Method for preparing levetiracetam

An ethyl acetate, equivalent technology, applied in organic chemical methods, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve the problems of poor product purity chromatographic purity, complex process, low step yield, etc.

Active Publication Date: 2020-01-17
HUNAN DONGTING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] However, the method for preparing levetiracetam in the prior art has defects such as complex process, low step yield, poor product purity, especially poor chromatographic purity, therefore, providing a new method for preparing levetiracetam can especially Overcome above-mentioned one or more defectives, still those skilled in the art expect urgently

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  • Method for preparing levetiracetam
  • Method for preparing levetiracetam
  • Method for preparing levetiracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Embodiment 1: preparation levetiracetam

[0081] (1) Suspend 0.5 mol of (S)-2-aminobutyric acid in 12 equivalents of methanol in a reaction flask, add 1.2 equivalents of the reaction solvent thionyl chloride dropwise at a temperature of 25°C, and slowly raise the temperature after the addition is completed To 45°C, keep stirring for 4 hours to complete the reaction, concentrate under reduced pressure at 45°C to remove the solvent, add 2 equivalents of reaction solvent after the product is viscous, stir and cool down to -2-2°C to form a suspension.

[0082] (if not specified otherwise, the material represented by equivalent weight in the present invention all refers to the relative molar amount compared with the starting material of this step)

[0083] (2) Slowly add 8 equivalents of cold (0°C) ammonia water and 0.2 equivalents of oleic acid to the reaction flask of the suspension obtained in the previous step, stir for 6 hours, heat up to 20°C and continue stirring fo...

Embodiment 2

[0087] Embodiment 2: preparation levetiracetam

[0088] (1) Suspend 0.5 mol of (S)-2-aminobutyric acid in 12 equivalents of methanol in a reaction flask, add 1.2 equivalents of the reaction solvent thionyl chloride dropwise at a temperature of 30°C, and slowly raise the temperature after the addition is completed to 50°C, keep stirring for 4 hours to complete the reaction, concentrate under reduced pressure at 40°C to remove the solvent, add 2 equivalents of reaction solvent after the product is viscous, stir and cool down to -1-5°C to form a suspension.

[0089] (2) Slowly add 6 equivalents of cold (0°C) ammonia water and 0.3 equivalents of oleic acid into the reaction flask of the suspension obtained in the previous step, stir to react for 7 hours, heat up to 20-25°C and continue stirring for 3 hours to complete the reaction, add 0.2 equivalents of ethanol, 85 ° C under reduced pressure to distill ammonia water until a large amount of product precipitates, then add 6 equiv...

Embodiment 3

[0093] Embodiment 3: preparation levetiracetam

[0094] (1) Suspend 0.5 mol of (S)-2-aminobutyric acid in 12 equivalents of methanol in a reaction flask, add 1.2 equivalents of the reaction solvent thionyl chloride dropwise at a temperature of 20°C, and slowly raise the temperature after the addition is completed to 40°C, keep stirring for 4 hours to complete the reaction, concentrate under reduced pressure at 50°C to remove the solvent, add 2 equivalents of reaction solvent after the product is viscous, stir and cool down to -5-1°C to form a suspension.

[0095] (2) Slowly add 10 equivalents of cold (0°C) ammonia water and 0.1 equivalents of oleic acid into the reaction flask of the suspension obtained in the previous step, stir for 5 hours, heat up to 15-20°C and continue stirring for 4 hours to complete the reaction, add 0.2 equivalents of ethanol, 85 ° C under reduced pressure to distill ammonia water until a large amount of product precipitates, then add 6 equivalents o...

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Abstract

The invention relates to a method for preparing levetiracetam. The method comprises the following steps: reacting aminobutyric acid in lower alcohol and thionyl chloride to obtain an intermediate I; adding ammonia water to continue the reaction, and adding hydrochloric acid to adjust the pH value to about 3 to salify to obtain a salified intermediate II refined product; reacting the intermediate II in the presence of KOH in the presence of a catalyst and dichloromethane, and then adding 4-chlorobutyryl chloride to continuously react; adding water to hydrolyze, adjusting the pH to be weakly alkaline by using diluted hydrochloric acid, and crystallizing to obtain a levetiracetam crude product; decolorizing and crystallizing in ethyl acetate to obtain a refined product of levetiracetam. The invention also relates to the levetiracetam prepared by the method and pharmaceutical application thereof, for example, the levetiracetam can be used for treating or preventing epilepsy, Parkinson's disease, dyskinesia, migraine, tremor, idiopathic tremor, bipolar disorder, chronic pain, neuropathic pain, or bronchial, asthma or allergic diseases.

Description

technical field [0001] The present invention relates to a novel process for the preparation of levetiracetam having the excellent properties as described in the present invention. Background technique [0002] European patent EP0162036B discloses a kind of levorotatory compound levetiracetam (Levetiracetam), and its chemical name is (S)-(-)-[α]-ethyl-2-oxo-1-pyrrolidineacetamide, ( -)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide. Molecular formula C8H14N2O2, molecular weight 170.21, its chemical structure is as follows: [0003] [0004] Levetiracetam is white to off-white crystalline powder, which is easily soluble in water (1.04g / mL), chloroform (653mg / mL) and methanol (536mg / mL), dissolved in ethanol (165mg / mL), slightly Soluble in acetonitrile (57mg / mL). [0005] Levetiracetam is a cholinergic agonist. The drug is very effective in animal models of epileptic seizures induced by ignition and chemicals, but it is ineffective in animal models of ultra-strong electric sh...

Claims

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Application Information

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IPC IPC(8): C07D207/27A61K31/4015A61P25/08A61P25/16A61P25/14A61P25/18A61P25/06A61P25/00A61P21/00A61P11/06A61P37/08A61P29/00
CPCC07D207/27A61P25/08A61P25/16A61P25/14A61P25/18A61P25/06A61P25/00A61P21/00A61P11/06A61P37/08A61P29/00C07B2200/13C07B2200/07
Inventor 王波侯奇伟康璐
Owner HUNAN DONGTING PHARMA
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