CN112521318A

CN112521318A - Preparation method of amisulpride important intermediate

Info

Publication number: CN112521318A
Application number: CN201910885046.9A
Authority: CN
Inventors: 吴边边; 李恩民; 赵国磊
Original assignee: Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Current assignee: Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Priority date: 2019-09-19
Filing date: 2019-09-19
Publication date: 2021-03-19

Abstract

Methyl 4-amino-5-thiophenyl-2-methoxybenzoate is an important intermediate of the antipsychotic amisulpride. The invention relates to a preparation method of 4-amino-5-thiophenyl-2-methoxy methyl benzoate, which has mild reaction conditions, easy operation and simple purification process.

Description

Preparation method of amisulpride important intermediate

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a synthesis method of 4-amino-5-thiophenyl-2-methoxybenzoic acid methyl ester.

Background

4-amino-5-ethylsulfonyl-2-methoxybenzoic acid (I) is an important intermediate of the antipsychotic amisulpride. Amisulpride, a broad spectrum antipsychotic drug developed by sanofitylabo, saint-delaburg, seofil, france, is widely used for adult schizophrenia patients with acute and chronic, positive and negative symptoms, is marketed in the united states in 1 month 1997 and in china in 2001, and is now becoming the first line drug for the treatment of acute progressive and chronic schizophrenia. The penaer researches the synthesis of the amisulpride intermediate 4-amino-5-thiophenyl-2-methoxy methyl benzoate (VI) and explores a synthesis method with industrial application prospect.

In the reports of references on the synthesis of amisulpride, the important solution is the synthesis of 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid, which is an important intermediate in the synthesis of amisulpride, and the synthesis can be roughly divided into four categories according to the difference of starting materials: 4-amino-2-methoxy-5-mercaptobenzoic acid is taken as a raw material; 4-acetamido-2-methoxy methyl benzoate is taken as a raw material; 4-amino-2-methoxybenzoic acid is taken as a raw material; p-aminosalicylic acid is used as a raw material. The synthetic route is as follows:

4-amino-2-methoxy-5-mercaptobenzoic acid is taken as a raw material:

4-amino-2-methoxybenzoic acid is used as a raw material:

。

p-aminosalicylic acid is used as a raw material:

in typical 3 synthetic routes, related synthesis of an intermediate of methyl 4-amino-5-ethylsulfonyl-2-methoxybenzoate (VI) is involved. In the above typical synthetic routes, an alkylating reagent is added to carry out alkylation reaction while simultaneously synthesizing the intermediate (VI), and the reaction is carried out in two steps and one step, while the intermediate methyl 4-amino-5-thiophenyl-2-methoxybenzoate is not separated out separately to obtain a pure product. The influence of the important intermediate on the quality and yield of the final product is not well understood and analyzed, and the characterization and synthesis process of the intermediate are not deeply researched. There is a need to develop an efficient and simple method for synthesizing the intermediate.

Disclosure of Invention

The method is obtained by simple salt-forming neutralization reaction, firstly, an alcohol mixed solvent is used for well dissolving a reaction substrate and an alkaline solvent, and the hydrolysis of methyl formate groups under an alkaline condition is protected in the alcohol solvent. Finally, insoluble impurities in the product are removed by a sulfur-based salifying method, so that the yield and purity are improved. The method has the advantages of simple and practical synthesis method and stable yield. Can provide effective reference for typical routes and also provides additional possibility for further industrialized production.

The method comprises the following steps:

dissolving a compound 4-amino-2-methoxy-5-thiocyanatobenzoic acid methyl ester (I) in an alcohol mixed solvent (II), adding an alkaline reagent (III) at the temperature of 5-90 ℃ for catalysis, and reacting for 0.5-9h to obtain a Na salt (IV) of the 4-amino-2-methoxy-5-thiocyanatobenzoic acid methyl ester.

（Ⅰ）（Ⅳ）

Filtering the reaction mother liquor to remove insoluble impurities, adding an acidic reagent (V) into the filtrate to adjust the pH value to 2-6, converting the filtrate into yellow suspension, and filtering to obtain a product of methyl 4-amino-5-thiophenyl-2-methoxybenzoate (VI).

（Ⅳ）（Ⅵ）

The specific implementation mode is as follows:

example 1:

0.5g of methyl 4-amino-2-methoxy-5-thiocyanatobenzoate was dissolved in 6ml of water and 3ml of methanol while keeping the temperature of the solution at 10 to 15 ℃ and stirred. 0.26g of Na₂S was dissolved in 2ml of water and added dropwise to the solution. After stirring for 1h, the reaction temperature was raised to 80 ℃ and the reaction was continued for 2 h. The reaction mother liquor was filtered, and the pH of the filtrate was adjusted to 2-3 using 3M hydrochloric acid, and the filtrate was filtered to give 0.38g of a yellow solid in 85% yield.

Example 2:

0.5g of methyl 4-amino-2-methoxy-5-thiocyanatobenzoate was dissolved in 6ml of water and 3ml of ethanol while keeping the temperature of the solution at 5 to 10 ℃ and stirred. 0.26g of Na₂S was dissolved in 2ml of water and added dropwise to the solution. After stirring for 1 hour, the reaction temperature was raised to room temperature and the reaction was continued for 8 hours. The reaction mother liquor was filtered and conditioned with 3M acetic acidThe pH of the filtrate was adjusted to 5-6 and filtered to give 0.35g of a yellow solid in 78% yield.

Claims

A method for preparing methyl 1.4-amino-5-thiophenyl-2-methoxybenzoate, which is characterized by comprising the following steps:

step a: dissolving 4-amino-2-methoxy-5-thiocyanatomethyl benzoate (I) in an alcohol mixed solvent (II), and reducing the mixture into Na salt (IV) of 4-amino-2-methoxy-5-thiocyanatomethyl benzoate through a substitution reaction under the catalysis of an alkaline reagent (III);

；

step b: filtering the mother liquor to remove impurities, adding an acidic reagent (V) into the filtrate to neutralize to obtain yellow suspension, and filtering to obtain a product of 4-amino-5-thiophenyl-2-methoxybenzoic acid methyl ester (VI);

。
2. the synthesis process of step a described in claim 1, wherein the alcohol mixed solvent (ii) is methanol and water, ethanol and water, and the ratio of the two mixed solvents is lower alcohol: water =1:1-1: 6.
3. The synthesis process as described in claim 1-2, the alkaline agent (III) being KOH, NaOH, Na₂S。
4. A synthesis process as described in claims 1 to 3, characterized in that the reaction temperature in step a is between 5 and 80 ℃ and the reaction time is between 2 and 8 hours.
5. The synthesis process as described in claims 1-4, the acidic reagent (V) in step b is hydrochloric acid, acetic acid, sulfuric acid.
6. The synthesis as described in claims 1 to 5, wherein in step b an acidic reagent (V) is added to adjust the pH to 2-6.