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Preparation method of (S)-oxiracetam

A compound, the technology of oxirane acetamide, applied in the direction of organic chemistry and the like, can solve the problems of high production cost and low yield, and achieve the effects of low cost, high yield and easy availability of raw materials

Active Publication Date: 2017-05-10
南京帝昌医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] All use chiral raw materials in the above-mentioned method, and production cost is higher, and also has the defect that yield is lower, seriously restricts the application of (S)-oxiracetam

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of (S)-3-hydroxy-butyrolactam

[0028] Add 10.1g (100mmol) of 2-oxiranyl acetamide, 0.95g (5mmol) of CuI, and 2g (200mmol) of cesium carbonate to 150ml of methanol saturated solution of ammonia gas, and carry out a stirring reaction at 55°C for 8h, and the reaction solution reduces Concentrate under reduced pressure, add water to 100ml, extract with dichloromethane three times, wash with saturated brine three times, concentrate the ethyl acetate phase under reduced pressure, recrystallize petroleum ether to obtain (S)-3-hydroxy-butyrolactam 8.71g, yield 86.3%, HPLC purity 99.42% (area normalization method), ee value 99.67%, 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

[0030] Preparation of (S)-3-hydroxy-butyrolactam

[0031]Add 1g (10mmol) of 2-oxiranyl acetamide, 1.5g (8mmol) of CuI, and 2g (200mmol) of cesium carbonate to 13ml of saturated methanol solution of ammonia gas, stir and react at 50°C for 10h, and decompress the reaction solution Concentrate, add water to 10ml, extract three times with dichloromethane, wash with saturated brine three times, concentrate the ethyl acetate phase under reduced pressure, recrystallize petroleum ether to obtain (S)-3-hydroxy-butyrolactam 0.9g, yield 89.3%, HPLC The purity is 99.54% (area normalization method), and the ee value is 99.71%.

Embodiment 3

[0033] Preparation of (S)-3-hydroxy-butyrolactam

[0034] 10.1g (100mmol) of 2-oxiranylacetamide, 0.4g (2mmol) of CuI, and 2g (250mmol) of cesium carbonate were added to 120ml of methanol saturated solution of ammonia gas, and the reaction was stirred at 60°C for 6h, and the reaction solution reduced Concentrate under reduced pressure, add 100ml of water, extract three times with dichloromethane, wash with saturated brine three times, concentrate under reduced pressure with ethyl acetate, recrystallize from petroleum ether to obtain 8.77g of (S)-3-hydroxy-butyrolactam, yield 86.7% , HPLC purity 99.47% (area normalization method), ee value 99.69%.

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Abstract

The invention discloses a preparation method of (S)-oxiracetam. The preparation method is characterized by comprising the following steps that 1, 2-epoxy ethylacetamide is cyclized in molecules in the presence of a catalyst and alkali to obtain a compound (S)-3-hydroxyl-butyrolactam shown as a formula II; 2, the (S)-3-hydroxyl-butyrolactam obtained in the step 1 reacts with tertiary butyl methyl chlorosilane to obtain a compound protected by the tertiary butyl methyl chlorosilane and shown as a formula III; 3, the compound shown as the formula III performs nucleophilic reaction with bromoacetonitrile under the alkaline condition to obtain a N-cyanomethide shown as a formula IV; 4, the N-cyanomethide shown as the formula IV is subjected to hydrolysis under the acid condition to obtain the (S)-oxiracetam (shown in the description). The method adopts conventional non-achiral raw materials and is low in cost, the (S)-oxiracetam is high in yield, an ee value is high, and a new way is provided for preparation of the (S)-oxiracetam.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of (S)-oxiracetam. Background technique [0002] Oxiracetam, chemically named 4-hydroxy-2-oxo-1-pyrrolidineacetamide, is clinically used for memory and memory disorders caused by mild to moderate vascular dementia, senile dementia, and traumatic brain injury. Mental retardation, the compound was synthesized by the Italian company Skebechem in 1974. The drug is a β-hydroxyl derivative of piracetam, which is a cyclic derivative of hydroxyaminobutyric acid (GABOB). Experiments have shown that it can improve the subjects' thinking, memory and learning ability. 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 brain phospholipids, stimulate the synthesis of brain ribonucleic acid and protein, and enhance the tolerance of cere...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/273
CPCC07D207/273
Inventor 王传秀
Owner 南京帝昌医药科技有限公司
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