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Synthesis method of oxiracetam

A synthesis method and compound technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of many by-products, harsh reaction conditions, low product and yield, etc., to improve purity and yield, suitable for industrial production, Avoid by-product effects

Active Publication Date: 2012-10-24
BRIGHTGENE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The purpose of the present invention is to provide a new method for synthesizing oxiracetam, which solves the problems of harsh reaction conditions, more by-products, low product and yield in the process of synthesizing oxiracetam

Method used

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  • Synthesis method of oxiracetam
  • Synthesis method of oxiracetam
  • Synthesis method of oxiracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] R 1 tert-butyldimethylsilyl

[0037] Preparation of 4-tert-butyldimethylsiloxy-2-oxopyrrolidone

[0038] Add 101.1 g (1.0 mol) of 4-hydroxy-2-oxopyrrolidone to 500 ml of DMF to dissolve, add 165.8 g (1.1 mol) of TBDMSCl and 102.1 g (1.5 mol) of imidazole, and react for 18 hours. The reaction solution was added to 1500.0g water, extracted with methyl tert-butyl ether (1000ml×3), washed once with 1000ml water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was crystallized from n-heptane, filtered and dried to obtain 4 - tert-butyldimethylsiloxy-2-oxopyrrolidone.

Embodiment 2

[0040] R 1 tert-butyldiphenylsilyl

[0041] Preparation of 4-tert-butyldiphenylsilyl-2-oxopyrrolidone

[0042] Add 200g (1.0mol) of 4-hydroxy-2-oxopyrrolidone into 500ml of DMF to dissolve, add 300g (1.1mol) of tert-butyldiphenylchlorosilane and 190.5g (1.5mol) of imidazole, and keep it at 40°C for 10 hours . The reaction solution was added to 2000.0g water, extracted with methyl tert-butyl ether (1500ml×3), washed once with 1000ml water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was crystallized from n-heptane, filtered and dried to obtain 4 - tert-butyldiphenylsilyl-2-oxopyrrolidone.

Embodiment 3

[0044] Preparation of Oxiracetam

[0045] Take 215.36 g of 4-tert-butyldimethylsilyloxy-2-oxopyrrolidone and 200.4 g of ethyl 2-bromoacetate in Example 1 and dissolve them in 800 ml of THF, and slowly add 1.6 M HMDSLi dropwise at 5°C Tetrahydrofuran solution 750ml, after dropping, keep the temperature and stir for 1 hour. TLC detection (developing agent dichloromethane: methanol = 30:1, phosphomolybdic acid for color development) the reaction is complete, add 900ml of water, separate the water layer, concentrate the organic layer to dryness, add 900ml of ethyl acetate to the residue, and wash once with water . Concentrate the ethyl acetate layer to dryness, add 600ml of n-heptane to crystallize, wash with 100ml of n-heptane, and dry to obtain ethyl 2-(4-tert-butyldimethylsilyloxy-2-oxopyrrolidin-1-yl)acetate Ester, the yield is 85%, and the HPLC detection shows that the purity is greater than 98%.

[0046] Take 301.45 g of the above-mentioned product 2-(4-tert-butyldimethy...

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Abstract

The invention provides a method for preparing oxiracetam, which comprises the steps of: reacting 2-(4-tertiary butyl disilyloxy-2-oxo pyrrolidine-1-yl) ethyl acetate or 2-(4-tertiary butyl diphenylsilyl-2-oxo pyrrolidine-1-yl) ethyl acetate as raw materials with low-molecular-weight halogenated acetic acid ester in a non-protonated solvent under basic condition, and respectively removing protecting groups to prepare oxiracetam. By adopting the method, the problems of the prior art that reaction conditions are rigor, byproducts are many, and the product purity and yield are low in the oxiracetam synthesis process are solved. The method is simple to operate, low in equipment requirements, and high in product purity and yield, and is particularly suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing oxiracetam. Background technique [0002] Oxiracetam, chemical name 2-(4-hydroxy-2-oxopyrrolidon-1-yl)acetamide, molecular formula C 6 h 10 N 2 o 3 , molecular weight 158.16. Oxiracetam is a compound that can promote phosphorylcholine, phosphorylethanolamine and brain metabolism. Long-term use of drugs containing this compound by the elderly can significantly improve tissue function and memory impairment, especially for the prevention and treatment of senile dementia. Significant effect. Drugs containing these compounds are also used in the treatment of senile cerebral insufficiency syndrome and mental behavioral disorders. [0003] The synthesis technology of oxiracetam that has been reported at present is mainly divided into two ways, one is to prepare pyrrolidone line and then synthesize it with amide or amide salt or ethyl haloacetate to obta...

Claims

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Application Information

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IPC IPC(8): C07D207/273
CPCY02P20/55
Inventor 袁建栋郁光亮
Owner BRIGHTGENE PHARMA
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