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Synthesis method of (S) (-)-amisulprideD-(-)-tartrate

The technology of a kind of amisulpride and synthetic method is applied in the field of synthesis of -amisulpride D--tartrate, which can solve the problems of large amount of waste liquid, large amount of synthetic solvent, high toxicity, etc. The effect of less dosage and high total yield

Active Publication Date: 2013-09-25
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore the prospect of clinical application is better, and U.S. Patent US 6,187,807 has set forth a kind of synthetic method of it, and this method is raw material with 2-methoxyl-4-amino-5-mercaptobenzoic acid, first with diethyl sulfate as ethyl oxidizing reagent to generate 2-methoxy-4-amino-5-ethylthiobenzoic acid, which is further oxidized to obtain 2-methoxy-4-amino-5-ethanesulfonylbenzoic acid, and then using ethyl chloroformate and (S) (-)-1-ethyl-2-aminomethylpyrrole, mixed acid anhydride reaction to obtain (S) (-)-amisulpride, and finally salted with D-(-)-tartaric acid to obtain ( S) (-)-amisulpride D-(-)-tartrate, this method has certain limitations, in the reaction of mixed anhydride method, involves the use of toxic ethyl chloroformate for phosgenation raw material, and synthetic solvent Large amount, more waste liquid

Method used

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  • Synthesis method of (S) (-)-amisulprideD-(-)-tartrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] In the three-necked flask, 300 g of methanol, 10 g of concentrated sulfuric acid, and 100 g of 2-methoxy-4-amino-5-ethanesulfonylbenzoic acid were sequentially added, and the temperature was raised to reflux for 6 hours. Under ice water cooling, add 10% sodium carbonate solution dropwise to adjust the pH. When the pH is 8, cool and stir with ice water for 1 hour, filter the filter cake and wash it with tap water, and dry the filter cake at 60°C to obtain an off-white solid, which is the ester. compounds. Yield: 93%, melting point: 155-165°C;

[0036] In the three-necked flask, add 60g of glycerol, 54g of (S)(-)-1-ethyl-2-aminomethylpyrrole, and 90g of esterified product in sequence; after adding, stir evenly, and heat up to 80-90°C for 12 hours , the reaction was completed, lowered to 0-5 ° C and stirred for 3 hours, suction filtered (the mother liquor was collected separately), the filter cake was washed with a small amount of cold ethanol, and drained, the filter cak...

Embodiment 2

[0040] In the three-necked flask, 400 g of methanol, 15 g of concentrated sulfuric acid, and 100 g of 2-methoxy-4-amino-5-ethanesulfonylbenzoic acid were sequentially added, and the temperature was raised to reflux for 8 hours. Under ice water cooling, add 10% sodium carbonate solution dropwise to adjust the pH. When the pH is 7.5, cool and stir with ice water for 1.5 hours, filter the filter cake and wash it with tap water. Dry the filter cake at 60°C to obtain an off-white solid, namely For esterification. Yield: 94.5%, melting point: 155-165°C;

[0041] In the there-necked flask, sequentially add 60g of glycerol, 54g of (S)(-)-1-ethyl-2-aminomethylpyrrole, and 90g of esterified product; stir evenly after adding, heat up to 90-100°C and react for 9 hours , the reaction was completed, lowered to 0-5 ° C and stirred for 3 hours, suction filtered (the mother liquor was collected separately), the filter cake was washed with a small amount of cold ethanol, and drained, the filte...

Embodiment 3

[0045]In the three-neck flask, add 350 g of ethanol, 12 g of concentrated sulfuric acid, and 100 g of 2-methoxy-4-amino-5-ethanesulfonylbenzoic acid in sequence, heat up to reflux for 6 hours, and cool down to room temperature, and a large amount of solids precipitate out. Under ice-water cooling, add 10% sodium carbonate solution dropwise to adjust the pH. When the pH is 8.5, cool and stir with ice water for 1 hour, filter the filter cake and wash it with tap water. Dry the filter cake at 60°C to obtain an off-white solid, namely For esterification. Yield 91%;

[0046] In the three-necked flask, add ethylene glycol 60g, (S)(-)-1-ethyl-2-aminomethylpyrrole 54g, and esterified product 90g; after adding, stir evenly, heat up to 70-80°C for 16 hours , the reaction was completed, lowered to 0-5 ° C and stirred for 3 hours, suction filtered (the mother liquor was collected separately), the filter cake was washed with a small amount of cold ethanol, and drained, the filter cake was...

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Abstract

The invention relates to a synthesis method of (S) (-)-amisulprideD-(-)-tartrate, comprising the following steps: (1) subjecting 2-methoxy-4-amino-5-ethylsulfonyl benzoate to react with low alcohols to obtain esters of the low alcohols; (2) subjecting the obtained esters of the low alcohols to react with (S) (-)-1-ethyl-2-aminomethylpyrrole to obtain (S) (-)-amisulpride; and (3) (S) (-)-amisulpride and D-(-)-tartrate acting to obtain (S) (-)-amisulprideD-(-)-tartrate. The process has the advantages of simple and convenient operation, mild conditions and high total yield, the solvent is less in use amount and can be recovered and all the raw materials are non-toxic or low-toxic.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing (S)(-)-amisulpride D-(-)-tartrate. Background technique [0002] (R, S)(-)-Amisulpride is the second-generation benzamide antipsychotic drug; it is used for the treatment of schizophrenia and depression. Compared with other antipsychotic drugs, it has certain advantages, good curative effect and small side effects . The medicine has dual functions, can not only treat acute positive symptoms of schizophrenic patients, but also treat negative symptoms of patients, has low extrapyramidal side effects, and is well tolerated. [0003] The therapeutic effect of (S)(-)-amisulpride has higher safety compared with the racemate, less side effects and lower dosage. Therefore the clinical application prospect is better, and U.S. Patent US 6,187,807 has set forth a kind of synthetic method of it, and this method is raw material with 2-methoxyl-4-amino-5-mercaptobenzoi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/09
Inventor 杨国军黄春森朱占元
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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