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Intermediate in amisulpride and method for preparing amisulpride by using intermediate

A technology of amisulpride and intermediates, applied in the field of preparation of amisulpride, can solve problems such as difficult to remove, reduce yield, affect product quality, etc., and achieve the effect of avoiding impurities and improving quality

Inactive Publication Date: 2012-12-05
四川省百草生物药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the above three methods, the direct condensation of 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid (4) and N-ethyl-2-aminomethylpyrrolidine (5) is adopted reaction to make amisulpride; but in the above reaction, the active amino and carboxyl groups present in the 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid compound are in the catalyst ethyl chloroformate, triethyl Condensation reaction is easy to occur under the catalysis of amine, and the properties of the obtained condensation product are similar to amisulpride, which is difficult to remove in the later stage of impurity removal process, which not only affects the quality of the product, but also reduces the yield

Method used

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  • Intermediate in amisulpride and method for preparing amisulpride by using intermediate
  • Intermediate in amisulpride and method for preparing amisulpride by using intermediate
  • Intermediate in amisulpride and method for preparing amisulpride by using intermediate

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Embodiment 1

[0033] Intermediate of amisulpride: Synthesis of 4-(N-tert-butoxycarbonyl)amino-2-methoxy-5-ethylsulfonylbenzoic acid:

[0034] After stirring and dissolving 26g of 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid (IV) and 150ml of ethanol, add 12g of sodium carbonate, add 30g of di-tert-butyl dicarbonate at 20°C, and heat to React at 30°C for 5 hours, cool the reaction solution to room temperature, then pour into ice water to separate layers, adjust the pH value of the water layer to 3-4 with dilute hydrochloric acid, stir to precipitate a solid, filter and wash the filter cake with a small amount of distilled water, and dissolve the obtained solid at 40 Drying under reduced pressure at °C yielded 31 g of 4-(N-tert-butoxycarbonyl)amino-2-methoxy-5-ethylsulfonylbenzoic acid (III).

Embodiment 2

[0036] Synthesis of amisulpride: 31g of 4-(N-tert-butoxycarbonyl)amino-2-methoxy-5-ethylsulfonylbenzoic acid was mixed with 12g of N-ethyl-2-aminomethylpyrrolidine Add 100ml of dichloromethane and stir to dissolve, add 19.5g of DCC and stir at 30°C for 12 hours, wash the reaction solution with ice water, distill off the dichloromethane to obtain 44g of 4-(N-tert-butoxycarbonyl) Amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-ethylsulfonyl-2-methoxybenzamide; Add 50ml of ethanol and 5ml of 2M hydrochloric acid to stir at room temperature Remove the BOC protecting group in 30 minutes, remove ethanol by distillation under reduced pressure, add 100ml distilled water and stir in the residue, separate out the solid, filter, and recrystallize with acetone to obtain 29.3g amisulpride, the yield is 74.8%, and the purity is 99.6 %.

Embodiment 3

[0038] Intermediate of amisulpride: Synthesis of 4-(N-tert-butoxycarbonyl)amino-2-methoxy-5-ethylsulfonylbenzoic acid:

[0039] Stir and dissolve 26g of 4-amino-2-methoxy-5-ethylsulfonylbenzoic acid (IV) and 150ml of DMF, add 12g of sodium carbonate, add 28g of di-tert-butyl dicarbonate at 20°C, and heat to 60°C React for 0.5 hours, cool the reaction solution to room temperature, then pour into ice water to separate layers, adjust the pH value of the water layer to 3-4 with dilute hydrochloric acid, stir to precipitate a solid, filter and wash the filter cake with a small amount of distilled water, and store the obtained solid at 45°C Drying under reduced pressure gave 31.4 g of 4-(N-tert-butoxycarbonyl)amino-2-methoxy-5-ethylsulfonylbenzoic acid (III).

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Abstract

The invention discloses an intermediate in amisulpride and a method for preparing amisulpride by using an intermediate. The method comprises the following steps: reacting 4-amino-2-methoxy group-5-ethylsulfonyl benzoic acid and di-tert-butyl dicarbonate ester so as to obtain the intermediate (4-(N-tert-tert-butoxycarbonyl)amino-2-methoxy group-5-ethylsulfonyl benzoic acid) of the amisulpride; and carrying out condensation reaction on the intermediate (4-(N-tert-butoxycarbonyl)amino-2-methoxy group-5-ethylsulfonyl benzoic acid) of the amisulpride and N-ethyl-2-aminomethyl pyrrolidine so as to obtain 4-(N-tert-tert-butoxycarbonyl)amino-N-((1-ethyl-2-pyrrolidyl)methyl)-5-ethylsulfonyl-2-methoxy benzamide, and carrying out deprotection of tert-butoxycarbonyl group (BOC) so as to obtain the amisulpride. According to the method, the process processing is simple, impurities which are hard to remove are avoided, the reaction yield is high and can be up to 76%, the purity of the obtained amisulpride is high, and the medical quality of the amisulpride is greatly improved.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to an intermediate of amisulpride: 4-(N-tert-butoxycarbonyl)amino-2-methoxy-5-ethylsulfonylbenzoic acid and a preparation method thereof And the method for preparing amisulpride by using the intermediate of amisulpride. Background technique [0002] Amisulpride (amisulpride, 1), chemical name: 4-amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-ethylsulfonyl-2-methoxybenzyl Amide is a new type of atypical antipsychotic drug developed by Sanifi-Synthelabo with significant efficacy. It is a benzamide derivative that has been widely used clinically in Europe and the world. Its main mechanism of action is to selectively antagonize dopamine D2 receptors and D3 receptors. It is clinically used to treat chronic and acute progressive schizophrenia. Its structural formula is as follows: [0003] [0004] The document "The Synthesis of Amisulpride" reports two preparation methods of Amisulpride: ...

Claims

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Application Information

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IPC IPC(8): C07C317/50C07C315/04C07D207/09
Inventor 蒋红斌杨文罗睿
Owner 四川省百草生物药业有限公司
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