阅读说明：本技术 (r)-4-羟基-2-氧代-1-吡咯烷乙酸酯的制备方法 (Preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate ) 是由 叶雷 于 2018-06-01 设计创作，主要内容包括：本发明提供了一种(R)-4-羟基-2-氧代-1-吡咯烷乙酸酯的制备方法,通过双相萃取的方式,先采用水将产物从反应体系溶剂中萃取出来,进入水相,再采用二氯甲烷将产物又从水中萃取进入二氯甲烷相中,从而在不能结晶的情况下很好的纯化(R)-4-羟基-2-氧-1-吡咯烷乙酸酯。该方法原料价廉易得,未使用毒性较大的原料或溶剂,对操作人员安全性好,且不需要大型设备,工业生产顺应性好。(The invention provides a preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate, which comprises the steps of firstly extracting a product from a reaction system solvent by water in a two-phase extraction mode, entering a water phase, and then extracting the product from the water by dichloromethane into the dichloromethane phase, thereby purifying the (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate well under the condition of no crystallization. The method has the advantages of cheap and easily available raw materials, no use of raw materials or solvents with high toxicity, good safety for operators, no need of large-scale equipment and good industrial production compliance.)

1. A preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate is characterized by adopting the following route:

Wherein R is₁Is C₁-C₆Alkyl of R₂is C₁-C₆alkyl groups of (a);

The preparation method comprises the steps of taking one or more of butyl acetate, toluene, DMF and DMSO as a reaction solvent, reacting for 3.5-7 hours at the temperature of 60-133 ℃, adding water into reaction liquid, extracting a product from a reaction system by using water, enabling the product to enter a water phase, extracting the product from the water phase by using dichloromethane, entering the dichloromethane phase, and concentrating to obtain (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate.

2. The method of claim 1, wherein: the above-mentionedC₁-C₆The alkyl group of (a) is methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, cyclopentyl or benzyl.

3. the method of claim 2, wherein: the R is₁Is C₁-C₆Alkyl groups of (a); r₂Is isopropyl, n-propyl, isobutyl, n-butyl or tert-butyl.

4. The method of claim 3, wherein: the R is₁Is methyl, ethyl, isopropyl, n-propyl; r₂Is isobutyl, n-butyl or tert-butyl.

5. the method of any one of claims 1-4, wherein: the reaction solvent is toluene.

6. the method of any one of claims 1-5, wherein: the intermediate I is prepared by adopting the following route:

Wherein X is halogen; the reaction solvent is one or a combination of more of methanol, ethanol, dichloromethane, tetrahydrofuran, acetone, butanone and ethyl butyrate; the catalyst is triethylamine, pyridine or lutidine; the reaction temperature is 22-63 ℃, and the reaction time is 4.5-8 hours; the molar ratio of the intermediate II to the haloacetate is as follows: 1: 1-3, wherein the molar ratio of the intermediate II to the catalyst is as follows: 1: 2-3.

7. The method of claim 6, wherein: the halogen is chlorine or bromine.

8. The method of any one of claims 1-7, wherein: the intermediate II is prepared by adopting the following route:

firstly, mixing R-4-amino-3-hydroxybutyric acid and 5-20 times of R by weight₁Mixing alcohol and sulfoxide chloride, and reacting at 0-50 ℃ for 1-4 hours, wherein the molar ratio of R-4-amino-3-hydroxybutyric acid to sulfoxide chloride is 1: 1-2; obtaining an alcoholic solution containing intermediate II, and then collecting intermediate II from the alcoholic solution containing intermediate II.

9. A preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate is characterized by adopting the following route:

wherein R is₁Is methyl, ethyl, isopropyl, n-propyl, R₂is isobutyl, n-butyl or tert-butyl; x is bromine;

The preparation process comprises the following steps:

Firstly, mixing R-4-amino-3-hydroxybutyric acid and 5-20 times of R by weight₁Mixing alcohol and thionyl chloride, reacting for 1.5-3.5 hours at 0-45 ℃, wherein the molar ratio of R-4-amino-3-hydroxybutyric acid to thionyl chloride is 1: 1-2; obtaining an alcoholic solution containing the intermediate II, and then collecting the intermediate II from the alcoholic solution containing the intermediate II;

the intermediate II and bromoacetate react under the action of a catalyst to prepare an intermediate I, wherein the catalyst is triethylamine, pyridine or lutidine, the reaction solvent is one or a combination of more of methanol, ethanol, dichloromethane, tetrahydrofuran, acetone, butanone or ethyl butyrate, the reaction temperature is 25-48 ℃, the reaction time is 4.5-7 hours, and the molar ratio of the intermediate II to the bromoacetate is as follows: 1: 1-3, wherein the molar ratio of the intermediate II to the alkali catalyst is as follows: 1: 2-3;

The intermediate I reacts in toluene at a temperature of 90-125 ℃ for 3.5-7 hours; and after the reaction is finished, adding water into the reaction liquid for extraction, then adding dichloromethane into the water phase for re-extraction, collecting the extracted dichloromethane, and concentrating to obtain the (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate.

Technical Field

The invention relates to (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate, in particular to a preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate.

Background

(R) -4-hydroxy-2-oxo-1-pyrrolidine acetate is an important intermediate for synthesizing (R) -4-hydroxy-2-oxo-1-pyrrolidine acetamide (CAS number 68252-28-8). (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate has the following structure (R)₂Is C₁-C₆Alkyl group (b):

Before (R) -4-hydroxy-2-oxo-1-pyrrolidine acetamide is not found to have sedative and antiepileptic activities, the technical personnel in the industry generally consider that the levorotatory isomer of 4-hydroxy-2-oxo-1-pyrrolidine acetamide is more suitable for developing an intelligence promoting medicament, and the dextrorotatory isomer (R) -4-hydroxy-2-oxo-1-pyrrolidine acetamide is treated as an impurity, so that the research on the synthesis method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetamide is less. Accordingly, the synthesis of the intermediate (R) -4-hydroxy-2-oxo-1-pyrrolidineacetic acid ester has been rarely studied. Chinese patent CN105330582A discloses a synthesis method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetamide, which comprises the steps of taking R-4-chloro-3-hydroxybutyric acid ester as a starting material, carrying out an azide reaction, then carrying out azide reduction, carrying out condensation with haloacetate, then closing a ring to obtain (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate, and then carrying out ammonolysis to obtain (R) -4-hydroxy-2-oxo-1-pyrrolidine acetamide. Since the intermediates of this route are oily and do not crystallize efficiently, the purity of (R) -4-hydroxy-2-oxo-1-pyrrolidineacetate has a large influence on the yield and purity of the final product (R) -4-hydroxy-2-oxo-1-pyrrolidineacetamide. A great amount of organic impurities and inorganic salts are generated in the reaction process, and how to effectively separate the (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate in the reaction system to improve the purity of the product becomes an important problem in the production practice.

Disclosure of Invention

in order to solve the problems in the prior art, the invention aims to provide a preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate, the (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate prepared by the method has high purity, is used as a pharmaceutical intermediate, is very suitable for the production of downstream products, has simple process and high economic benefit, and is suitable for industrial mass production.

Except for special description, the parts are parts by weight, and the percentages are mass percentages.

the purpose of the invention is realized as follows:

The preparation method of the (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate is characterized by adopting the following route:

Wherein R is₁Is C₁-C₆alkyl of R₂Is C₁-C₆Alkyl group of (1).

The preparation process comprises the following steps:

One or more of butyl acetate, toluene, DMF and DMSO are mixed to be used as a reaction solvent, the reaction is carried out for 3.5 to 7 hours at the temperature of 60 to 133 ℃, then water is added into the reaction liquid, the product is extracted from the reaction system by water and enters a water phase, the product is extracted from the water phase by dichloromethane and enters a dichloromethane phase, and then (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate is obtained by concentration.

For the problem that the (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate is difficult to effectively separate due to the generation of a large amount of organic impurities and inorganic salts in the reaction system, the inventor finally develops a two-phase extraction mode formed by combining water and dichloromethane through a large amount of experiments, thereby not only ensuring the yield and the purity of a final product, but also realizing the safety and the economical efficiency of the reaction process, successfully avoiding highly toxic reagents or solvents, avoiding operation steps such as column passing, ion exchange and the like which are difficult to industrialize, and realizing the high-efficiency separation of the target product (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate.

In the above process, the above-mentioned C₁-C₆The alkyl group of (a) is preferably a methyl group, an ethyl group, an isopropyl group, a n-propyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a cyclopentyl group or a benzyl group.

It has also been found in the study that not all of the above-mentioned (R) -4-hydroxy-2-oxo-1-pyrrolidineacetic esters₂Is C1-C₆The alkyl esters of (a) are suitable for the above two-phase extraction, and some ester compounds are difficult to enter the aqueous phase from the reaction solvent, and some ester compounds are difficult to enter methylene chloride from the aqueous phase. Preferably, the process for producing (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate is characterized by: r1 is C₁-C₆Alkyl of R₂Is isopropyl, n-propyl, isobutyl, n-butyl or tert-butyl; further, R₁Is methyl, ethyl, isopropyl, n-propyl, R₂is isobutyl, n-butyl or tert-butyl.

The inventor also found that when the reaction solvent is toluene, the content of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate obtained by two-phase extraction is significantly higher than that of butyl acetate, DMF and DMSO; thus, toluene is preferred as the reaction solvent.

the above intermediate I is preferably prepared by the following route:

Wherein X is halogen; the reaction solvent is one or a combination of more of methanol, ethanol, dichloromethane, tetrahydrofuran, acetone, butanone and ethyl butyrate; the catalyst is triethylamine, pyridine or lutidine; the reaction temperature is 22-63 ℃ and the reaction time is 4.5-8 hours.

the halogen is preferably chlorine or bromine.

Preferably, the molar ratio of the intermediate II to the haloacetate is: 1: 1-3, wherein the molar ratio of the intermediate II to the catalyst is as follows: 1: 2-3.

the above intermediate II is preferably prepared by the following route:

Firstly, mixing R-4-amino-3-hydroxybutyric acid and 5-20 times of R by weight₁Alcohols (e.g. C, methanol, ethanol, n-propanol, isopropanol, cyclopentanol, etc.)₁-C₆Alcohol of (1), then adding thionyl chloride to react for 1 to 4 hours at 0 to 50 ℃, wherein the molar ratio of the R-4-amino-3-hydroxybutyric acid to the thionyl chloride is 1: 1-2; obtaining an alcoholic solution containing intermediate II, and then collecting intermediate II from the alcoholic solution containing intermediate II.

Specifically, the preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate is characterized by comprising the following steps:

Wherein R is₁Is methyl, ethyl, isopropyl, n-propyl, R₂Is isobutyl, n-butyl or tert-butyl; x is bromine;

The preparation process comprises the following steps:

Firstly, mixing R-4-amino-3-hydroxybutyric acid and 5-20 times of R by weight₁Mixing alcohol and then adding thionyl chloride to react for 1.5 to 3.5 hours at the temperature of between 0 and 45 ℃, and obtaining R-4-amino-3-hydroxylThe molar ratio of butyric acid to thionyl chloride is 1: 1-2; obtaining an alcoholic solution containing the intermediate II, and then collecting the intermediate II from the alcoholic solution containing the intermediate II;

The intermediate II and bromoacetate react under the action of a catalyst to prepare an intermediate I, wherein the catalyst is triethylamine, pyridine or lutidine, the reaction solvent is one or a combination of more of methanol, ethanol, dichloromethane, tetrahydrofuran, acetone, butanone or ethyl butyrate, the reaction temperature is 25-48 ℃, the reaction time is 4.5-7 hours, and the molar ratio of the intermediate II to the bromoacetate is as follows: 1: 1-3, wherein the molar ratio of the intermediate II to the alkali catalyst is as follows: 1: 2-3;

The intermediate I reacts in toluene at a temperature of 90-125 ℃ for 3.5-7 hours; and after the reaction is finished, adding water into the reaction liquid for extraction, then adding dichloromethane into the water phase for re-extraction, collecting the extracted dichloromethane, and concentrating to obtain the (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate.

Has the advantages that:

The invention provides a preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate, which comprises the steps of firstly extracting a product from a reaction system solvent by water in a specific two-phase extraction mode, allowing the product to enter a water phase, and extracting the product from the water by dichloromethane to enter a dichloromethane phase, thereby well ensuring the yield and purity of a final product under the condition of no crystallization, realizing the safety and economy of a reaction process, successfully avoiding a highly toxic reagent or solvent, avoiding operation steps such as column passing, ion exchange and the like which are difficult to industrialize, and realizing the high-efficiency separation of the target product (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate. The invention has the advantages of cheap and easily obtained raw materials, no use of raw materials or solvents with high toxicity, good safety for operators, no need of large-scale equipment, good industrial production compliance and being close to the practical production of enterprises. The yield of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetamide prepared by aminolysis of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate prepared by the method can reach 46-50% (calculated by R-4-amino-3-hydroxybutyric acid), the purity is as high as 99.9%, and the method has obvious economical efficiency and operability.

examples

in order to make the objects and technical solutions of the present invention clearer, preferred embodiments of the present invention are described in detail below. It is to be noted that: the following examples are intended to illustrate the invention further and are not to be construed as limiting the scope of the invention. The invention is not limited to the embodiments described above, but rather, many modifications and variations may be made by one skilled in the art without departing from the scope of the invention. The raw materials and reagents used in the invention are all commercial products.