阅读说明：本技术 一种氨磺必利的制备方法 (Preparation method of amisulpride ) 是由 金鹏 于 2021-07-28 设计创作，主要内容包括：本发明公开了一种氨磺必利的制备方法,包括以下步骤：4-氨基-2-甲氧基-5-乙基磺酰基苯甲酸甲酯和N-乙基-2-氨甲基吡咯在70～90℃下进行酯交换反应,边反应边蒸馏出甲醇；当甲醇不再蒸馏出来时,停止反应,进行减压蒸馏,得到氨磺必利粗品,进行重结晶,得到氨磺必利。该制备方法生产成本低,工艺简单,制备过程中不生产废水,对环境友好。应用本发明的制备方法来生产氨磺必利,副反应少,杂质量少,产品收率高,摩尔收率达到95％以上,所得的氨磺必利的纯度高。(The invention discloses a preparation method of amisulpride, which comprises the following steps: carrying out ester exchange reaction on 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate and N-ethyl-2-aminomethyl pyrrole at 70-90 ℃, and distilling out methanol while carrying out the reaction; when methanol is not distilled out any more, the reaction is stopped, reduced pressure distillation is carried out to obtain crude amisulpride, and recrystallization is carried out to obtain amisulpride. The preparation method has the advantages of low production cost, simple process, no production of wastewater in the preparation process and environmental friendliness. The amisulpride produced by the preparation method has the advantages of less side reaction, less impurity amount, high product yield, molar yield of more than 95 percent and high purity of the amisulpride.)

1. A preparation method of amisulpride is characterized by comprising the following steps: carrying out ester exchange reaction on 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate and N-ethyl-2-aminomethyl pyrrole at 70-90 ℃, and distilling out methanol while carrying out the reaction; then carrying out reduced pressure distillation to obtain a crude amisulpride product, and carrying out recrystallization to obtain amisulpride;

the specific synthetic route is as follows:

2. the method for producing amisulpride according to claim 1, wherein the temperature of the reduced pressure distillation is 60 to 70 ℃.

3. The method for producing amisulpride according to claim 1 or 2, wherein the reduced pressure distillation is performed at a pressure of 3 to 5 mmHg.

4. A process for the preparation of amisulpride according to claim 1, wherein the step of recrystallizing is: adding acetone into the amisulpride crude product to prepare a saturated solution, cooling, crystallizing, carrying out suction filtration to obtain a solid, washing with water, and drying to obtain amisulpride.

5. The method for preparing amisulpride according to claim 4, wherein the temperature of the cooling crystallization is 10 to 20 ℃.

6. The method for preparing amisulpride according to claim 4, wherein the drying temperature is 50 to 60 ℃.

7. The method for producing amisulpride according to claim 1, wherein the mass ratio of the methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to the N-ethyl-2-aminomethylpyrrole is 1: 4 to 5.

8. A process for the preparation of amisulpride according to claim 1, wherein water is further added as a solvent for N-ethyl-2-aminomethylpyrrole in the transesterification reaction.

9. The method for producing amisulpride according to claim 8, wherein the mass ratio of the methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to the N-ethyl-2-aminomethylpyrrole is 1: 1 to 2.

10. The method for preparing amisulpride according to claim 8, wherein the mass ratio of the N-ethyl-2-aminomethylpyrrole to the water is 2 to 2.5: 1.

Technical Field

The invention relates to the field of synthesis and preparation of chemical and chemical bulk drugs, in particular to a method for preparing amisulpride.

Background

Amisulpride tablets are used for the treatment of acute or chronic schizophrenia, mainly with positive symptoms (e.g. delirium hallucinogenic cognitive impairment) and/or negative symptoms (e.g. delayed apathy and social withdrawal), including schizophrenia characterized by negative symptoms. The chemical name is as follows: 4-amino-N- [ (1-ethyl-2-pyrrolidine) methyl ] -5-ethylsulfonyl-2-methoxybenzamide. The specific structural formula is as follows:

chinese patent CN103819383A discloses a synthetic method of amisulpride, which comprises the following steps: step a: esterifying 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid (amioic acid) and lower alcohol under catalysis of thionyl chloride to obtain 4-amino-2-methoxy-5-ethylsulfonyl benzoate (A-4); step b: condensing the 4-amino-2-methoxy-5-ethylsulfonyl benzoate (A-4) obtained in the step a with N-ethyl-2-aminomethyl pyrrole to obtain amisulpride. The patent uses expensive amiric acid as a raw material, and the amiric acid and alcohol are catalyzed by corrosive thionyl chloride to obtain ester. Then isopropanol or acetonitrile is used as a solvent to obtain amisulpride. The patent has high cost for producing amisulpride, and the thionyl chloride easily causes pollution to the environment and has bad production conditions.

Chinese patent CN112624951A relates to a method for preparing amisulpride, which comprises the following steps: under the condition of taking organic base as a catalyst, carrying out condensation reaction on 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate (A-4), N-ethyl-2-aminomethyl pyrrolidine and a solvent at 50-100 ℃, concentrating a reaction solution to remove the solvent after the reaction is finished, filtering and drying to obtain amisulpride; wherein the organic base is sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium tert-butoxide or sodium tert-butoxide. The solvent is a common recyclable solvent, the yield is more than 90%, the purity can reach 99.7%, the single impurity content is less than 0.1%, the requirement of a medicinal preparation is met, and the method is suitable for industrial production. Because strong alkali sodium alkoxide, potassium alkoxide and the like are used as catalysts, neutralization treatment is needed after reaction; the patent also uses a solvent, needs to be recovered, has a complex process, is not easy to operate in industrial production, needs wastewater treatment and has high cost.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide the preparation method of amisulpride, which does not need to add a catalyst and a solvent, has low production cost and simple process, reduces the cost, does not need a neutralization extraction step, improves the yield, does not generate wastewater in the preparation process, and is environment-friendly.

The purpose of the invention is realized by adopting the following technical scheme:

a method for preparing amisulpride, comprising the following steps: carrying out ester exchange reaction on 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate and N-ethyl-2-aminomethyl pyrrole at 70-90 ℃, and distilling out methanol while carrying out the reaction; stopping the reaction when the methanol is not distilled out any more, carrying out reduced pressure distillation to obtain a crude amisulpride product, and carrying out recrystallization to obtain amisulpride;

the specific synthetic route is as follows:

further, the temperature of the reduced pressure distillation is 60-70 ℃.

Further, the reduced pressure distillation is carried out under a pressure of 3-5 mmHg.

Further, the step of recrystallizing is: adding acetone into the amisulpride crude product to prepare a saturated solution, cooling, crystallizing, carrying out suction filtration to obtain a solid, washing with water, and drying to obtain amisulpride. Wherein the temperature of the cooling crystallization is 10-20 ℃. The drying temperature is 50-60 ℃.

Further, the mass ratio of the methyl 4-amino-2-methoxy-5-ethylsulfonyl benzoate to the N-ethyl-2-aminomethyl pyrrole is 1: 4 to 5.

Still further, in the transesterification, water is added as a solvent for N-ethyl-2-aminomethylpyrrole. Wherein the mass ratio of the 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate to the N-ethyl-2-aminomethyl pyrrole is 1: 1 to 2. The mass ratio of the N-ethyl-2-aminomethyl pyrrole to the water is 2-2.5: 1.

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

(1) the invention adopts 4-amino-2-methoxy-5-ethyl sulfonyl methyl benzoate as a raw material to directly carry out ester exchange reaction with N-ethyl-2-aminomethyl pyrrole without adding a catalyst and an organic solvent (the organic solvent used for the ester exchange reaction in the prior art is basically toxic), can obtain amisulpride, and has the advantages of low production cost, simple process, no production of wastewater in the preparation process and environmental friendliness. The amisulpride produced by the preparation method has the advantages of less side reaction, less impurity amount, high product yield, more than 95 percent of molar yield and capability of obtaining the purity of the amisulpride meeting the requirements of pharmacopoeia only by one-time recrystallization.

(2) In the preparation method of amisulpride, N-ethyl-2-aminomethyl pyrrole recovered by reduced pressure distillation can be applied to the next reaction.

(3) In the preparation method of amisulpride, the component for carrying out the ester exchange reaction also comprises water, the water is used as a solvent of the N-ethyl-2-aminomethyl pyrrole, if no water is added, the excessive N-ethyl-2-aminomethyl pyrrole is required to react with the 4-amino-2-methoxy-5-ethyl sulfonyl methyl benzoate, the 4-amino-2-methoxy-5-ethyl sulfonyl methyl benzoate is ensured to be completely reacted, and if the water is added, the adding amount of the N-ethyl-2-aminomethyl pyrrole can be reduced.

Detailed Description

The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment.

The invention provides a preparation method of amisulpride, which comprises the following specific synthetic route:

the principle is as follows: 4-amino-2-methoxy-5-ethyl sulfonyl methyl benzoate (A-4) is adopted as a raw material to directly carry out ester exchange reaction with N-ethyl-2-aminomethyl pyrrole to obtain the amisulpride. The method can be divided into two methods of ester exchange reaction without adding water and with adding water, and comprises the following steps:

(without adding water) method one: adding 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate (A-4) and N-ethyl-2-aminomethyl pyrrole into a normal pressure distillation device, and carrying out ester exchange reaction at 70-90 ℃ while distilling methanol. When the methanol fraction is no longer distilled off, the reaction is stopped, and the excess N-ethyl-2-aminomethylpyrrole is distilled off under reduced pressure at a pressure of 3-5mmHg at 60-70 ℃. The N-ethyl-2-aminomethyl pyrrole recovered by reduced pressure distillation can be used for the next reaction. And (3) obtaining a crude amisulpride product in a distillation flask, adding acetone to prepare a saturated solution, and recrystallizing to obtain the amisulpride product. Wherein the mass ratio of the 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate to the N-ethyl-2-aminomethyl pyrrole is 1: 4 to 5.

(Water addition) method II: adding 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate (A-4), water and N-ethyl-2-aminomethyl pyrrole into a normal pressure distillation device, and carrying out ester exchange reaction at 70-90 ℃ while distilling methanol. When the methanol fraction is no longer distilled off, the reaction is stopped. And (3) performing reduced pressure distillation, namely distilling out water and excessive N-ethyl-2-aminomethyl pyrrole under the pressure of 3-5mmHg at the temperature of 60-70 ℃ under reduced pressure. The N-ethyl-2-aminomethyl pyrrole aqueous solution recovered by reduced pressure distillation can be used for the next reaction. And (3) obtaining a crude amisulpride product in a distillation flask, adding acetone to prepare a saturated solution, and recrystallizing to obtain the amisulpride product. Wherein the mass ratio of the 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate to the N-ethyl-2-aminomethyl pyrrole is 1: 1 to 2. The mass ratio of the N-ethyl-2-aminomethyl pyrrole to the water is 2-2.5: 1.

example 1

In a 5L three-necked flask, 500g of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate (A-4) was added, 2000g of N-ethyl-2-aminomethylpyrrole (the mass ratio of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to N-ethyl-2-aminomethylpyrrole was 1: 4) was added, and an atmospheric distillation apparatus was equipped at the outlet. The transesterification was carried out at 80 ℃ while distilling off methanol. After 10 hours, the reaction was stopped when the methanol fraction was no longer distilled off. Then, the excess N-ethyl-2-aminomethyl pyrrole was distilled off under reduced pressure at 60 ℃ under 3 mmHg. The N-ethyl-2-aminomethyl pyrrole recovered by reduced pressure distillation can be used for the next reaction. After reduced pressure distillation, a crude amisulpride product is obtained in a three-neck flask, 2000g of acetone is added to obtain a solution, and then recrystallization operation is carried out, wherein the method specifically comprises the following steps: firstly, cooling and crystallizing the solution at 10 ℃, carrying out suction filtration to obtain a solid, washing the solid with water for three times, and carrying out vacuum drying at 50 ℃ to obtain 650g of amisulpride product, wherein the yield is as follows: 96.2 percent. HPLC analysis, purity: 99.85 percent and less than 0.1 percent of single impurity.

Example 2

10Kg of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate (A-4) and 50Kg of N-ethyl-2-aminomethylpyrrole (the mass ratio of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to N-ethyl-2-aminomethylpyrrole is 1: 5) were put into a 100L stainless steel reaction vessel, and the ester exchange reaction was carried out at 70 ℃ while distilling off methanol. After 12 hours, the reaction was stopped when the methanol fraction was no longer distilled off. The excess N-ethyl-2-aminomethylpyrrole is distilled off under reduced pressure at 70 ℃ and a pressure of 5 mmHg. The N-ethyl-2-aminomethyl pyrrole recovered by reduced pressure distillation can be used for the next reaction. Obtaining a crude product of amisulpride in the reaction kettle after reduced pressure distillation, adding 40kg of acetone to obtain a solution, and then performing recrystallization operation, wherein the method specifically comprises the following steps: cooling and crystallizing the solution at 20 ℃, performing suction filtration to obtain a solid, washing the solid with water for three times, and performing vacuum drying at 60 ℃ to obtain 13.2g of amisulpride product, wherein the yield is as follows: 97.1 percent. HPLC analysis, purity: 99.9 percent and less than 0.1 percent of single impurity.

Example 3

In a 5L three-necked flask, 500g of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate (A-4), 1000g of N-ethyl-2-aminomethylpyrrole (the mass ratio of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to N-ethyl-2-aminomethylpyrrole is 1: 2) and 3000g of purified water were added, and an outlet was equipped with an atmospheric distillation apparatus. The transesterification was carried out at 90 ℃ while distilling off methanol. After 8 hours, the reaction was stopped when the methanol fraction was no longer distilled off. And (3) replacing reduced pressure distillation, and distilling out excessive N-ethyl-2-aminomethyl pyrrole aqueous solution under the reduced pressure of 4mmHg and the temperature of 65 ℃. The N-ethyl-2-aminomethyl pyrrole aqueous solution recovered by reduced pressure distillation can be used for the next reaction. Obtaining a crude product of amisulpride in a three-neck flask after reduced pressure distillation, adding 2500g of acetone to obtain a solution, and then performing recrystallization operation, wherein the method specifically comprises the following steps: cooling and crystallizing the solution at 15 ℃, performing suction filtration to obtain a solid, washing the solid with water for three times, and performing vacuum drying at 55 ℃ to obtain 642g of amisulpride product, wherein the yield is as follows: 95.1 percent. HPLC analysis, purity: 99.88 percent and less than 0.1 percent of single impurity.

The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.