JPH0931058A - Production of 4-hydroxy-2-pyprolidone - Google Patents

Abstract

PROBLEM TO BE SOLVED: To economically obtain a compound useful as a synthetic intermediate for medicines, agrochemicals, etc., in high yield and a short process without almost producing by-products. SOLUTION: A 4-halogeno-3-hydroxybutanoic acid ester expressed by formula II (X is a halogen such as Cl or Br; R is a 1-4C alkyl such as ethyl), e.g. methyl 4-chloro-3-hydroxybutanoate is reacted with an alkali metal amide, e.g. sodium amide or lithium amide in a solvent such as N,N-dimethylformamide at an ambient temperature to a reflux temperature of the solvent and passed through a 3,4-epoxybutanoic acid ester and a 4-amino-3-hydroxybutanoic acid ester as intermediates to provide the objective 4-hydroxy-2-pyrrolidone which is a compound expressed by formula I. The alkali metal amide is preferably used in an amount of 2-3mol based on the compound of formula II.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing 4-hydroxy-2-pyrrolidone useful as a synthetic intermediate for medicines, agricultural chemicals and the like.

[0002]

2. Description of the Related Art 4-Hydroxy-2-pyrrolidone is used as a synthetic intermediate for medicines, agricultural chemicals and the like, and its production method is known as follows. That is, a method of synthesizing 4-chloro-3-hydroxybutanoic acid ester and ammonia (JP-A-57-18375).
No. 6, gazette, Tetrahedron, 41, 5607.
(1985), JP 61-176564 A), 4
-Chloro-3-hydroxybutanoic acid ester and benzylamine (Japanese Unexamined Patent Publication No. 1-45360), cyclobutanone derivative and optically active α-methylbenzylamine (Synthetic)
Comm. , 21,693 (1991)), a method of synthesizing 3,4-epoxybutanoic acid amide and optically active α-methylbenzylamine (J. Chem. Research.
ch (s), 1990, 376), 4-amino-3-hydroxybutanoic acid (hereinafter referred to as GABOB) by heat dehydration to synthesize (Tetrahedron Let)
t., 21, 443 (1980), J. Org. Che
m. , 19, 1589 (1954)), optically active GAB
Method of synthesis from OB and hexamethyldisilazane (S
synthesis, 1978, 614), optical activity 4-
Method of synthesizing from hydroxyproline (JP-A-63-2)
No. 50352), a method of synthesizing 4-bromocrotonic acid ester (J. Org. Chem., 44, 27).
98 (1979)) and the like.

[0003]

However, these synthetic methods industrially have the following problems. That is, in the method of synthesizing 4-chloro-3-hydroxybutanoic acid ester and ammonia, many by-products are generated, and it is difficult to achieve a high yield. The method using benzylamine or α-methylbenzylamine requires a step of debenzylation group or demethylbenzyl group after the formation of pyrrolidone skeleton, and these steps are very difficult to perform, such as using a metal alkali in ammonia at low temperature. Is complicated. The method of synthesizing GABOB by heating and dehydrating it has a low yield, and when an optically active substance is used, racemization occurs. Although the method of synthesizing optically active GABOB and hexamethyldisilazane has a high yield, hexamethyldisilazane is expensive, and a desilylation step is required after the pyrrolidone skeleton is formed. The method of synthesizing from optically active 4-hydroxyproline and the method of synthesizing from 4-bromocrotonic acid ester have long steps and are not practical. Therefore, there has been a demand for development of a more efficient method for synthesizing 4-hydroxy-2-pyrrolidone.

[0004]

The inventors of the present invention have conducted extensive studies to solve the above-mentioned problems, and as a result, 4-hydroxy-2 was obtained in a high yield with almost no by-products, in a short process, and at a low cost. -The present invention has been completed by finding a new method for synthesizing pyrrolidone.

The present invention is, namely, 4 represented by the equation (2).
-Halogeno-3-hydroxybutanoic acid ester is reacted with an alkali metal amide to produce 4-hydroxy-2-pyrrolidone represented by the formula (1) through intermediates of the formulas (3) and (4). Regarding the method. The reaction route is as follows.

[0006]

Embedded image

[0007]

Embedded image (In the formula, X represents a halogen atom, and R represents an alkyl group having 1 to 4 carbon atoms.)

[0008]

Embedded image

The 4-halogeno-3-hydroxybutanoic acid ester of the formula (2) used as a raw material is methyl 4-chloro-3-hydroxybutanoate, ethyl 4-chloro-3-hydroxybutanoate, 4-chloro-3. -Isopropyl hydroxybutanoate, butyl 4-chloro-3-hydroxybutanoate, 4-chloro-3-hydroxybutanoic acid t
-Butyl, methyl 4-bromo-3-hydroxybutanoate, ethyl 4-bromo-3-hydroxybutanoate, 4-
Isopropyl bromo-3-hydroxybutanoate, butyl 4-bromo-3-hydroxybutanoate, 4-bromo-3
-T-butyl hydroxybutanoate and the like can be mentioned. Several methods for producing these compounds have been proposed, for example, a method of reacting epichlorohydrin, carbon monoxide and an alcohol (JP-A-57-183749) or a diketene, a halogen and an alcohol. Method for reducing γ-halo-acetoacetic acid ester (JP-A-58-58)
According to Japanese Patent No. 157747), it can be easily obtained. When an optically active 4-halogeno-3-hydroxybutanoic acid ester is required as a raw material, it can be obtained by using an optically active epichlorohydrin as a raw material by the method described in JP-A-57-183749. it can.

4-Hydroxy-2-pyrrolidone represented by the formula 1 can be produced as follows. That is,
When 4-halogeno-3-hydroxybutanoic acid ester represented by Formula 2 is reacted with an alkali metal amide in a solvent, 3,4-epoxybutanoic acid ester (Formula 3), and 4-
4-Hydroxy-2-pyrrolidone is readily obtained via the presumed intermediate of amino-3-hydroxybutanoic acid ester (Formula 4).

The solvent used is an aprotic polar solvent such as N, N-dimethylformamide, dimethylsulfoxide, sulfolane or hexamethylphosphoramide,
Ether-based solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, diethylene glycol monomethyl ether, dichloromethane, dichloroethane,
Examples include chlorine-based solvents such as chloroform, aromatic solvents such as toluene and xylene, and mixed solvents thereof.

As the alkali metal amide used, sodium amide or lithium amide is preferably used.
The amount of the alkali metal amide used is 2 to 5 mol, preferably 2 to 3 mol, based on 4-halogeno-3-hydroxybutanoic acid ester. Even if used in excess, it does not affect the yield but is economically disadvantageous. The reaction temperature is from room temperature to the reflux temperature of the solvent. If the temperature is too low, the reaction rate decreases significantly, which is not practical. The 4-hydroxy-2-pyrrolidone thus obtained can be isolated in high purity and high yield by a conventional purification method such as recrystallization.

When an optically active 4-halogeno-3-hydroxybutanoic acid ester is used as the 4-halogeno-3-hydroxybutanoic acid ester used as a raw material, optically active 4-hydroxy-2-pyrrolidone can be synthesized. . For example, if S-form 4-chloro-3-hydroxybutanoate is used, S-form 4-hydroxy-2
-Pyrrolidone is obtained. The same applies to the case of the R-form. When an ester with high optical purity is used, pyrrolidone with high optical purity can be synthesized without causing a remarkable racemization reaction during the reaction.

[0014]

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

Example 1 Ethyl R-4-chloro-3-hydroxybutanoate 10.
0 g (60.1 mmol, optical purity 98.3% e.
e. ), And to a mixture of 100 mL of ether, 4.9 g (126.2 mmol) of sodium amide was added, and the mixture was stirred at 25 ° C. for 1 hour.
Stirred for 0 hours. After completion of the reaction, concentration was carried out, and the obtained crude product was recrystallized from acetone-water to give 4.2 g of R-4-hydroxy-2-pyrrolidone as a colorless crystalline solid (41.
9 mol, yield 70%, optical purity 98.1% e. e. ,
Specific rotation [α] ²² _D = 57.4 ° (C = 1.0, H
₂ O)) was obtained.

Example 2 Methyl S-4-chloro-3-hydroxybutanoate 10.
0 g (65.6 mmol, optical purity 98.3% e.
e. ), And 5.4 g (137.8 mmol) of sodium amide were added to a mixture of 100 mL of toluene, and the mixture was stirred at 25 ° C. for 7 hours.
Stirred for hours. After completion of the reaction, concentration was carried out, and then treatment was carried out in the same manner as in Example 1 to give 5.0 g of S-4-hydroxy-2-pyrrolidone (49.2 mol, yield 75%, optical purity 98.1% ee) ., Specific rotation [α] ²² _D = -5
7.5 ° (C = 1.0, H ₂ O)) was obtained.

Example 3 Methyl R-4-chloro-3-hydroxybutanoate 10.
0 g (65.6 mmol, optical purity 98.5% e.
e. ), 5.4 g (137.8 mmol) of sodium amide was added to a mixture of 100 mL of tetrahydrofuran,
The mixture was stirred at 40 ° C for 6 hours. After completion of the reaction, concentration was carried out, and then treatment was carried out in the same manner as in Example 1 to carry out 4.8 g of R-4-hydroxy-2-pyrrolidone (47.2 mol, yield 7
2%, optical purity 98.2% e. e. , Specific rotation [α] ²²
_D = 57.5 ° (C = 1.0, H ₂ O)) was obtained.

Example 4 Methyl R-4-chloro-3-hydroxybutanoate 10.
0 g (65.6 mmol, optical purity 99.1% e.p.
e. ) And methylene chloride (100 mL) were added with lithium amide (3.2 g, 137.8 mmol), and the mixture was stirred at 30 ° C. for 8 hours. After completion of the reaction, concentration was carried out, and then treatment was carried out in the same manner as in Example 1 to give R-4-hydroxy-2-
Pyrrolidone 3.8 g (38.0 mol, yield 58%, optical purity 98.5% ee, specific optical rotation [α] ²² _D = 5
7.7 ° (C = 1.0, H ₂ O)) was obtained.

[0019]

INDUSTRIAL APPLICABILITY According to the present invention, 4-hydroxy-2-pyrrolidone can be produced economically advantageously in a short process, in a high yield, with almost no generation of by-products. Moreover, if a raw material ester having a high optical purity is used, 4-hydroxy-2 having a high optical purity can be obtained without causing a remarkable racemization reaction.
-Pyrrolidone is obtained.

Claims (5)

[Claims] 1. 4-halogeno-3-represented by formula (2)
A hydroxybutanoic acid ester (wherein X represents a halogen atom and R represents an alkyl group having 1 to 4 carbon atoms) and an alkali metal amide are reacted with each other, and are represented by the formula (1). A method for producing 4-hydroxy-2-pyrrolidone. Embedded image Embedded image 2. A 4-hydroxy-2-pyrrolidone produced by the method according to claim 1, wherein the 4-halogeno-3-hydroxybutanoic acid ester is an optically active substance. How to make pyrrolidone. 3. The method for producing 4-hydroxy-2-pyrrolidone according to claim 1, wherein the halogen atom is a chlorine atom or a bromine atom. 4. The 4-hydroxy-2 according to claim 1, wherein the alkyl group is a methyl group or an ethyl group.
-Pyrrolidone manufacturing method. 5. The method for producing 4-hydroxy-2-pyrrolidone according to claim 1, wherein the alkali metal amide is sodium amide or lithium amide.