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Method for preparing intelligence-improving medicine (S)-oxiracetam

A technology of drugs and compounds, which is applied in the field of preparation of nootropic drug-oxiracetam, can solve the problems of restricting the production of oxiracetam, high production cost, low yield, etc., and achieve high product yield and easy operation , good selective effect

Active Publication Date: 2017-01-25
王正强
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the above-mentioned methods, there is the problem that the production cost is too high due to the use of chiral raw materials, and there is still a defect of low yield, which seriously restricts the production of (S)-oxiracetam

Method used

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  • Method for preparing intelligence-improving medicine (S)-oxiracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of (S)-4-hydroxy-2-oxopyrrolidine

[0029] 15.82 g (100 mmol) of 2-oxiranyl isobutyl acetate and 1.83 g (15 mmol) of 4-dimethylaminopyridine were added to 160 ml of methanol-saturated solution of ammonia gas, and the reaction was stirred at room temperature for 8 h. Concentrate under pressure, add water to 100 ml, extract three times with ethyl acetate, wash three times with saturated brine, concentrate the organic phase under reduced pressure, and recrystallize from petroleum ether to obtain (S)-4-hydroxy-2-oxopyrrolidine 7.87 g, yield 77.8% , HPLC purity 99.65% (area normalization method), ee value 99.35%.

[0030] 1 HNMR(300MHz, DMSO-d6)δ7.23(1H,br,s), 5.45(1H,br,s), 4.05(1H,m), 3.51(1H,m), 3.40(1H,m), 2.34 (1H,m), 2.23 (1H,m).

Embodiment 2

[0032] Preparation of (S)-4-hydroxy-2-oxopyrrolidine

[0033] 15.82 g (100 mmol) of 2-oxiranyl isobutyl acetate and 1.22 g (10 mmol) of 4-dimethylaminopyridine were added to 200 ml of saturated methanol solution of ammonia gas, and the reaction was stirred at room temperature for 10 h, and the reaction solution was reduced in size. Concentrate under pressure, add water to 120 ml, extract three times with ethyl acetate, wash three times with saturated brine, concentrate the organic phase under reduced pressure, and recrystallize from petroleum ether to obtain (S)-4-hydroxy-2-oxopyrrolidine 8.02 g, yield 79.3% , HPLC purity 99.47% (area normalization method), ee value 99.52%.

Embodiment 3

[0035] Preparation of (S)-4-hydroxy-2-oxopyrrolidine

[0036] 15.82 g (100 mmol) of 2-oxiranyl isobutyl acetate and 1.22 g (10 mmol) of 4-dimethylaminopyridine were added to 80 ml of a saturated methanol solution of ammonia gas, and the reaction was stirred at room temperature for 8 h, and the reaction solution was reduced in size. Concentrated under pressure, added 100 ml of water, extracted three times with ethyl acetate, washed three times with saturated brine, the organic phase was concentrated under reduced pressure, and recrystallized from petroleum ether to obtain (S)-4-hydroxy-2-oxopyrrolidine 7.76 g, yield 76.7 g %, HPLC purity 99.62% (area normalization method), ee value 99.50%.

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Abstract

The invention discloses a method for preparing an intelligence-improving medicine (S)-oxiracetam. The method comprises the following steps: (1) under the catalysis of 4-dimethylaminopyridine, enabling 2-oxiraneisobutylacetate to contact with ammonia gas to react, so as to obtain (S)-4-hydroxyl-2-oxopyrrolidine; (2) enabling the (S)-4-hydroxyl-2-oxopyrrolidine obtained by the step (1) to react with tert-butyldimethylsilyl chloride, so as to obtain a compound shown as a formula III, which is protected by tert-butyl dimethylsilane; (3) enabling the compound shown as the formula III and 2-bromoacetic ester to be subjected to a nucleophilic reaction under an alkaline condition, so as to obtain a compound shown as a formula IV; (4) under the catalysis of ammonium chloride, enabling the compound shown as the formula IV and ammonia gas to be subjected to an ammonolysis reaction, so as to obtain the (S)-oxiracetam as shown in the description. The (S)-oxiracetam prepared by the method provided by the invention is high in yield, high in ee value and relatively low in cost, and a preparation process is simple and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of a nootropic drug (S)-oxiracetam. Background technique [0002] Oxiracetam (oxiracetam), chemical name is 4-hydroxy-2-oxo-1-pyrrolidine acetamide, clinically used for memory and memory and brain injury caused by mild to moderate vascular dementia, senile dementia and brain trauma. Intellectual disability, the compound was synthesized by the Italian company Skobeichem in 1974. The drug is a β-hydroxy derivative of piracetam, a cyclic derivative of hydroxyaminobutyric acid (GABOB). Tests have shown that oxiracetam can increase the level of ATP in the brain by stimulating the conversion of adenosine diphosphate to adenosine triphosphate (ATP), accelerate the metabolism of cerebral phospholipids, stimulate the synthesis of ribonucleic acid and protein in the brain, and enhance the response of the cerebral cortex to hypoxia. Tolerance ability...

Claims

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Application Information

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IPC IPC(8): C07D207/273A61P25/28
CPCC07B2200/07C07D207/273
Inventor 王传秀
Owner 王正强
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