Preparation method of (S)(-)-amisulpride

The technology of amisulpride and compound is applied in the field of preparation of antipsychotic drug-amisulpride, can solve the problems of slow reaction speed, difficult to industrialized production, and high reaction temperature, and achieves mild reaction conditions, short reaction time, raw materials, etc. low toxicity

Inactive Publication Date: 2015-06-24
HUBEI JINGJIANGYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In the above-mentioned various literature reports, there are many methods and patent protections for the synthesis of the key intermediate (II). This intermediate and another intermediate (III) have been industrially produced in China, but as the key step of Most of the condensation processes used highly toxic reagent ethyl chloroformate, which is highly toxic and unfavorable for industrial production
[0015] In patents CN103819383 and CN101898991, although the use of highly toxic reagents is avoided, the yield and purity of the product are also high, but the reaction temperature is high and the amplification effect is obvious. When it is enlarged to the kilogram level, the reaction speed is slow and the reaction time is as long as several days. Reach the level of small laboratory tests, therefore, it is not easy for industrial production

Method used

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  • Preparation method of (S)(-)-amisulpride
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  • Preparation method of (S)(-)-amisulpride

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Example 1: Preparation of (S)-1-ethylpyrrolidine-2-carboxylic acid

[0040] Put 75g of L-proline, 131g of potassium hydroxide and 500ml of absolute ethanol into a 1000ml four-neck flask, stir at 25°C until completely dissolved, then slowly add dropwise a solution of 85g of bromoethane and 100ml of absolute ethanol. After the dropwise addition was completed, the stirring reaction was continued for 4 h, and then the temperature was raised to 35° C. for 1.5 h. After the reaction was completed, adjust the pH to 4-5 with concentrated hydrochloric acid, filter with suction, recover ethanol under reduced pressure, and precipitate a white solid, which was dried to obtain 88.1 g of the target product, with a yield of 94.7%.

Embodiment 2

[0041] Example 2: Preparation of (S)-N-(2,4-dimethoxybenzyl)-1-ethylpyrrolidine-2-carboxamide

[0042] Add 112g of N,N-carbonyldiimidazole (CDI) and 400ml of dichloromethane into a 1000ml four-neck flask, stir to dissolve, and add (S)-1-ethylpyrrolidine-2-carboxylic acid obtained in the previous step in batches 86g, stirred at room temperature for 3h, then added dropwise to a solution of 110g of 2,4-dimethoxybenzylamine and 100ml of dichloromethane at a controlled temperature of 0-10°C. Add 300ml of water, stir, stand still, and separate layers. The organic layer is washed with 300ml of 5% sodium bicarbonate in water, dried over anhydrous sodium sulfate, filtered, and the organic solvent is evaporated under reduced pressure to obtain 151.2g of a light yellow solid. The rate is 86.3%.

Embodiment 3

[0043] Example 3: Preparation of (S)-(2,4-dimethoxyphenyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]methanamine

[0044] Under nitrogen protection, 146 g of (S)-N-(2,4-dimethoxybenzyl)-1-ethylpyrrolidine-2-carboxamide and 500 ml of anhydrous tetrahydrofuran (THF) obtained in the previous step were added to In a 2000ml four-neck flask, cool down to -15~-10°C, add dropwise 750ml of 1mol / L diborane tetrahydrofuran solution, after the drop is complete, heat up to 35°C and stir to react overnight, then cool down to -15°C, add dropwise 200ml Ice water, release a lot of gas. The mixed solution was adjusted to pH 10-11 with 10% potassium hydroxide, extracted three times with 500ml ether, combined the organic layers, washed twice with 50ml of saturated aqueous sodium chloride solution, washed once with 500ml of water, dried over anhydrous sodium sulfate, After filtration, the solvent was distilled off under reduced pressure at 25°C to obtain 118.3 g of light yellow oil. Yield 85.1%.

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Abstract

The invention relates to a preparation method of (S)(-)-amisulpride. According to the preparation method, by introducing an R2 group which is selected from benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, p-nitrobenzyl and p-methylbenzyl, on one hand, the steric hindrance is increased, the side reaction is avoided, on the other hand, amino is activated, the nucleophilicity of amino is increased, and the condensation reaction can be easily carried out at mild conditions. The preparation method has the characteristics that the raw materials are low in toxicity and easily available, and the reaction conditions are mild; the generation of chiral isomer dextroisomers is avoided; the preparation method is applicable to the industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of an antipsychotic drug (S)(-)-amisulpride. Background technique [0002] Amisulpride is a new type of atypical antipsychotic drug developed by Sanofi-Sythelabo in France, which can selectively act on dopamine D 2 and D 3 Benzamide derivatives are widely used clinically in Europe and around the world. They were launched in China in 2011. They are mainly used to treat positive and negative symptoms of acute or chronic schizophrenia, and have extrapyramidal side effects. Less, will not raise blood sugar and other advantages. The pharmacological activity of its levorotatory (S)(-)-amisulpride is more than twice that of the racemic form, with less toxic and side effects and higher safety. (S)(-)-Amisulpride structural formula is: [0003] [0004] The synthetic method of amisulpride reported in the literature has the following classes: [0005] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/09
CPCC07D207/09
Inventor 王力王诗宏王华权洪磊
Owner HUBEI JINGJIANGYUAN PHARMA
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