CN112624951B - Preparation method of amisulpride - Google Patents
Preparation method of amisulpride Download PDFInfo
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- CN112624951B CN112624951B CN202011594851.5A CN202011594851A CN112624951B CN 112624951 B CN112624951 B CN 112624951B CN 202011594851 A CN202011594851 A CN 202011594851A CN 112624951 B CN112624951 B CN 112624951B
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention relates to a preparation method of amisulpride, which comprises the following steps: 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid methyl ester in the presence of an organic base as a catalystCarrying out condensation reaction on N-ethyl-2-aminomethyl pyrrolidine and a solvent at 50-100 ℃, concentrating the 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, and the specific synthetic route is as follows. The preparation method of the invention does not use a catalyst harmful to the environment in the reaction process, has simple post-treatment, the solvent is a common recyclable solvent, the yield reaches more than 90 percent, the purity can reach 99.7 percent, the single impurity is less than 0.1 percent, the preparation method meets the requirements of medicinal preparations, and the preparation method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of amisulpride.
Background
Amisulpride is a novel atypical antipsychotic developed by Sanofi-Synthelabo company of France, belongs to benzamide derivatives, can selectively act on dopamine D2 and D3 receptors, competitively antagonizes 5-hydroxytryptamine receptors, particularly can well eliminate side reactions blocked by most medicaments on D2 receptors, and has the advantages of few adverse reactions, no blood sugar increase and the like. Has obvious effect on treating positive and negative symptoms of schizophrenia of patients needing long-term maintenance treatment in acute or chronic states. The chemical name is as follows: 4-amino-N- [ (1-ethyl-2-pyrrolidinyl) methyl ] -5- (ethylsulfonyl) -2-methoxybenzamide having the following structural formula:
chinese patent CN102838520A discloses a method for preparing amisulpride, wherein under alkaline conditions, 4-amino-5- (ethylsulfonyl) -2-methoxybenzoic acid reacts with N-ethyl-2-aminomethylpyrrolidine in the presence of phenyl chloroformate or oxalyl chloride to obtain amisulpride, and during the reaction, the raw materials of phenyl chloroformate or oxalyl chloride are used, wherein the oxalyl chloride can be violently decomposed in water or alcohol, and the phenyl chloroformate can generate toxic gas in water or heat, so that the requirements on the reaction conditions and the operation of personnel are high, which is not favorable for safe production, and the specific synthetic route is as follows:
the Chinese new drug journal, 2009,18(16), 1554, reports a synthesis method of amisulpride, 4-amino-5- (ethylsulfonyl) -2-methoxybenzoic acid reacts with 1-ethyl-2-aminomethyl pyrrolidine in the presence of ethyl chloroformate to prepare amisulpride, during the reaction, the ethyl chloroformate used as a raw material belongs to a virulent drug, which can cause a safety problem and is not beneficial to environmental protection, and the specific synthetic route is as follows:
patent CN103819383A discloses a synthesis method of amisulpride, which is obtained by condensing lower alcohol ester of 2-methoxy-4-amino-5-ethanesulfonyl benzoic acid with N-ethyl-2-aminomethyl pyrrole. But in the reaction process, a large amount of byproducts are generated, the purity of amisulpride is low, the impurity content is high, and the single impurity is not lower than 1%.
Patent CN101898991A discloses a synthesis method of (S) (-) -amisulpride D- (-) -tartrate, which uses glycerol as solvent, reacts 2-methoxy-4-amino-5-ethanesulfonyl benzoic acid with lower alcohol to obtain lower alcohol ester, and then condenses with (S) (-) -1-ethyl-2-aminomethyl pyrrole to obtain (S) (-) -amisulpride. The glycerol is used as a solvent when the amisulpride is prepared, the glycerol has a melting point of 17.8 ℃, has high viscosity and is inconvenient to use, the glycerol can perform alcohol ester exchange with 2-methoxy-4-amino-5-ethyl sulfonyl methyl benzoate in the reaction process, a byproduct, namely the 2-methoxy-4-amino-5-ethyl sulfonyl methyl benzoate glycerol ester can be generated, and the byproduct is difficult to remove in the subsequent treatment process, so that the quality of the amisulpride finished product is seriously influenced.
Disclosure of Invention
The invention aims to provide a preparation method of amisulpride based on the prior art.
The technical scheme of the invention is as follows:
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, N-ethyl-2-aminomethyl pyrrolidine and a solvent at 50-100 ℃, concentrating a reaction solution after the reaction is finished to remove the solvent, 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, and the specific synthetic route is as follows:
the invention takes 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate and N-ethyl-2-aminomethyl pyrrolidine as raw materials, the condensation reaction is carried out under the catalysis of organic base to prepare the amisulpride, no catalyst harmful to the environment is used in the reaction process, the post-treatment is simple, the yield reaches more than 90 percent, the purity can reach 99.7 percent, and the single impurity is less than 0.1 percent, thus meeting the requirements of medicinal preparations.
In a preferred embodiment, the molar ratio of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to organic base is 1:1.0 to 5.0, and may be, but is not limited to, 1:1.0, 1:1.3, 1:1.5, 1:1.8, 1:2.0, 1:2.3, 1:2.5, 1:2.8, 1:3.0, 1:3.5, 1:3.3, 1:3.5, 1:4.0, 1:4.5, or 1:5.0, and the molar ratio of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to organic base may be further preferably 1:1.8 to 2.8 for better effects and material saving.
The organic base used in the present invention is typically a sodium or potassium short chain fatty alcohol, wherein the short chain fatty alcohol may be, but is not limited to, methanol, ethanol, propanol, isopropanol, or tert-butanol. During the reaction, solid powder of the organic base may be added, or the organic base may be dissolved in the corresponding alcohol and added to the reaction in the form of a solution.
In a preferred embodiment, the alkali is sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide, and during the reaction, solid powder of sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide may be added directly, or sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide dissolved in the corresponding alcohol may be added in the form of a solution, for example, sodium methoxide methanol solution, sodium ethoxide ethanol solution, potassium tert-butoxide-butanol solution or sodium tert-butoxide-butanol solution.
In a preferred embodiment, the molar ratio of methyl 4-amino-2-methoxy-5-ethylsulfonyl benzoate to N-ethyl-2-aminomethylpyrrolidine is 1:1.0 to 5.0, and may be, but not limited to, 1:1.0, 1:1.3, 1:1.5, 1:1.8, 1:2.0, 1:2.3, 1:2.5, 1:2.8, 1:3.0, 1:3.5, 1:3.3, 1:3.5, 1:4.0, 1:4.5 or 1:5.0, and the molar ratio of methyl 4-amino-2-methoxy-5-ethylsulfonyl benzoate to N-ethyl-2-aminomethylpyrrolidine may be further preferably 1:1.0 to 3.0 for better effects and material saving.
Compared with the prior art, the method has the advantages that the organic base is used as the catalyst, the condensation reaction can be carried out at a lower temperature to prepare amisulpride, the generation of byproducts can be reduced, and the purity of the product is improved. In one embodiment, the reaction temperature is 50 to 100 ℃, and may be, but is not limited to, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 83 ℃, 85 ℃, 90 ℃ or 100 ℃, preferably 60 to 90 ℃, and more preferably 60 to 85 ℃.
In one embodiment, the reaction temperature is 5 to 40 hours, but is not limited to 5 hours, 8 hours, 10 hours, 12 hours, 16 hours, 18 hours, 20 hours, 24 hours, 28 hours, 30 hours, 35 hours or 40 hours, and more preferably 18 to 24 hours.
For the purposes of the present invention, the reaction solvent is methanol, ethanol, isopropanol, tert-butanol, acetonitrile, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide, preferably the solvent is methanol, ethanol, isopropanol or tert-butanol.
The preparation method of amisulpride provided by the invention has simple post-treatment, and the specific post-treatment process comprises the following steps: concentrating the reaction solution to remove the solvent, adding water into the concentrated reaction solution, stirring at 10-20 deg.C for crystallization, and filtering; adding the obtained crystals into water, pulping, filtering again, and drying to obtain amisulpride.
In a preferred embodiment, the reaction solution is concentrated to remove the solvent, and the amount of water added to the concentrated reaction solution is the same as the amount of water added during beating. In a more preferred embodiment, the mass/volume ratio of methyl 4-amino-2-methoxy-5-ethylsulfobenzoate to added water is 0.05 to 0.5g/ml, and may be, but is not limited to, 0.05g/ml, 0.08g/ml, 0.1g/ml, 0.12g/ml, 0.14g/ml, 0.16g/ml, 0.2g/ml, 0.3g/ml, 0.4g/ml or 0.5g/ml, and more preferably 0.1 to 0.2 g/ml.
In a preferable scheme, the drying temperature is 40-60 ℃, and preferably 50 ℃.
By adopting the technical scheme of the invention, the advantages are as follows:
the invention takes 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate and N-ethyl-2-aminomethyl pyrrolidine as raw materials, the condensation reaction is carried out under the catalysis of organic base to prepare amisulpride, no catalyst harmful to the environment is used in the reaction process, the post-treatment is simple, the solvent is a common recyclable solvent, the yield reaches over 90 percent, the purity can reach 99.7 percent, the single impurity is less than 0.1 percent, the requirement of medicinal preparations is met, and the invention is suitable for industrial production.
Drawings
Figure 1 is a High Performance Liquid Chromatography (HPLC) profile of amisulpride prepared in example 1;
figure 2 is a High Performance Liquid Chromatography (HPLC) profile of amisulpride prepared in example 2;
figure 3 is a High Performance Liquid Chromatography (HPLC) profile of amisulpride prepared in example 3;
figure 4 is a High Performance Liquid Chromatography (HPLC) profile of amisulpride prepared in example 4;
figure 5 is a High Performance Liquid Chromatography (HPLC) profile of amisulpride prepared in example 5.
Detailed Description
The present invention is further illustrated by the following examples, which are intended to more specifically illustrate preferred embodiments of the present invention and are not intended to limit the technical scope of the present invention. Any methods and materials similar or equivalent to those described herein can be used in the practice of the present invention; unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
The experimental procedures, in which specific conditions are not specified, in the following examples are generally conducted according to conventional conditions or conditions recommended by manufacturers.
Example 1
106.5g of methyl 4-amino-2-methoxy-5-ethylsulfonyl benzoate (methyl amelicate), 99.8g N-ethyl-2-aminomethyl pyrrolidine and 156.0g of 30 wt% sodium methoxide methanol solution are added into 1065ml of methanol, after uniform stirring, the temperature is raised to 65 ℃ for heat preservation reaction for 20h, after the reaction is finished, the reaction solution is concentrated until the solvent does not drip out, then 530ml of water is added into the concentrated reaction solution, stirring is carried out for 4h at the temperature of 10-20 ℃ to separate out white solid, filtering is carried out, 530ml of water is added into the obtained white solid for pulping for 1h, filtering and washing are carried out, air drying is carried out at the temperature of 50 ℃ for 15h to obtain 136.1g of white solid sulpiride, the HPLC purity is 99.91%, the yield is 94.5%, and the residual of the methyl 4-amino-2-methoxy-5-ethylsulfonyl benzoate (methyl amelicate) is 0.07%, the total amount of other impurities was 0.02%.
Example 2
27.5g of 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate, 39.0g of 39.0g N-ethyl-2-aminomethyl pyrrolidine and 50.0g of sodium ethoxide ethanol solution with the concentration of 20 percent are added into 275ml of ethanol, after the mixture is uniformly stirred, the mixture is heated to 75 ℃ for heat preservation reaction for 24h, after the reaction is finished, the reaction solution is concentrated until the solvent does not drip out, then 140ml of water is added into the concentrated reaction solution, the mixture is stirred for 4h at the temperature of 10-20 ℃ to separate out white solid, the white solid is filtered, 140ml of water is added into the obtained white solid, the mixture is pulped for 1h, the white solid is filtered and washed, and the mixture is dried by air blowing at the temperature of 50 ℃ for 15h to obtain 35.5g of the white solid amisulpride, the purity of HPLC is 99.84 percent, the yield is 95.6 percent, the residual 0.06 percent of methyl alidate and the total amount of other impurities is 0.10 percent.
Example 3
136.6g of methyl 4-amino-2-methoxy-5-ethylsulfonyl benzoate, 64.2g N-ethyl-2-aminomethyl pyrrolidine and 96.1g of sodium tert-butoxide are added into 956.2ml of tert-butyl alcohol, after the mixture is uniformly stirred, the temperature is raised to 83 ℃, the temperature is kept for reaction for 18h, after the reaction is finished, the reaction liquid is concentrated until the solvent does not drip out, 820ml of water is added into the concentrated reaction liquid, the mixture is stirred for 4h at the temperature of 10-20 ℃, white solid is separated out, the mixture is filtered, 820ml of water is added into the obtained white solid, the mixture is pulped for 1h, the white solid is filtered and washed, and the mixture is dried by blowing at the temperature of 50 ℃ for 15h, 172.6g of the white solid amisulpride is obtained, the HPLC purity is 99.86%, the yield is 93.7%, the residual methyl amiloride is 0.05%, and the total amount of other impurities is 0.09%.
Example 4
22.0g of 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate, 30.8g of 30.8g N-ethyl-2-aminomethyl pyrrolidine and 18.1g of potassium tert-butoxide are added into 220ml of tert-butyl alcohol, after uniform stirring, the temperature is raised to 83 ℃, the reaction is kept for 20h, after the reaction is finished, the reaction liquid is concentrated until the solvent does not drip out, then 110ml of water is added into the concentrated reaction liquid, the mixture is stirred for 4h at 10-20 ℃, white solid is separated out, the mixture is filtered, 110ml of water is added into the obtained white solid, the mixture is pulped for 1h, the mixture is filtered and washed, and the mixture is dried by blowing for 15h at 50 ℃, so 28.7g of white solid amisulpride is obtained, the HPLC purity is 99.79%, the yield is 96.5%, the residual amount of methyl amiloride is 0.09%, and the total amount of other impurities is 0.12%.
Example 5
Adding 40kg of 4-amino-2-methoxy-5-ethylsulfonyl methyl benzoate, 37.6kg of N-ethyl-2-aminomethyl pyrrolidine and 55kg of 30 wt% sodium methoxide methanol solution into 220L of methanol, uniformly stirring, heating to 65 ℃, preserving heat and reacting for 20h, concentrating the reaction liquid until the solvent does not drip out after the reaction is finished, then adding 200L of water into the concentrated reaction liquid, stirring for 4h at 10-20 ℃, separating out a white solid, filtering, adding 200L of water into the obtained white solid, pulping for 1h, filtering, washing, and drying by blowing for 15h at 50 ℃ to obtain 51.6kg of white solid amisulpride, wherein the HPLC purity is 99.93%, the yield is 95.5%, the residual amount of methyl amiloride is 0.03%, and the total amount of unknown single impurities is 0.04%.
Claims (18)
1. The preparation method of sulpride is characterized by comprising 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, N-ethyl-2-aminomethyl pyrrolidine and a solvent at 50-100 ℃, concentrating a reaction solution after the reaction is finished to remove the solvent, 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, and the specific synthetic route is as follows:
2. the method for preparing amisulpride according to claim 1, wherein the molar ratio of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to organic base is 1:1.0 to 5.0.
3. The method for preparing amisulpride according to claim 2, wherein the molar ratio of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to organic base is 1: 1.8-2.8.
4. The method for preparing amisulpride according to claim 2 or 3, wherein the organic base is sodium methoxide, sodium ethoxide, potassium tert-butoxide, or sodium tert-butoxide.
5. The method for preparing amisulpride according to claim 1, wherein the molar ratio of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to N-ethyl-2-aminomethylpyrrolidine is 1:1.0 to 5.0.
6. The method for preparing amisulpride according to claim 5, wherein the molar ratio of methyl 4-amino-2-methoxy-5-ethylsulfonylbenzoate to N-ethyl-2-aminomethylpyrrolidine is 1:1.0 to 3.0.
7. The method for producing amisulpride according to claim 1, wherein the reaction temperature is 60 to 90 ℃.
8. The method for preparing amisulpride according to claim 7, wherein the reaction temperature is 60-85 ℃.
9. The method for preparing amisulpride according to claim 1, wherein the reaction time is 5 to 40 hours.
10. The method for preparing amisulpride according to claim 9, characterized in that the reaction time is 18 to 24 hours.
11. The method for producing amisulpride according to claim 1, characterized in that the solvent is methanol, ethanol, isopropanol, tert-butanol, acetonitrile, N-dimethylformamide, N-dimethylacetamide, or dimethylsulfoxide.
12. The method for producing amisulpride according to claim 11, wherein the solvent is methanol, ethanol, isopropanol or tert-butanol.
13. The method of claim 1, wherein the post-treatment step comprises the steps of: concentrating the reaction solution to remove the solvent, adding water into the concentrated reaction solution, stirring at 10-20 deg.C for crystallization, and filtering; adding the obtained crystals into water, pulping, filtering again, and drying to obtain amisulpride.
14. The method of claim 13, wherein the amount of water added to the concentrated reaction solution is the same as the amount of water added during beating.
15. The method for preparing amisulpride according to claim 13, wherein the mass-to-volume ratio of methyl 4-amino-2-methoxy-5-ethylsulfobenzoate to added water is 0.05 to 0.5 g/ml.
16. The method for preparing amisulpride according to claim 15, wherein the mass-to-volume ratio of methyl 4-amino-2-methoxy-5-ethylsulfobenzoate to added water is 0.1 to 0.2 g/ml.
17. The method for producing amisulpride according to claim 13, wherein the drying temperature is 40 to 60 ℃.
18. The method of claim 17, wherein the drying temperature is 50 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101898991A (en) * | 2009-05-31 | 2010-12-01 | 江苏天士力帝益药业有限公司 | Synthesis method of (S) (-)-amisulprideD-(-)-tartrate |
| CN103819383A (en) * | 2012-11-19 | 2014-05-28 | 上海美迪西生物医药有限公司 | Synthesis method for amisulpride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101898991A (en) * | 2009-05-31 | 2010-12-01 | 江苏天士力帝益药业有限公司 | Synthesis method of (S) (-)-amisulprideD-(-)-tartrate |
| CN103819383A (en) * | 2012-11-19 | 2014-05-28 | 上海美迪西生物医药有限公司 | Synthesis method for amisulpride |
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