Preparation method of amisulpride

Abstract

The invention discloses a preparation method of amisulpride, and belongs to the technical field of preparation of anti-schizophrenia drugs. Comprising the following steps: mixing 2-methoxy-4-amino-5-ethyl sulfonyl benzoic acid, 9-fluorenylmethoxycarbonyl chloride and an alkaline solution to form a reaction solution, and sequentially carrying out low-temperature reaction and heating reaction on the reaction solution to obtain Fmoc-2-methoxy-4-amino-5-ethyl sulfonyl benzoic acid; the preparation method comprises the following steps: mixing N-ethyl-2-aminomethylpyrrole, an organic mixed solvent, a dehydration condensation agent and Fmoc-2-methoxy-4-amino-5-ethylsulfonyl benzoic acid, and reacting to obtain Fmoc-amisulpride; the Fmoc-amisulpride and diethylamine are mixed and subjected to a reaction, and the amisulpride is obtained. Another new synthesis path of amisulpride is innovatively designed, and meanwhile, the amisulpride has good yield performance.

Description

Technical Field

[0001] The invention belongs to the technical field of anti-schizophrenia drug preparation, and particularly relates to a method for preparing amisulpride. Background Art

[0002] Schizophrenia is a serious mental disorder characterized by disordered thinking, emotions, and behaviors. Patients often show symptoms such as hallucinations, delusions, or reduced social function, which seriously affect their daily life and social interaction. The disease is more common in adolescents and young adults. The etiology of schizophrenia is complex, involving multiple factors such as genetics, environment, and neurobiology. Antipsychotic drugs are mainly divided into two categories: typical antipsychotics (first-generation drugs) and atypical antipsychotics (second-generation drugs). Typical antipsychotics such as chlorpromazine and haloperidol mainly work by blocking dopamine receptors. Although they can effectively relieve positive symptoms, they often cause more serious side effects, such as extrapyramidal reactions and tardive dyskinesia. Atypical antipsychotics such as amisulpride, olanzapine, quetiapine, etc., in addition to antagonizing dopamine receptors, also have a certain antagonistic effect on 5-hydroxytryptamine receptors, which can improve negative symptoms and cognitive function, and have relatively few side effects.

[0003] Amisulpride is also called Amisulpride, with the trade name of Solyon, the chemical name of which is 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide, and the molecular formula is C 17 H 27N3O4S. Amisulpride belongs to the benzamide class of neuroleptic drugs, which can selectively bind to the DA2 and DA3 dopamine receptors of the limbic system, but not to the serotonergic receptors or other histamine, cholinergic receptors, and adrenergic receptors. The synthesis methods of amisulpride recorded in the prior art mainly include the following: (1) using 4-amino-2-methoxy-5-mercaptobenzoic acid as a raw material, reacting it with diethyl sulfate under alkaline conditions to obtain 4-amino-2-methoxy-5-ethylthiobenzoic acid, and then oxidizing it with oxyacetic acid to obtain 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid, and finally reacting it with N-ethyl-2-aminomethylpyrrole under the action of an organic base and ethyl chloroformate to obtain amisulpride; (2) using 4-acetylamino-2-methoxybenzoic acid methyl ester as a raw material, sulfonating it with concentrated sulfuric acid to obtain 3-methoxyformyl-6-acetylamino-4-methoxybenzenesulfonic acid, and then successively hydrolyzing it, chlorinating it with phosphorus pentachloride, reducing it with sodium sulfite and ethyl bromide. (3) Using 4-amino-2-methoxybenzoic acid as the raw material, chlorosulfonic acid is used to catalyze the reaction to obtain 4-amino-5-chlorosulfonyl-2-methoxybenzoic acid, which is then reduced with stannous chloride and hydrochloric acid and reacted with diethyl sulfate in the presence of sodium hydroxide to obtain 4-amino-5-ethylthio-2-methoxybenzoic acid, which is then oxidized with peracetic acid to obtain 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid, which is then reacted with N-ethyl-2-aminomethylpyrrole in the presence of an organic base and ethyl chloroformate to obtain amisulpride. Since 4-amino-2-methoxy-5-mercaptobenzoic acid, 4-acetylamino-2-methoxybenzoic acid methyl ester and 4-amino-2-methoxybenzoic acid are not easy to purchase, other synthetic routes have been developed in the prior art.

[0004] Patent CN110577482A discloses a method for preparing amisulpride, which uses 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid and thionyl chloride as raw materials, obtains 2-methoxy-4-amino-5-ethylsulfonylbenzoyl chloride through acylation reaction, and then obtains amisulpride through amidation reaction with N-ethyl-2-aminomethylpyrrolidine. However, since the primary amine on 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid is also easy to react with thionyl chloride, thionyl chloride is consumed and by-products are increased, resulting in a low total yield of amisulpride.

[0005] Patent CN112624951A discloses a method for preparing amisulpride. In the invention, 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester, N-ethyl-2-aminomethylpyrrolidine and a solvent are subjected to a condensation reaction under specific temperature conditions with an organic base as a catalyst to obtain amisulpride.

[0006] Patent CN113735755A discloses a method for preparing amisulpride. The invention uses 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester and N-ethyl-2-aminomethylpyrrole as raw materials, performs an ester exchange reaction at a specific temperature, and distills out methanol during the reaction; when methanol no longer distills out, stops the reaction, performs reduced pressure distillation, and obtains amisulpride.

[0007] The new atypical antipsychotic drug amisulpride is used to treat acute or chronic schizophrenia with mainly positive or negative symptoms. It has good tolerability and clinical efficacy, and has obvious advantages over typical antipsychotic drugs. It has become the first-line drug for anti-schizophrenia. Therefore, the development of a new synthetic route for amisulpride will not only help expand new means of amisulpride synthesis, but also reduce the cost of enterprises using the patented amisulpride synthetic route. Summary of the invention

[0008] In view of the deficiencies of the prior art, the present invention uses 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid as a raw material, reacts with 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) to obtain Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, and Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid and N-ethyl-2-aminomethylpyrrole are amidated and condensed under the catalysis of a dehydration condensation agent to obtain Fmoc-amisulpride, and finally the Fmoc protecting group is deprotected in an alkaline environment at room temperature to obtain amisulpride. Specifically, the technical solution of the present invention includes the following contents: A method for preparing amisulpride, comprising the following steps: 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, 9-fluorenylmethoxycarbonyl chloride and an alkaline solution are mixed to form a reaction solution, the reaction solution is reacted at -2°C to 0°C for 50min to 60min and at 25°C±1°C for 4h to 6h in sequence, and after the reaction is completed, Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid is obtained by extraction and separation; N-ethyl-2-aminomethylpyrrole, an organic mixed solvent, a dehydration condensation agent and the Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid are mixed and reacted at 25° C.±2° C. for 10 h to 15 h to obtain Fmoc-amisulpride; The Fmoc-amisulpride and diethylamine are mixed and deprotected at 25°C±2°C for 1h~2h to obtain the amisulpride.

[0009] Furthermore, the synthetic route of the preparation method of amisulpride is as follows:

[0010] Furthermore, the alkaline solution includes a sodium carbonate solution with a mass concentration of 10% or a potassium carbonate solution with a mass concentration of 10%.

[0011] Furthermore, the mass ratio of the 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid:9-fluorenylmethoxycarbonyl chloride:alkaline solution is 1:1-1.25:5-10.

[0012] Furthermore, the organic mixed solvent is composed of dimethyl sulfoxide and dichloromethane mixed in a mass ratio of 1:1.

[0013] Furthermore, the dehydration condensation agent is composed of N,N'-diisopropylcarbodiimide and 1-hydroxybenzotriazole in a mass ratio of 1:1.

[0014] Furthermore, the mass ratio of the N-ethyl-2-aminomethylpyrrole: the organic mixed solvent: the dehydration condensation agent: the Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid is 0.4-0.5:10-15:0.8-1:1.

[0015] Furthermore, the mass ratio of Fmoc-amisulpride:diethylamine is 1:10-15.

[0016] Compared with the prior art, the present invention has the following beneficial effects: The present invention innovatively develops a method of using 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid as a raw material and 9-fluorenylmethoxycarbonyl chloride (Fmoc-Cl) as a protecting group to protect the amino group on its structure to obtain Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, then using a dehydrating condensation agent to activate the carboxyl group on Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, and then performing amidation condensation with the amino group on N-ethyl-2-aminomethylpyrrole to obtain Fmoc-amisulpride, and finally deprotecting the Fmoc protecting group in an alkaline environment to obtain amisulpride. Fmoc protection of the amino group on 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid can effectively reduce the condensation esterification of the carboxyl group and the amino group on its own structure during the amidation reaction, thereby reducing the occurrence of side reactions. Moreover, the Fmoc protecting group is sensitive to alkali and can be quickly removed by alkali treatment in a room temperature environment, while the alkali treatment in a room temperature environment is difficult to hydrolyze the amide bond obtained by amidation condensation. The amide bond is easily hydrolyzed in an acidic environment, but in an alkaline environment, high alkalinity and high temperature are required to be maintained to easily hydrolyze, thereby reducing the possibility of the amide bond being hydrolyzed to generate by-products. By reducing the esterification condensation of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid itself and maintaining the alkali treatment at room temperature to remove the Fmoc protecting group, not only a new synthesis route of amisulpride is developed, but also the yield of amisulpride is improved. DETAILED DESCRIPTION

[0017] The technical solution of the present invention will be clearly and completely described below through the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0018] Unless otherwise specified, the raw materials and reagents used in the present invention are commercially available or can be prepared by known methods.

[0019] Embodiment 1: A method for preparing amisulpride specifically comprises the following process: Weigh 20g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, dissolve it in 100g of potassium carbonate with a mass concentration of 10%, stir it evenly, and then cool it to -2~0℃ for storage. Take 20g of 9-fluorenylmethoxycarbonyl chloride and dissolve it in 60g of acetone, then add it dropwise to the -2~0℃ 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid solution and mix and stir evenly to form a reaction solution, stir the reaction solution at a stirring speed of 100r / min and control the stirring reaction in a 0℃ environment for 50min, then heat it to 25±1℃ and continue stirring the reaction for 4h. After the reaction is completed, add 400g of deionized water, then extract it with ether to obtain an organic layer, then add hydrochloric acid solution to the organic layer to adjust the pH to 3~4, precipitate solids, collect the solids by filtration and rinse with water, then reduce the pressure and dry to remove water and extractant to obtain Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid; Take 10g of Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid and dissolve it in 100g of organic mixed solvent (composed of 50g of dimethyl sulfoxide and 50g of dichloromethane), add 4g of N,N'-diisopropylcarbodiimide and 4g of 1-hydroxybenzotriazole, stir evenly, activate at room temperature for 20min, then add 4g of N-ethyl-2-aminomethylpyrrole, stir evenly to obtain a reaction solution, and place the reaction solution in a water bath at 25±2℃ to react for 10h. After the reaction is completed, the system after the reaction is dialyzed with a dialysis bag with a molecular weight cutoff of 500kDa, and then dried to obtain Fmoc-amisulpride, which weighs 12.14g on an electronic balance; 12.14g of dried Fmoc-amisulpride was dispersed in 100g of anhydrous ethanol, and then 121.4g of diethylamine was added and stirred at a temperature of 25±2℃ for 1h. After stirring, it was placed in a rotary evaporator for rotary evaporation separation and purification to obtain amisulpride, which was weighed by an electronic balance at 7.37 and the calculated yield (based on Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid) was 97.36%; the melting point was measured by a micro melting point instrument at 125.3℃; the purity was detected by high performance liquid chromatography (chromatographic column: C18, mobile phase: methanol-0.25% sulfuric acid containing 0.7g / L sodium octane sulfonate <25:75>, flow rate: 1.5ml / min, column temperature: 40℃, detection wavelength: 225nm, injection volume: 20μL) and the purity was 98.45%.

[0020] Embodiment 2: A method for preparing amisulpride specifically comprises the following process: Weigh 20g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, dissolve and disperse in 120g of potassium carbonate with a mass concentration of 10%, stir evenly, and then cool to -2~0℃ for storage. Take 21g of 9-fluorenylmethoxycarbonyl chloride and dissolve it in 63g of acetone, then add it dropwise to the -2~0℃ 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid solution and mix and stir evenly to form a reaction solution, stir the reaction solution at a stirring speed of 100r / min and control the stirring reaction in a 0℃ environment for 50min, then heat it to 25±1℃ and continue stirring the reaction for 4h. After the reaction is completed, add 400g of deionized water, then extract with ether to obtain an organic layer, then add hydrochloric acid solution to the organic layer to adjust the pH to 3~4, precipitate solids, collect solids by filtration and rinse with water, then reduce the pressure and dry to remove water and extractant to obtain Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid; Take 10g of Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid and dissolve it in 110g of organic mixed solvent (composed of 55g of dimethyl sulfoxide and 55g of dichloromethane), add 4g of N,N'-diisopropylcarbodiimide and 4g of 1-hydroxybenzotriazole, stir evenly, activate at room temperature for 20min, then add 4.2g of N-ethyl-2-aminomethylpyrrole, stir evenly to obtain a reaction solution, and place the reaction solution in a water bath at 25±2℃ to react for 11h. After the reaction is completed, the system after the reaction is dialyzed with a dialysis bag with a molecular weight cutoff of 500kDa, and then dried to obtain Fmoc-amisulpride, which is weighed 12.17g on an electronic balance; 12.17g of dried Fmoc-amisulpride was dispersed in 100g of anhydrous ethanol, and then 121.7g of diethylamine was added and stirred at a temperature of 25±2℃ for 1h. After stirring, it was placed in a rotary evaporator for rotary evaporation separation and purification to obtain amisulpride, which was weighed by an electronic balance at 7.42 and the calculated yield (based on Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid) was 97.76%; the melting point was measured by a micro melting point instrument at 125.1℃; the purity was detected by high performance liquid chromatography (chromatographic column: C18, mobile phase: methanol-0.25% sulfuric acid containing 0.7g / L sodium octane sulfonate <25:75>, flow rate: 1.5ml / min, column temperature: 40℃, detection wavelength: 225nm, injection volume: 20μL) and the purity was 98.57%.

[0021] Embodiment 3: A method for preparing amisulpride specifically comprises the following process: Weigh 20g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, dissolve and disperse in 140g of potassium carbonate with a mass concentration of 10%, stir evenly, and then cool to -2~0℃ for storage. Take 22g of 9-fluorenylmethoxycarbonyl chloride, dissolve it in 66g of acetone, and then drop it into the -2~0℃ 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid solution, mix and stir evenly to form a reaction solution, stir the reaction solution at a stirring speed of 150r / min and control the stirring reaction in a -1℃ environment for 55min, then heat it to 25±1℃ and continue stirring the reaction for 5h. After the reaction is completed, add 500g of deionized water, then extract with ether to obtain an organic layer, then drop hydrochloric acid solution into the organic layer to adjust the pH to 3~4, precipitate solids, collect the solids by filtration and rinse with water, then reduce the pressure and dry to remove water and extractant to obtain Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid; Take 10g of Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid and dissolve it in 120g of organic mixed solvent (60g of dimethyl sulfoxide and 60g of dichloromethane), add 4.5g of N,N'-diisopropylcarbodiimide and 4.5g of 1-hydroxybenzotriazole, stir evenly, activate at room temperature for 25min, then add 4.4g of N-ethyl-2-aminomethylpyrrole, stir evenly to obtain a reaction solution, and place the reaction solution in a water bath at 25±2℃ to react for 12h. After the reaction is completed, the system after the reaction is dialyzed with a dialysis bag with a molecular weight cutoff of 500kDa, and then dried to obtain Fmoc-amisulpride, which is weighed 12.18g on an electronic balance; 12.18g of dried Fmoc-amisulpride was dispersed in 100g of anhydrous ethanol, and then 146.16g of diethylamine was added and stirred at a temperature of 25±2℃ for 1h. After stirring, it was placed in a rotary evaporator for rotary evaporation separation and purification to obtain amisulpride, which was weighed by an electronic balance and weighed 7.45g. The calculated yield (based on Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid) was 98.16%; the melting point was measured by a micro melting point instrument and was 126.7℃; the purity was detected by high performance liquid chromatography (chromatographic column: C18, mobile phase: methanol-0.25% sulfuric acid containing 0.7g / L sodium octane sulfonate <25:75>, flow rate: 1.5ml / min, column temperature: 40℃, detection wavelength: 225nm, injection volume: 20μL) and the purity was 98.79%.

[0022] Embodiment 4: A method for preparing amisulpride specifically comprises the following process: Weigh 20g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, dissolve and disperse in 160g of sodium carbonate with a mass concentration of 10%, stir evenly, and then cool to -2~0℃ for storage. Take 23g of 9-fluorenylmethoxycarbonyl chloride and dissolve it in 69g of acetone, then add it dropwise to the -2~0℃ 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid solution and mix and stir evenly to form a reaction solution, stir the reaction solution at a stirring speed of 150r / min and control the stirring reaction in a -1℃ environment for 55min, then heat to 25±1℃ and continue stirring the reaction for 5h. After the reaction is completed, add 500g of deionized water, then extract with ether to obtain an organic layer, then add hydrochloric acid solution to the organic layer to adjust the pH to 3~4, precipitate solids, collect the solids by filtration and rinse with water, then reduce the pressure and dry to remove water and extractant to obtain Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid; Take 10g of Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid and dissolve it in 130g of organic mixed solvent (65g of dimethyl sulfoxide and 65g of dichloromethane), add 4.5g of N,N'-diisopropylcarbodiimide and 4.5g of 1-hydroxybenzotriazole, stir evenly, activate at room temperature for 25min, then add 4.6g of N-ethyl-2-aminomethylpyrrole, stir evenly to obtain a reaction solution, and place the reaction solution in a water bath at 25±2℃ to react for 13h. After the reaction is completed, the system after the reaction is dialyzed with a dialysis bag with a molecular weight cutoff of 500kDa, and then dried to obtain Fmoc-amisulpride, which weighs 12.20g on an electronic balance; 12.20g of dried Fmoc-amisulpride was dispersed in 200g of anhydrous ethanol, and then 146.4g of diethylamine was added and stirred for 2h at a temperature of 25±2℃. After stirring, it was placed in a rotary evaporator for rotary evaporation separation and purification to obtain amisulpride, which was weighed by an electronic balance at 7.51 and the calculated yield (based on Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid) was 98.82%; the melting point was measured by a micro melting point instrument at 126.5℃; the purity was detected by high performance liquid chromatography (chromatographic column: C18, mobile phase: methanol-0.25% sulfuric acid containing 0.7g / L sodium octane sulfonate <25:75>, flow rate: 1.5ml / min, column temperature: 40℃, detection wavelength: 225nm, injection volume: 20μL) and the purity was 99.02%.

[0023] Embodiment 5: A method for preparing amisulpride specifically comprises the following process: Weigh 20g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, dissolve and disperse in 180g of sodium carbonate with a mass concentration of 10%, stir evenly, and then cool to -2~0℃ for storage. Take 24g of 9-fluorenylmethoxycarbonyl chloride, dissolve it in 72g of acetone, and then drop it into the -2~0℃ 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid solution, mix and stir evenly to form a reaction solution, stir the reaction solution at a stirring speed of 200r / min and control the stirring reaction in a -2℃ environment for 60min, then heat it to 25±1℃ and continue stirring the reaction for 6h. After the reaction is completed, add 600g of deionized water, then extract with ether to obtain an organic layer, then drop hydrochloric acid solution into the organic layer to adjust the pH to 3~4, precipitate solids, filter and collect solids and rinse with water, then reduce pressure and dry to remove water and extractant to obtain Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid; Take 10g of Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid and dissolve it in 140g of organic mixed solvent (composed of 70g of dimethyl sulfoxide and 70g of dichloromethane), add 5g of N,N'-diisopropylcarbodiimide and 5g of 1-hydroxybenzotriazole, stir evenly, activate at room temperature for 30min, then add 4.8g of N-ethyl-2-aminomethylpyrrole, stir evenly to obtain a reaction solution, and place the reaction solution in a water bath at 25±2℃ to react for 14h. After the reaction is completed, the system after the reaction is dialyzed with a dialysis bag with a molecular weight cutoff of 500kDa, and then dried to obtain Fmoc-amisulpride, which is weighed 12.23g on an electronic balance; 12.23g of dried Fmoc-amisulpride was dispersed in 200g of anhydrous ethanol, and then 183.45g of diethylamine was added and stirred for 2h at a temperature of 25±2℃. After stirring, it was placed in a rotary evaporator for rotary evaporation separation and purification to obtain amisulpride, which was weighed by an electronic balance to be 7.55g, and the calculated yield (based on Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid) was 99.08%; the melting point was measured by a micro melting point instrument to be 126.2℃; the purity was detected by high performance liquid chromatography (chromatographic column: C18, mobile phase: methanol-0.25% sulfuric acid containing 0.7g / L sodium octane sulfonate <25:75>, flow rate: 1.5ml / min, column temperature: 40℃, detection wavelength: 225nm, injection volume: 20μL) and the purity was 99.31%.

[0024] Embodiment 6: A method for preparing amisulpride specifically comprises the following process: Weigh 20g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, dissolve it in 200g of sodium carbonate with a mass concentration of 10%, stir it evenly, and then cool it to -2~0℃ for storage. Take 25g of 9-fluorenylmethoxycarbonyl chloride, dissolve it in 75g of acetone, and then drop it into the -2~0℃ 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid solution, mix and stir evenly to form a reaction solution, stir the reaction solution at a stirring speed of 200r / min and control the stirring reaction in a -2℃ environment for 60min, then heat it to 25±1℃ and continue stirring the reaction for 6h. After the reaction is completed, add 600g of deionized water, then extract it with ether to obtain an organic layer, then drop hydrochloric acid solution into the organic layer to adjust the pH to 3~4, precipitate solids, collect solids by filtration and rinse with water, then reduce the pressure and dry to remove water and extractant to obtain Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid; Take 10g of Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid and dissolve it in 150g of organic mixed solvent (composed of 75g of dimethyl sulfoxide and 75g of dichloromethane), add 5g of N,N'-diisopropylcarbodiimide and 5g of 1-hydroxybenzotriazole, stir evenly, activate at room temperature for 30min, then add 5g of N-ethyl-2-aminomethylpyrrole, stir evenly to obtain a reaction solution, and place the reaction solution in a water bath at 25±2℃ to react for 15h. After the reaction is completed, the system after the reaction is dialyzed with a dialysis bag with a molecular weight cutoff of 500kDa, and then dried to obtain Fmoc-amisulpride, which weighs 12.21g on an electronic balance; 12.21g of dried Fmoc-amisulpride was dispersed in 200g of anhydrous ethanol, and then 183.15g of diethylamine was added and stirred for 2h at a temperature of 25±2℃. After stirring, it was placed in a rotary evaporator for rotary evaporation separation and purification to obtain amisulpride, which was weighed by an electronic balance at 7.52 and had a calculated yield (based on Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid) of 98.82%; the melting point was measured at 125.8℃ by a microscopic melting point instrument; and the purity was detected by high performance liquid chromatography (chromatographic column: C18, mobile phase: methanol-0.25% sulfuric acid containing 0.7g / L sodium octane sulfonate <25:75>, flow rate: 1.5ml / min, column temperature: 40℃, detection wavelength: 225nm, injection volume: 20μL) and was 99.18%.

[0025] The above-described embodiments provide a detailed description of the technical solutions and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected.

Claims

1. A method for preparing amisulpride, characterized in that, The preparation method comprises the following steps: 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, 9-fluorenylmethoxycarbonyl chloride and an alkaline solution are mixed to form a reaction solution, the reaction solution is reacted at -2°C to 0°C for 50min to 60min and at 25°C±1°C for 4h to 6h in sequence, and after the reaction is completed, Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid is obtained by extraction and separation; N-ethyl-2-aminomethylpyrrole, an organic mixed solvent, a dehydration condensation agent and the Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid are mixed and reacted at 25° C.±2° C. for 10 h to 15 h to obtain Fmoc-amisulpride; The Fmoc-amisulpride and diethylamine are mixed and deprotected at 25° C.±2° C. for 1 h to 2 h to obtain the amisulpride.

2. A method for preparing amisulpride according to claim 1, characterized in that, The alkaline solution includes a sodium carbonate solution with a mass concentration of 10% or a potassium carbonate solution with a mass concentration of 10%.

3. A method for preparing amisulpride according to claim 1, characterized in that, The mass ratio of the 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid:9-fluorenylmethoxycarbonyl chloride:alkaline solution is 1:1-1.25:5-10.

4. A method for preparing amisulpride according to claim 1, characterized in that, The organic mixed solvent is composed of dimethyl sulfoxide and dichloromethane mixed in a mass ratio of 1:

1.

5. A method for preparing amisulpride according to claim 1, characterized in that, The dehydration condensation agent is composed of N,N'-diisopropylcarbodiimide and 1-hydroxybenzotriazole in a mass ratio of 1:

1.

6. A method for preparing amisulpride according to claim 1, characterized in that, The mass ratio of the N-ethyl-2-aminomethylpyrrole: the organic mixed solvent: the dehydration condensation agent: the Fmoc-2-methoxy-4-amino-5-ethylsulfonylbenzoic acid is 0.4-0.5:10-15:0.8-1:

1.

7. A method for preparing amisulpride according to claim 1, characterized in that, The mass ratio of Fmoc-amisulpride to diethylamine is 1:10-15.

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