CN109678739B

CN109678739B - Synthetic method of R-3-chloroserine methyl ester hydrochloride

Info

Publication number: CN109678739B
Application number: CN201811613850.3A
Authority: CN
Inventors: 王丹; 杨文�; 李军; 张新伟; 刘丽莉; 袁志法
Original assignee: China Sinopharm International Corp
Current assignee: China Sinopharm International Corp
Priority date: 2018-12-27
Filing date: 2018-12-27
Publication date: 2020-05-05
Anticipated expiration: 2038-12-27
Also published as: CN109678739A; WO2020134137A1

Abstract

The invention belongs to the field of drug synthesis, and discloses a synthesis method of R-3-chloroserine methyl ester hydrochloride, which comprises the following steps: adding paraformaldehyde into D-serine, reacting at room temperature, and crystallizing in a small volume to obtain D-serine NCA; adding thionyl chloride into the D-serine NCA in methanol, reacting at room temperature, and adding petroleum ether to obtain R-3-chloroserine methyl ester hydrochloride. The method has the advantages of simple process operation, environment friendliness, mild reaction conditions, high purity of the final product up to 99 percent, high yield up to 94.72 percent and contribution to industrial production.

Description

Synthetic method of R-3-chloroserine methyl ester hydrochloride

Technical Field

The invention relates to the field of drug synthesis, and relates to a preparation method of R-3-chloroserine methyl ester hydrochloride.

Background

The antibiotic is a secondary metabolite of a class which is generated by microorganisms (including bacteria, fungi and actinomycetes) or higher animals and plants in the living process and has anti-pathogen or other activities, and a chemical substance which can interfere the development function of other living cells, the antibiotics which are commonly used in clinic comprise genetically modified engineering bacteria, extracts in culture solution and chemically synthesized or semisynthetic compounds, the cycloserine, also called D-4-amino-3-oxazolidinone, is an antibiotic drug and has good inhibiting effect on tubercle bacillus, and the D-cycloserine is a special regulating factor of excitatory amino acid (N-methyl-D-aspartate) receptors in the central nervous system and has good auxiliary curative effect on treating psychological diseases such as psychological phobia, depression and schizophrenia, and the like, and the D-cycloserine is an important intermediate of synthesizing atypical β -lactam antibiotic Lactivin, and has wide market application prospect.

The existing synthetic route of the cycloserine is mainly synthesized by the following routes:

the synthetic route is as follows (US2772280, US2772281, US2640565, US2794022, US2918472 and the research on the chemical synthesis process of cycloserine, journal of Wassi pharmacy, 1995,10 (1): 39-39): the route has long steps, needs to be split, and has higher synthesis cost.

GB 1031267 reports a preparation method of D-cycloserine by using β - (α ' -ethoxyethylene) -aminoxy- α -bromomethyl propionate as a raw material, wherein β - (α ' -ethoxyethylene) -aminoxy- α -bromomethyl propionate is aminated under the action of liquid ammonia to generate β - (α ' -ethoxyethylene) -aminoxy- α -aminopropionamide, then β -aminoxy-alaninamide dihydrochloride is obtained after HCl gas treatment, DL-cycloserine is generated by cyclization under the action of KOH, and finally D-cycloserine is obtained by splitting with tartaric acid.

The preparation method of D-cycloserine by using D-1-triphenylmethyl aziridine-2-methyl formate as raw material is reported in GB 854922. D-1-triphenylmethyl aziridine-2-methyl formate firstly reacts with hydroxylamine hydrochloride at room temperature to generate D-1-triphenylmethyl aziridine-2-hydroxamic acid, then the D-1-triphenylmethyl aziridine-2-hydroxamic acid is subjected to ring opening under the action of HCl gas to generate D- α -amino- β -chloropropyl hydroxamic acid hydrochloride, and the D-cycloserine is prepared by ring opening under the action of strong-base anion exchange resin.

PlttenerP.A. et al propose a simple method for synthesizing D-cycloserine using D-serine methyl ester hydrochloride as a raw material. Namely, the D-serine methyl ester hydrochloride (1) and phosphorus pentachloride are subjected to chlorination reaction to generate D-2-amino-3-chlorolactamic acid methyl ester hydrochloride (II), the II and hydroxylamine are cyclized in sodium hydroxide solution to generate D-ring serine (I), and the cyclization yield is 40%. The synthetic route is shown as the following formula:

the method uses expensive D-serine methyl ester hydrochloride as raw material, has high cost, uses a large amount of PCl5 which is difficult to treat in the production process, and causes serious pollution to the environment.

R-3-chloroserine methyl ester hydrochloride is an important intermediate of cycloserine, and the synthesis of R-3-chloroserine methyl ester hydrochloride is not reported at home and abroad. In order to overcome the defects of expensive raw materials, low purity, low yield and environmental pollution of the existing D-cycloserine synthesis technology, the application provides a new route of R-3-chloroserine methyl ester hydrochloride, the reactions are all conventional operations, and the operation is simple and convenient; and the raw materials are all sold in the market, the price is proper, the supply is sufficient, and the industrial prospect is better.

Disclosure of Invention

Based on the technical problems in the background art, the invention provides the R-3-chloroserine methyl ester hydrochloride, and the method has the advantages of low cost, low environmental pressure, high yield and contribution to large-scale production.

A synthetic method of R-3-chloroserine methyl ester hydrochloride is characterized by comprising the following steps:

1) synthesis of D-serine-N-carboxyanhydride: adding polyformaldehyde into D-serine, reacting at room temperature for 0.5-3 hours, recovering the solvent, and crystallizing to obtain D-serine-N-carboxyl acid anhydride (D-serine NCA);

2) synthesis of R-3-chloroserine methyl ester hydrochloride: adding D-serine NCA into a solvent, adding thionyl chloride, reacting at 15-25 ℃ for 1-3 hours, recovering the solvent, and adding petroleum ether for crystallization to obtain R-3-chloroserine methyl ester hydrochloride.

Preferably, the molar ratio of D-serine to paraformaldehyde in the reaction is 1: 1.2-1.5.

Preferably, the molar ratio of the D-serine NCA to the thionyl chloride to the petroleum ether in the reaction is 1: 1.5-2.0: 1.

preferably, the solvent in step 1) is anhydrous tetrahydrofuran or dichloromethane.

Preferably, the solvent in step 2) is methanol or ethanol.

The synthetic route of the invention is as follows:

(1)

(2)

compared with the prior art, the invention has the beneficial effects that:

r-3-chloroserine methyl ester hydrochloride is an important intermediate of cycloserine, synthesis of R-3-chloroserine methyl ester hydrochloride is not reported at home and abroad, and hydroxyl is not easily substituted in the cyclization process, so the intermediate is not used in the prior art. Compared with the existing cycloserine synthesis intermediate, the invention provides a synthesis method of R-3-chloroserine methyl ester hydrochloride, NCA is formed in the step 1), hydroxyl is easier to be substituted, and R-3-chloroserine methyl ester hydrochloride is easy to prepare, so that higher yield is obtained, the method is suitable for industrial production, has high purity, and has direct influence on the yield of cycloserine; meanwhile, the method avoids the use of a large amount of PCl5 or acyl chloride reagents in the existing cycloserine synthesis technology, and is more environment-friendly; and (3) ending the process, filtering to remove salt, and concentrating to obtain the product, wherein the process is simple, the industrialization is easier, the purity of the final product is as high as 99%, and the yield is as high as 94.72%.

Detailed Description

The present invention will be further illustrated with reference to the following specific examples.

Example 1

1) Adding 108g of paraformaldehyde into 105g of D-serine in 500ml of tetrahydrofuran, reacting at room temperature for 2 hours, recovering the tetrahydrofuran, and crystallizing to obtain D-serine NCA in a small volume;

2) adding 110mL of thionyl chloride into D-serine NCA in methanol, reacting at 15 ℃ for 1 hour, recovering the methanol, and adding 300mL of petroleum ether to obtain R-3-chloroserine methyl ester hydrochloride; (the obtained product R-3-chloroserine methyl ester hydrochloride had a mass of 160.92g, a purity of 99.421%, and a yield of 91.93%).

Example 2

1) Adding 126g of paraformaldehyde into 105g of D-serine in 500ml of tetrahydrofuran, reacting at room temperature for 0.5 hour, recovering tetrahydrofuran, and crystallizing to obtain D-serine NCA;

2) adding 130mL of thionyl chloride into D-serine NCA in methanol, reacting for 3 hours at 20 ℃, recovering the methanol, and adding 300mL of petroleum ether to obtain R-3-chloroserine methyl ester hydrochloride; (the obtained product R-3-chloroserine methyl ester hydrochloride has the mass of 166.87g, the purity of 99.488% and the yield of 93.11%).

Example 3

1) Adding 135g of paraformaldehyde into 105g of D-serine in 500ml of tetrahydrofuran, reacting at room temperature for 3 hours, recovering tetrahydrofuran, and crystallizing to obtain D-serine NCA;

2) adding 145mL of thionyl chloride into the D-serine NCA in methanol, reacting for 2 hours at 25 ℃, recovering the methanol, and adding 300mL of petroleum ether to obtain R-3-chloroserine methyl ester hydrochloride; (the obtained product R-3-chloroserine methyl ester hydrochloride had a mass of 165.63g, a purity of 99.526% and a yield of 94.72%).

Claims

1. A synthetic method of R-3-chloroserine methyl ester hydrochloride is characterized by comprising the following steps:

1) synthesis of D-serine-N-carboxyanhydride: adding polyformaldehyde into D-serine, reacting at room temperature for 0.5-3 hours, recovering the solvent, and crystallizing to obtain D-serine-N-carboxyl anhydride;

2) synthesis of R-3-chloroserine methyl ester hydrochloride: adding D-serine NCA into a solvent, adding thionyl chloride, reacting at 15-25 ℃ for 1-3 hours, recovering the solvent, and adding petroleum ether for crystallization to obtain R-3-chloroserine methyl ester hydrochloride, wherein the solvent is methanol.

2. The method for synthesizing R-3-chloroserine methyl ester hydrochloride according to claim 1, wherein the molar ratio of D-serine to paraformaldehyde in the reaction is 1: 1.2-1.5.

3. The method for synthesizing R-3-chloroserine methyl ester hydrochloride according to claim 1, characterized in that the molar ratio of D-serine NCA to thionyl chloride to petroleum ether in the reaction is 1: 1.5-2.0: 1.

4. the method for synthesizing R-3-chloroserine methyl ester hydrochloride according to claim 1, characterized in that the solvent in step 1) is anhydrous tetrahydrofuran or dichloromethane.