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Synthesis method for amisulpride

A synthetic method, the technology of amisulpride, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of expensive and toxic reagents, numerous steps, and low yield, and achieve the effects of high atom utilization, simple equipment, and short routes

Inactive Publication Date: 2014-05-28
SHANGHAI MEDICILON INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when these methods are synthesizing amisulpride compounds, limitations such as low yield, numerous steps, expensive reagents and high toxicity limit the production in industry

Method used

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  • Synthesis method for amisulpride
  • Synthesis method for amisulpride
  • Synthesis method for amisulpride

Examples

Experimental program
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Effect test

Embodiment 1

[0047]In a 10L four-neck flask, add 1kg of 2-methoxy-4-amino-5-ethanesulfonylbenzoic acid and 3kg of methanol in sequence, stir mechanically (100 rpm, internal temperature 30°C), and slowly Slowly add 300g of thionyl chloride, raise the temperature to reflux, reflux for 5 hours, cool the reaction system to 0°C, adjust the pH value to 9 with saturated sodium carbonate aqueous solution, add water to dilute to 4L (containing the volume of sodium carbonate aqueous solution), and filter with suction. The filter cake was dried at 50°C to obtain a light yellow solid, yield: 97.5%, purity: 97.7%; in a three-necked flask, add 1.2kg of esterified product, 675g of N-ethyl-2-aminopyrrole, and 1.2kg of isopropanol in sequence Stir mechanically, heat to an internal temperature of 80-85°C, react for 28 hours, when the temperature drops to 40-50°C, add 3L of water, stir at room temperature for 10 hours, a white solid precipitates, then stir at 0-5°C for 3 hours, filter, After washing with wat...

Embodiment 2

[0049] In a 10L four-necked flask, add 1kg of 2-methoxy-4-amino-5-ethanesulfonylbenzoic acid and 2.5kg of methanol in sequence, stir mechanically (100 rpm, internal temperature 30°C), and Slowly add 250g of thionyl chloride, raise the temperature to reflux, the internal temperature is 68°C, reflux for 7.5 hours, cool the reaction system to 0°C, adjust the pH value to 8 with saturated aqueous sodium carbonate solution, dilute to 4L with water (containing aqueous sodium carbonate volume), suction filtration, and the filter cake was dried at 50°C to obtain a light yellow solid, yield: 98%, purity: 95.2%;,

[0050] In the three-necked flask, add 1.2kg of esterified product, 675g of N-ethyl-2-aminopyrrole, and 1.2kg of isopropanol in sequence, stir mechanically, heat to an internal temperature of 95-100°C, react for 20 hours, and cool down to 40-50°C After a while, add 3L of water, stir at room temperature for 12 hours, a white solid precipitates, then stir at 0-5°C for 3 hours, fi...

Embodiment 3

[0052] In a 10L four-neck flask, add 1kg of 2-methoxy-4-amino-5-ethanesulfonylbenzoic acid and 3.5kg of ethanol in sequence, stir mechanically (rotating speed: 100 rpm, internal temperature: 30°C), at room temperature Slowly add 100g of thionyl chloride, raise the temperature to reflux, the internal temperature is 68°C, reflux for 5 hours, cool the reaction system to 0°C, adjust the pH value to 10 with saturated sodium carbonate aqueous solution, add water to 4L (containing sodium carbonate aqueous solution volume), suction filtration, the filter cake was dried at 50°C to obtain a light yellow solid, yield: 89.3%, purity: 96.1%;

[0053] In the three-necked flask, sequentially add 1.2kg of esterified product, 675g of N-ethyl-2-aminopyrrole, and 1.2kg of isopropanol with mechanical stirring, heat to an internal temperature of 100-105°C, react for 40 hours, and cool down to 40-50°C After a while, add 3L of water, stir at room temperature for 10 hours, a white solid precipitates,...

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Abstract

The invention relates to a synthesis method for amisulpride. The method comprises the following steps: a, esterifying 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid (I) and low alcohol (II) under the catalysis of thionyl chloride to obtain low alcohol ester (III), b, performing condensation on the low alcohol ester (III) obtained in the step a and N-ethyl-2-aminomethylpyrrolidine (IV) to obtain the amisulpride (V). The synthesis method is short in synthesis route (a target compound can be obtained by two steps), high in yield and atom utilization rate and easy to operate, reaction conditions are mild, a product purification post-treatment process is simple, the use of a catalyst harmful to the environment during the reaction is avoided, and a common recyclable solvent can be used as a reaction solvent.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of amisulpride. Background technique [0002] Amisulpril is indicated for the treatment of acute or chronic schizophrenia with predominantly positive symptoms (eg, delirium, hallucinations, cognitive impairment) and / or negative symptoms (eg, slowed reactions, apathy, and social withdrawal), including negative Symptoms are characteristic of schizophrenia. Therefore, the drug has duality, low side effects and good tolerance. Amisulpride compound is an uncommon compound in nature, and the common synthetic methods roughly include: (1) taking 4-amino-2-methoxybenzoic acid as raw material through sulfonylation with chlorosulfonic acid, and with stannous chloride , hydrochloric acid to obtain unstable disulfides, hydrolysis in alkaline solution to obtain thiols, oxidation to obtain 3-ethylsulfonyl-4-amino-6-methoxybenzoic acid, and ...

Claims

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Application Information

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IPC IPC(8): C07D207/09
CPCC07D207/09
Inventor 解建仁陈春麟周南梅马玉晴赵义娟
Owner SHANGHAI MEDICILON INC
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