro-3-hydroxybutyric acid, (4) 4-chloro-3-hydroxybutyric acid ester is treated with an acid,
Alternatively, a method of hydrolysis in the presence of a base catalyst (Japanese Patent Laid-Open No. Sho 5
7-028035), but is known to be an optically active 4
No example has been reported of producing an optically active 4-halo-3-hydroxybutyric acid derivative by hydrolyzing a -halo-3-hydroxybutyric acid ester in the presence of an acid or base catalyst.

Further, as a method for producing optically active 3,4-epoxybutyric acid, (5) optically active 3-hydroxybutyrolactone is reacted with hydrobromic acid / acetic acid to obtain optically active 3-acetoxy-4-bromobutyric acid. Method of converting to and treating with base (WO00 / 4
6186), (6) 3-butenoic acid ester is converted to 3,4-epoxybutyric acid ester with m-chloroperbenzoic acid, and the resulting product is hydrolyzed with an enzyme to be separated (Tetrahedro).
n Letters. , 33, 2455 (199
2), Tetrahedron Letters. ,
30, 2513 (1989), Helv. Chim.
Acta. 70, 142 (1987), J. Am. Or
g. Chem. 53, 104 (1988)), etc. are known.

[0004]

However, in the above methods (1) and (5), it is difficult to inexpensively supply the starting material, 3-hydroxybutyrolactone. In the method (2), a raw material, 4-halo-3-hydroxybutyronitrile, must be synthesized by using a highly toxic and expensive cyan compound. The method (3) is not economical because it requires purification with an ion exchange resin after completion of the reaction. The method (4) is a method for producing a racemate, and in the case of an optically active substance, it may cause racemization, and as a by-product, 3
-Easily produces hydroxybutyrolactone. In the method (6), m-chloroperbenzoic acid, which must be handled with care, must be used.

As described above, any of the methods has a problem to be solved as an economical method for industrially producing an optically active 3-hydroxybutyric acid derivative.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the inventors of the present invention have found that the optically active 4-chloro-3-hydroxybutyric acid ester and the like which are readily available can be used. From halo-3-hydroxybutyrate,
Highly effective optical activity of optically active 4-halo-3-hydroxybutyric acid derivative, optically active 3,4-epoxybutyric acid, etc.
It was found that a 3-hydroxybutyric acid derivative can be produced,
The present invention has been completed.

That is, the present invention provides the following formula (1);

[0008]

[Chemical 8]

(In the formula, R ₁ represents an alkyl group having 1 to 10 carbon atoms, X represents a halogen atom, and * represents an asymmetric carbon atom.) Hydroxybutyric acid ester is hydrolyzed in formic acid, acetic acid, or a mixed solvent thereof using an acid catalyst, the following formula (2):

[0010]

[Chemical 9]

(In the formula, X and * are the same as above. R ₂ represents a hydrogen atom, a formyl group or an acetyl group.) A process for producing an optically active 4-halo-3-hydroxybutyric acid derivative. Is.

In the present invention, the optically active 4-halo-3-hydroxybutyric acid ester represented by the above formula (1) is hydrolyzed in formic acid, acetic acid or a mixed solvent thereof using an acid catalyst. The optically active 4-halo-3-hydroxybutyric acid derivative represented by the above formula (2) is thereby obtained, and then treated with a base, the following formula (3);

[0013]

[Chemical 10]

A method for producing an optically active 3,4-epoxybutyric acid represented by the formula (* represents an asymmetric carbon atom).

The present invention also provides that, in the above formula (2), X
Is also a bromine atom and R ₂ is a hydrogen atom, which is also optically active 4-bromo-3-hydroxybutyric acid.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.

In the present invention, the optically active 4-halo-3-hydroxybutyric acid ester represented by the above formula (1) is hydrolyzed in formic acid, acetic acid or a mixed solvent thereof using an acid catalyst. Is represented by the formula (2)
A halo-2-hydroxybutyric acid derivative is prepared, and then the compound is treated with a base to produce the optically active 3,4-epoxybutyric acid represented by the formula (3).

In the optically active 4-halo-3-hydroxybutyric acid ester represented by the above formula (1), which is the starting material of the present invention, X represents a halogen atom, for example, a fluorine atom, a chlorine atom, a bromine atom, Examples thereof include iodine atom. From the viewpoint of easy availability, chlorine atom and bromine atom are preferable.

R ₁ in the above formula (1) represents an alkyl group having 1 to 10 carbon atoms. The alkyl group having 1 to 10 carbon atoms is not particularly limited, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-pentyl group, and the like. A methyl group and an ethyl group are preferred, and an ethyl group is more preferred.

The optically active 4-halo-3-hydroxybutyric acid ester represented by the above formula (1) can be easily prepared by a known method. For example, optically active 4-chloro-3-hydroxybutyric acid ester can be obtained by asymmetrically reducing 4-chloroacetoacetic acid ester with a microorganism or an enzyme (JP-A-64-60391).

The 4-bromo-3-hydroxybutyric acid ester is obtained by reacting an optically active 3-hydroxybutyrolactone with hydrobromic acid / acetic acid / ethyl alcohol (WO00 / 071503), an optically active 4-bromoacetoacetic acid ester. Method for asymmetric reduction with microorganisms or enzymes (JP-A-9-25667, JP-A-8-33639)
3, JP-A-6-38776, etc.), a method for asymmetric hydrogenation of an optically active 4-bromoacetoacetic acid ester using a ruthenium-optically active phosphine complex as a catalyst (JP-A 1-2112).
551, JP-A-63-310847) and the like.

However, in order to obtain a high-purity optically active 4-bromo-3-hydroxybutyric acid ester in a high yield, the present inventors prefer to use the above-mentioned known method to prepare it.
It has been found that it is preferable to replace the chlorine atom of the optically active 4-chloro-3-hydroxybutyric acid ester with a bromine atom (halogen exchange). The halogen exchange is optically active 4
It can be carried out by reacting -chloro-3-hydroxybutyric acid ester with a brominated metal salt. Until now, the chlorine atom of optically active 4-chloro-3-hydroxybutyric acid ester has been subjected to halogen exchange reaction to give optically active 4-bromo-3-hydroxy-3-butyric acid.
There is no known case of induction of hydroxybutyric acid ester.

Examples of the metal bromide include alkali metal bromide and the like, preferably lithium bromide, sodium bromide, potassium bromide and calcium bromide magnesium bromide, more preferably sodium bromide. Is.

The amount of the metal bromide salt used varies depending on the type of the metal salt and solvent used and the reaction conditions, but it is generally preferred to be 1 to 100 equivalents relative to the optically active 4-chloro-3-hydroxybutyric acid ester. Can react to. Considering economy, it is preferably 1 to 20 equivalents, more preferably 1 to 10 equivalents.

As the solvent for the bromination reaction, for example, N,
N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetone, acetonitrile, 2-
Examples include polar solvents such as butanone, preferably N, N
An aprotic polar solvent such as dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide,
More preferred is N, N-dimethylformamide.

Usually, for the bromination reaction by the halogen exchange reaction for primary alkyl chlorides, a reaction condition of a high temperature of 90 ° C. or higher and a long time is applied. However,
It is known that 4-chloro-3-hydroxybutyric acid ester and 4-bromo-3-hydroxybutyric acid ester produced by this reaction cause decomposition under conditions of high temperature and long time. Therefore, the reaction can be carried out, for example, in the above solvent by stirring at 50 to 100 ° C., preferably 60 to 90 ° C., and the reaction time is about 3 to 15 hours, though the reaction varies depending on the type of solvent, and the above conditions were used. In this case, surprisingly, optically active 4-bromo-3-hydroxybutyric acid ester can be obtained in high yield.

The optically active 4-bromo-3-hydroxybutyric acid ester thus produced is added, for example, to the reaction solution at 0 ° C. to 25 ° C., and water is added to the reaction solution. Extract and
It can be obtained by performing operations such as washing and concentration. The optically active 4-bromo-obtained in this way
The 3-hydroxybutyric acid ester may be further purified by column chromatography, distillation or the like, or may be used as it is in the present invention.

Next, the optical activity 4 represented by the above formula (1)
-Halo-3-hydroxybutyric acid ester is hydrolyzed in formic acid, acetic acid, or a mixed solvent thereof using an acid catalyst to give an optically active 4-halo-3-hydroxybutyric acid represented by the above formula (2). The process of producing the derivative will be described.

In the optically active 4-halo-3-hydroxybutyric acid derivative represented by the above formula (2), X represents a halogen atom and is the same as defined in the above formula (1). R ₂ represents a hydrogen atom, a formyl group or an acetyl group.

Examples of the acid catalyst used in the above reaction include inorganic acids such as hydrobromic acid, sulfuric acid and hydrochloric acid, organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and Dowex 50 and the like. A cation exchange resin can also be used. Preferred are hydrobromic acid, sulfuric acid, and hydrochloric acid.

In the reaction of this step, formic acid, acetic acid,
Alternatively, it is performed using a mixed solvent thereof. When formic acid or acetic acid is used as the solvent for the above reaction, surprisingly,
By-products of 3-hydroxybutyrolactone can be suppressed.

The above reaction may vary depending on the kind of the solvent, but it can be selected, for example, in the above solvent from mild conditions of -50 ° C to 100 ° C, preferably 25 ° C to 60 ° C, and a reaction time of 30 minutes to 24 ° C. It can be performed by stirring for about an hour.

After the above reaction, an aqueous solution of an alkali metal hydroxide such as an aqueous solution of sodium hydroxide or an aqueous solution of potassium hydroxide is added at 0 ° C. to 25 ° C. to adjust the pH to 1
To 7, preferably pH of 3 to 4, and then optically extracted with an organic solvent such as ethyl acetate, toluene, benzene, diethyl ether, dichloromethane, washed, concentrated, etc. It is possible to obtain a 3-hydroxybutyric acid derivative (2). Obtained optically active 4-halo-3-hydroxybutyric acid derivative (2)
May be further purified by column chromatography, distillation or the like, or can be directly used for the next epoxidation reaction.

In this step, when acetic acid is used as the solvent, the compound (2), which is a product, is obtained as a compound or a mixture in which R ₂ is a hydrogen atom or an acetyl group. When formic acid is used as the solvent in this step, the product compound (2) is R ₂
Is obtained as either a hydrogen atom or a formyl group, or as a mixture.

In the compound (2), optically active 4-bromo-3-hydroxybutyric acid in which X is a bromine atom and R ₂ is a hydrogen atom is a novel compound which has not been published in the literature.

Next, the optically active 4-halo-3-hydroxybutyric acid derivative obtained as described above is treated with a base to give the optically active 3,4-carboxylic acid represented by the above formula (3).
The process of producing epoxy butyric acid will be described.

The base used in the above reaction is not particularly limited, but for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, or alkaline earth metals such as calcium hydroxide and magnesium hydroxide. Examples thereof include metal hydroxides and amines such as triethylamine and pyridine, and sodium hydroxide and triethylamine are preferable.

The amount of the base used in this step varies depending on the reaction conditions and the kind of the base, but is 1 to 5 equivalents, preferably 2 to 5 equivalents with respect to the compound represented by the above formula (4).
3 equivalents can be used.

The solvent used in the above reaction is not particularly limited, and examples thereof include water, methanol, ethanol, tetrahydrofuran, dioxane, N, N-dimethylformamide and the like, and these may be used alone,
You may use it as a mixed solvent. Preferred are water, methanol and ethanol.

The above reaction is carried out in
It can be carried out at 50 ° C to 100 ° C, preferably-
It is 10 ° C to 30 ° C. The reaction time is 30 minutes to 2
It can be performed by stirring for about 0 hours.

The produced optically active 3,4-epoxybutyric acid (3) is added to the reaction solution at 0 ° C. to 25 ° C. with an acidic aqueous solution such as dilute hydrochloric acid to adjust the pH to 1 to 7, preferably 3 to. It can be obtained by carrying out operations such as extraction with an organic solvent such as ethyl acetate, toluene, benzene, diethyl ether, dichloromethane and the like, followed by washing, concentration, etc. The thus obtained optically active 3,4-epoxybutyric acid (3) target product can be further purified by column chromatography, distillation or the like to improve the purity.

[0042]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

(Example 1) (S) -4-bromo-3-hi
Preparation of Ethyl Droxybutyrate (S) -4-Chloro-3-hydroxybutyrate ethyl (1.
01 g, 6.0 mmol) and sodium bromide (6.16)
g, 60 mmol) to N, N-dimethylformamide (10
g) After stirring in the solution at 80 ° C. for 6 hours, (S)-
Ethyl 4-bromo-3-hydroxybutyrate (yield 80
%) Was confirmed. The analysis was performed by HPLC under the following conditions. Column: Alltima C8 MICRON 4.6x
250 mm Mobile phase: acetonitrile / water = 18/82 (vol /
vol) Flow rate: 1 ml / min Detection: UV 210 nm ¹ H NMR (400 MHz, CDCl ₃ ) δ4.25
(M, 1H), 4.19 (q, J = 7.3 Hz, 2
H), 3.51 (dd, J = 4.9, 12 Hz, 1
H), 3.50 (dd, J = 5.9, 12 Hz, 1
H), 3.20 (m, 1H), 2.67 (dd, J =
4.3, 11 Hz, 1H), 2.65 (dd, J = 6.
8, 11Hz, 1H), 1.29 (t, J = 5.7H
z, 3H).

(Example 2) (S) -4-chloro-3-hi
Droxybutyric acid and (S) -4-chloro-3-acetoxy
Production of cibutyric acid Ethyl (S) -4-chloro-3-hydroxybutyrate (1.
(00 g, 6.0 mmol) was reacted in 5.0 g of a 30% hydrobromic acid / acetic acid solution at 60 ° C. for 24 hours, then allowed to cool, and the pH of the 30 wt% sodium hydroxide solution was cooled under ice cooling.
The reaction was stopped by adding the solution until 3.5 was reached, and extraction was performed 3 times with 20 ml of ethyl acetate. The obtained organic phases were mixed, dried over magnesium sulfate, filtered, and concentrated to give (S) -4-chloro-3-hydroxybutyric acid and (S) -4-chloro-3-acetoxybutyric acid as a mixture. The yield was 80%. The produced (S) -4-chloro-3-hydroxybutyric acid and (S) -4-chloro-3-acetoxybutyric acid were in a molar ratio of 1: 7. (S) -4-chloro-3-acetoxybutyric acid: ¹ H NMR
(400 MHz, CDCl ₃ ) δ 5.37 (m, 1
H), 3.74 (dd, J = 4.9, 8.3 Hz, 1
H), 3.73 (dd, J = 4.9, 8.3 Hz, 1)
H), 2.84 (dd, J = 5.8, 13 Hz, 1
H), 2.83 (dd, J = 7.3, 13 Hz, 1
H), 2.01 (S, 3H).

(Example 3) (S) -4-chloro-3-hi
Droxybutyric acid and (S) -4-chloro-3-acetoxy
Production of cibutyric acid Ethyl (S) -4-chloro-3-hydroxybutyrate (1.
00 g, 6.0 mmol) concentrated sulfuric acid / acetic acid solution = 1 /
After reacting in 5.0 g of 2 (vol / vol) at 60 ° C. for 24 hours, the mixture was allowed to cool, and 30 wt% sodium hydroxide solution (vol / vol) was added under ice cooling until the pH reached 3.5. Then, the reaction was stopped and the mixture was extracted 3 times with 20 ml of ethyl acetate. When the obtained organic phases were mixed, dried over magnesium sulfate, filtered, and concentrated, (S) -4-
Chloro-3-hydroxybutyric acid and (S) -4-chloro-3
-Acetoxybutyric acid was obtained as a mixture with a yield of 75%. The produced (S) -4-chloro-3-hydroxybutyric acid and (S) -4-chloro-3-acetoxybutyric acid were in a molar ratio of 1:10.

(Example 4) (S) -4-chloro-3-hi
Droxybutyric acid and (S) -4-chloro-3-acetoxy
Production of cibutyric acid Ethyl (S) -4-chloro-3-hydroxybutyrate (1.
(00 g, 6.0 mmol) concentrated hydrochloric acid / acetic acid solution = 1 /
After reacting in 5.0 g of 2 (vol / vol) at 60 ° C. for 24 hours, the mixture was allowed to cool, and the reaction was stopped by adding a 30 wt% sodium hydroxide solution under ice cooling until the pH reached 3.5. , And extracted with 20 ml of ethyl acetate three times. The obtained organic phases were mixed, dried over magnesium sulfate, filtered, and concentrated to give (S) -4-chloro-3-hydroxybutyric acid and (S) -4-chloro-3-acetoxybutyric acid as a mixture. The yield was 78%. Generated (S)-
The molar ratio of 4-chloro-3-hydroxybutyric acid and (S) -4-chloro-3-acetoxybutyric acid was 1: 1.

(Example 5) (S) -4-chloro-3-hi
Droxybutyric acid and (S) -4-chloro-3-formyl
Production of oxybutyric acid Ethyl (S) -4-chloro-3-hydroxybutyrate (1.
(00 g, 6.0 mmol) concentrated hydrochloric acid / formic acid solution = 1 /
After reacting in 5.0 g of 2 (vol / vol) at 60 ° C. for 8 hours, the mixture was allowed to cool, and the reaction was stopped by adding a 30 wt% sodium hydroxide solution under ice cooling until the pH reached 3.5. , And extracted with 20 ml of ethyl acetate three times. The obtained organic phases are mixed, dried over magnesium sulfate and then filtered,
Upon concentration, (S) -4-chloro-3-hydroxybutyric acid and (S) -4-chloro-3-formyloxybutyric acid were obtained as a mixture with a yield of 80%. Generated (S)-
The molar ratio of 4-chloro-3-hydroxybutyric acid and (S) -4-chloro-3-formyloxybutyric acid was 1: 0.8. (S) -4-chloro-3-formyloxybutyric acid: ¹ H
NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1
H), 5.53 (m, 1H), 3.77 (dd, J =
3.0, 7.4 Hz, 1H), 3.76 (dd, J =
2.4, 7.4 Hz, 1H), 2.72 (dd, J =
4.9, 14 Hz, 1H), 2.70 (dd, J = 7.
8, 14 Hz, 1H).

Example 6 (S) -4-Bromo-3-hi
Droxybutyric acid and (S) -4-bromo-3-acetoxy
Preparation of cibutyric acid Ethyl (S) -4-bromo-3-hydroxybutyrate (1.
00 g, 4.8 mmol) concentrated hydrochloric acid / acetic acid solution = 1 /
After reacting in 5.0 g of 2 (vol / vol) for 4 hours, the mixture was allowed to cool, and the reaction was stopped by adding a 30 wt% sodium hydroxide solution under ice cooling until the pH reached 3.5, and adding ethyl acetate. Extraction was performed 3 times with 20 ml. The obtained organic phases were mixed, dried over magnesium sulfate, filtered, and concentrated to give a mixture of (S) -4-bromo-3-hydroxybutyric acid and (S) -bromoacetobutyric acid in a yield of 71%.
Obtained in. The generated (S) -4-bromo-3-hydroxybutyric acid and (S) -bromoacetobutyric acid are in a molar ratio of 1 :.
It was 0.4. (S) -4-Bromo-3-hydroxybutyric acid: ¹ H NMR
(400 MHz, CDCl ₃ ) δ 4.28 (m, 1
H), 3.53 (dd, J = 4.9, 14 Hz, 1
H), 3.51 (dd, J = 5.4, 14 Hz, 1
H), 2.74 (dd, J = 4.4, 14 Hz, 1
H), 2.73 (dd, J = 7.8, 14 Hz, 1
H). (S) -4-Bromo-3-acetoxybutyric acid: ¹ H
NMR (400 MHz, CDCl ₃ ) δ 5.36 (m,
1H), 3.60 (dd, J = 4.9, 10 Hz, 1
H), 3.59 (dd, J = 5.4, 10 Hz, 1
H), 2.85 (dd, J = 5.4, 12 Hz, 1
H), 2.83 (dd, J = 6.4, 12 Hz, 1
H), 2.01 (S, 3H).

Example 7 (S) -4-Bromo-3-hi
Droxybutyric acid and (S) -4-bromo-4-formylo
Production of Xybutyric acid Ethyl (S) -4-bromo-3-hydroxybutyrate (1.
00 g, 4.8 mmol) concentrated hydrochloric acid / formic acid solution = 1 /
After reacting in 5.0 g of 2 (vol / vol) for 4 hours, the mixture was allowed to cool, and the reaction was stopped by adding a 30 wt% sodium hydroxide solution under ice cooling until the pH reached 3.5, and adding ethyl acetate. Extraction was performed 3 times with 20 ml. The obtained organic phases were mixed, dried over magnesium sulfate, filtered, and concentrated to give a mixture of (S) -4-bromo-3-hydroxybutyric acid and (S) -4-bromo-3-formyloxybutyric acid. As a 71% yield. Generated (S) -4-
Bromo-3-hydroxybutyric acid and (S) -4-bromo-3
-Formyoxybutyric acid was in a molar ratio of 1: 0.4. (S) -4-Bromo-3-formyloxybutyric acid: ¹ H N
MR (400 MHz, CDCl ₃ ) δ 8.01 (s, 1
H), 5.49 (m, 1H), 3.62 (dd, J =
2.4, 7.4 Hz, 1H), 3.51 (dd, J =
2.0, 7.4 Hz, 1H), 2.90 (dd, J =
5.9, 14 Hz, 1H), 2.88 (dd, J = 7.
8, 14 Hz, 1H).

(Example 8) (S) -3,4 epoxybutyric acid
The mixture (500 mg, 3.2 mmol) of (S) -4-chloro-3-hydroxybutyric acid and (S) -4-chloro-3-formyloxybutyric acid obtained in Example 2 was cooled with ice, 1N
NaOH (8.2 ml, 2.5 eq) was added dropwise over 30 minutes. After completion of dropping, the mixture was stirred for 2 hours, and 1N HCl was added.
Was added until pH = 3.5, the reaction was stopped, and the mixture was extracted twice with 20 ml of ethyl acetate. The obtained organic phases were mixed, dried over magnesium sulfate, filtered, and concentrated to obtain (S) -3,4-epoxybutyric acid in a yield of 24%. ¹ H NMR (400 MHz, D ₂ O) δ 3.38-4.
42 (m, 1H), 2.84-2.88 (m, 2H),
2.46-1.51 (m, 2H).

[0051]

INDUSTRIAL APPLICABILITY Since the present invention has the above-mentioned constitution, it is possible to obtain an optically active 4-halo-3-hydroxybutyric acid ester which is useful as an intermediate for agricultural chemicals and pharmaceuticals from an easily available and inexpensive optically active 4-chloro-3-hydroxybutyric acid ester. 3-hydroxybutyric acid derivative and 3,4
-Epoxy butyric acid can be produced industrially advantageously.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07C 69/675 C07C 69/675 C07D 301/24 C07D 301/24 303/14 303/14 // C07B 53 / 00 C07B 53/00 C 61/00 300 61/00 300 C07M 7:00 C07M 7:00 F Term (reference) 4C048 AA01 BB16 CC01 UU02 UU03 XX02 4H006 AA02 AC30 AC46 AC48 AC81 BA66 BB17 BB20 BB41 BB42 BC10 BE61BM73 BM72 BM72 BN10 BS10 KA06 KA31 4H039 CA65 CA66 CD10 CE20

Claims (15)

[Claims] 1. The following formula (1); (In the formula, R ₁ represents an alkyl group having 1 to 10 carbon atoms, X 1
Represents a halogen atom, and * represents an asymmetric carbon atom. ) The optically active 4-halo-3-hydroxybutyric acid ester derivative represented by the formula (2) is hydrolyzed in formic acid, acetic acid, or a mixed solvent thereof using an acid catalyst; Chemical 2] (In the formula, X and * are the same as above. R ₂ represents a hydrogen atom, a formyl group, or an acetyl group.) A method for producing an optically active 4-halo-3-hydroxybutyric acid derivative. 2. The method according to claim 1, wherein any one of hydrobromic acid, hydrochloric acid and sulfuric acid is used as the acid catalyst. 3. The production method according to claim 1, wherein in the formula (1), X is a chlorine atom or a bromine atom. 4. In the above formula (1), R ₁ is a methyl group,
Or it is an ethyl group, The manufacturing method in any one of Claims 1-3. 5. The following formula (1): (In the formula, R ₁ represents an alkyl group having 1 to 10 carbon atoms, X 1
Represents a halogen atom, and * represents an asymmetric carbon atom. ) By hydrolyzing the optically active 4-halo-3-hydroxybutyric acid ester derivative in formic acid, acetic acid, or a mixed solvent thereof with an acid catalyst, the following formula (2); (In the formula, X and * are the same as above. R ₂ represents a hydrogen atom, a formyl group, or an acetyl group.) To give an optically active 4-halo-3-hydroxybutyric acid derivative, which is then treated with a base. Which is characterized by the following formula (3): (In the formula, * is the same as the above.) Optical activity 3, 4
-Method for producing epoxy butyric acid. 6. In the step of producing the compound represented by the above formula (2) from the compound represented by the above formula (1), either hydrobromic acid, hydrochloric acid or sulfuric acid is used as an acid catalyst. The manufacturing method according to claim 5. 7. The method according to claim 5, wherein X in the above formula (1) is a chlorine atom or a bromine atom. 8. In the above formula (1), R ₁ is a methyl group,
Or it is an ethyl group, The manufacturing method in any one of Claims 5-7. 9. In the above formula (2), X is a bromine atom or R
Optically active 4-bromo-3-hydroxybutyric acid in which ₂ is a hydrogen atom. 10. The following formula (4); (In the formula, R ₁ represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, and * represents an asymmetric carbon atom), and the optically active 4-chloro-3-hydroxybutyric acid ester is represented by metal bromide. The following formula (5) characterized by reacting with a salt; (In the formula, R ₁ and * are the same as above.) A method for producing an optically active 4-bromo-3-hydroxybutyric acid ester. 11. The method according to claim 10, wherein sodium bromide is used as the metal bromide salt. 12. The method according to claim 10, wherein an aprotic polar solvent is used as a reaction solvent. 13. N, N-as an aprotic polar solvent
The production method according to claim 12, wherein dimethylformamide is used. 14. The reaction is carried out at 50 to 100 ° C.
The manufacturing method in any one of -13. 15. The production method according to claim 10, wherein R ₁ is a methyl group or an ethyl group.