JPS6327477A - Production of oxiracetam - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a cerebral metabolism improver, in short steps at a low cost, by using a halogenoacetic acid ester and ammonia as easily and inexpensively available raw materials and passing through glycinamide and oxiracetam as intermediates. CONSTITUTION:A halogenoacetic acid ester is made to react with preferably 3-50mol, especially 10-30mol of ammonia (based on 1mol of the ester) at 10-100 deg.C in the presence of a solvent (preferably an aliphatic alcohol) and the reaction mixture is concentrated to obtain glycinamide, its salt or their mixture. The above glycinamide, etc., is reacted with 4-chloro-3-hydroxybutyric acid ester of formula (R is lower alkyl) in a solvent (especially preferably ethanol) preferably in the presence of a neutralizing agent at 60-160 deg.C. The obtained liquid containing oxiracetam is filtered to remove insoluble components and concentrated to obtain the objective compound as precipitate.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing oxiracetam (4-hydroxy-2-oxy-1-pyrrolidine acetamide), which is used as a medicine (brain metabolism improving agent).

[Conventional technology]

Conventionally, methods for synthesizing oxiracetam, which is the object of the present invention, include a method in which ethyl iminodiacetate and ethoxycarponylacetyl chloride are used as base materials and obtained through a five-step reaction [Japanese Patent Publication No. 58-22054] and (2) )γ
- Amino-β-hydroxybutyric acid t-m material is reacted with hexamethyldisiladene, etc., and then a three-step reaction is performed (Japanese Unexamined Patent Publication No. 53-101!167). .

[Problem that the invention seeks to solve]

All of the conventional methods have drawbacks such as using the same raw materials and requiring multiple reaction steps.

[Means for solving problems]

The present invention is a method for producing oxiracetam comprising the following steps (1), (21 and (3)).

(1) Glycinamide manufacturing process in which the halidenoacetate t1 is reacted with ammonia in the presence of a solvent and the reaction solution is concentrated to obtain glycinamide, its salt, or a mixture thereof (2) The glycinamide, its salt, or a mixture thereof is reacted with 4-chloro-5-hydroxybutyric acid ester represented by the general formula % (R represents a lower alkyl group) in the presence of a solvent to obtain an oxiracetam-containing liquid (aJ titl liquid) According to the present invention, an isolation process for obtaining Oxiracetam 7, which is obtained by concentrating and precipitating Oxiracetam after filtration of the unbath product, is carried out by a two-step easy reaction process using a coolant that is easier and cheaper to obtain than in conventional production methods. , Oxiracetam is obtained.

Each step will be described in detail below.

In this step, harodenoacetic acid ester is reacted with ammonia in the presence of a solvent, and the reaction solution is condensed to obtain glycinamide or a salt thereof. The halogenoacetate used in the present invention is not particularly limited, but methyl chloroacetate, ethyl chloroacetate, prozal chloroacetate, methyl bromoacetate, ethyl bromoacetate, and propyl bromoacetate are easily available industrially. preferable. Ammonia is 3 to 50 times, preferably 10 to 3 times as much as the harodenoacetic ester.
0 times molar amount is used. If it is too small, a large amount of iminodiacetic acid amide will be produced, and if it is too large, there will be no effect.

Furthermore, the amount of ammonia can be reduced by adding hexamethylenetetramine to the heathered yarn as a catalyst.

In carrying out the method of the present invention, the entire reaction is carried out in an autoclave at a predetermined temperature by either bulk charging or partial addition of halidenoacetic ester.

The reaction temperature is preferably -10 to 100°C, particularly 0 to 80°C.

At lower temperatures, the reaction is slow, and at higher temperatures, selectivity does not increase.

The present invention preferably uses a solvent. There are no particular restrictions on the solvent, and aqueous ammonia is the easiest to obtain industrially, but since alcohol is produced after the reaction, the same B
Using an aliphatic alcohol solvent is more advantageous in terms of solvent recovery and reuse after the reaction.

The method of separating glycinamide or its salt from the reaction solution is not particularly limited, but the amination solution can be deammoniated, further concentrated and desolvented to precipitate glycinamide or its salt.

A product with relatively high purity can be obtained by passing the product through during concentration or by washing with alcohol after removing the solvent. However, according to the present invention, glycinamide, its salt, or a mixture thereof after desolventization is not particularly produced in 1'ft. It can be used in the oxiracetamization process.

2. Oxiracetamization step In this step, the glycinamide, its salt, or a mixture thereof is expressed by the general formula % (R represents a lower alkyl group) in the presence of a total solvent. It is reacted with 4-chloro-3-hydroxybutyric acid ester and contains oxiracetam.

4-chloro-3-hydroxybutyric acid ester, which is a raw material in the method of the present invention, is easily prepared, for example, by carbonylation reaction of shrimp chlorohydrin, which is inexpensively available as an industrial raw material (Japanese Patent Application Laid-open No. 68644).

There is no particular restriction on R as long as it is a lower alkyl group, but R is a substituent that is eliminated during one production process, and it is not economical to use it with 4 or more carbon atoms. Therefore, it is preferable to have 1 to 6 carbon atoms.

In carrying out the method of the present invention, it is desirable to use solvents, such as water, protic solvents such as methanol, ethanol, propatool, butanol, 2-methoxyethanol, and dioxane, 1.2-dimethoxyethane, diglyme, etc. Like! Ether solvents and mixed solvents thereof can be used, but protic solvents are preferred, and ethanol is particularly preferred.

During this reaction, hydrogen halide is produced as a by-product, but it is preferable to add a neutralizing agent to this hydrogen halide in order to reduce the reaction rate. Inorganic bases for neutralization include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, and alkali metal carbonates such as sodium carbonate, sodium bicarbonate, and potassium carbonate. However, in consideration of yield and economy, alkali metal carbon #I salts are preferred, and sodium carbonate is particularly preferred.

As the organic base, amines such as ammonia, triethylamine, dimethylaniline, and glycinamide are used.

The reaction temperature is 60-160°C, preferably 70-13°C.
The temperature is 0°C, and the reaction time varies depending on the temperature and other conditions.
~70 hours. Note that a catalytic amount of iodide such as potassium iodide and sodium iodide promotes this reaction.

3. Isolation step The reaction solution is filtered to remove precipitated salts, concentrated, and cooled to remove the precipitated oxiracetam t? [Oxiracetam t? 10-50%, preferably 20-30%
I will do it up to If the amount is less than this, the loss to the filtrate will be large, and if it is more than this, more impurities will be mixed in.

If the solvent is water, the solubility of oxiracetam is too high, so use water as much as possible. Oxiracetam is obtained by removing and then treating with a solvent in which oxiracetam has low solubility, such as an aliphatic alcohol.

Highly pure oxiracetam can be obtained by washing the same substance in this state. There are no particular restrictions on cleaning agents, but methanol, acetone, and
Ethanol and propatool are preferred. The i of the cleaning agent is
0.5 to 6 times, preferably 1 to 2 times as heavy! use

If it is less than this, there will be no washing effect, and if there are 2 more, aI! The loss to the liquid will be greater.

Furthermore, in order to obtain oxiracetam with pure purity, there is a method in which, for example, oxiracetam is diluted in a water bath, completely desalted by treatment with an ion exchange resin, and further decolorized by treatment with activated ash. The ion exchange resin is not particularly limited and may be a commercially available strong acidic ion exchange resin. In this ion exchange resin treatment, the precipitated salt m of the reaction solution is reduced to 1 after passing through it. It is also possible to do so, but only if the ionic A4N resin can be used in the reaction bath. Activated carbon is also not particularly limited, and commercially available ones are sufficient. The activated carbon treatment solution was concentrated, a poor solvent was added, and after cooling, it was precipitated and oxiracetam tl-
1i1 & get it. As a poor solvent, there is no particular problem as long as it is soluble in water and oxiracetam is insoluble, but since the chemical product dries easily, aliphatic lower alcohols with a low boiling point, such as methanol, ethanol, and oxiracetam, are recommended. Panol, aliphatic lower ketones, acetone, methyl ethyl ketone, diethyl ketone, etc. are preferred.

〔Example〕

Further details will be explained below with reference to Examples.

Example 1 Methyl chloroacetate (108.5 g, 1 mol) and 20
Thiammonia-methanol fa-1ft < 1.27
59% NH3 (15 mol) (methyl chloroacetate/ammonia - 1/15: molar ratio) Heated to 40°C for 15 hours with stirring in an autoclave. After the reaction, quantification using liquid chromatography (hereinafter abbreviated as HLO) revealed that glycinamide was 7661%.
It was found that 19.6 units of iminodiacetic acid amide were produced.

By condensing the reaction i'ti glycinamide 0.77
The white solid containing moles is 130! ! Obtained.

Example 2 Solid obtained according to Example 1 84.4, ? (contains 0.5 mol of glycinamide b), methyl 4-10 rho-6-hydroxybutyrate (76,511,0.5 mol), sodium carbonate (53,9,0.5 mol) [glycinamide P
Methyl 74-chloro-6-hydroxybutyrate/sodium carbonate-1/1/1 (molar ratio)] and ethanol C5
009) Refluxed for 20 hours. When the reaction solution was subjected to HLO analysis, it was found that oxiracetam was obtained in a yield of 53%.

Example 6 After filtering the reaction solution of Example 2 and concentrating the total amount to 200 g (condensation rate 21%), oxiracetam precipitates out. 5°C
Oxiracetam with a purity of 70% is obtained by cooling to 50.8.9 (Oxiracetam 35.6,!
i') Obtained. This was washed with 55 g of methanol (1.5 times heavier than oxiracetam) under warm mold conditions to obtain 56.3 g of tam (oxiracetam 54.5 & ) with a purity of 95%.

This was diluted with 20% aqueous solution, treated with strong acidic ion exchange resin,
and treated with activated carbon. The mixture was condensed to a total amount of 55 g, added to 779 g of methanol, and cooled to 0°C. Oxiracetam was precipitated. The crystals were collected and dried under vacuum to yield 28 g of oxiracetam (isolated yield 35-4%, melting point 161-163).
°C) was obtained.

〔Effect of the invention〕

By the method of the present invention, oxiracetam t- is industrially advantageously produced from easily and inexpensively available raw materials through short reaction steps.

Claims (1)

[Scope of Claims] A method for producing oxiracetam comprising the following steps (1), (2) and (3). (1) Glycinamide manufacturing process in which a halogenoacetic acid ester is reacted with ammonia in the presence of a solvent and the reaction solution is concentrated to obtain glycinamide, its salt, or a mixture thereof. (2) The glycinamide, its salt, or a mixture thereof. The mixture is reacted with 4-chloro-3-hydroxybutyric acid ester represented by the general formula ▲Mathematical formula, chemical formula, table, etc.▼ (R represents a lower alkyl group) in the presence of a solvent to obtain an oxiracetam-containing liquid. Racetamization step (3) Isolation step of obtaining precipitated oxiracetam by concentrating the liquid after filtering the insoluble matter