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Method for preparing levetiracetam

A technology for aminobutyramide and aminolysis reaction, which is applied in the field of drug preparation, can solve the problems of complex process, long steps, low yield and the like, and achieves the effects of high resolution yield, short reaction steps and mild reaction conditions

Active Publication Date: 2012-03-21
ZHEJIANG JIANGBEI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw materials of this traditional process are cheap and easy to buy, but the disadvantages are long steps, low yield and too complicated process

Method used

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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

[0027] A preparation method of levetiracetam, comprising the steps of:

[0028] Step 1: 2-aminobutyramide synthetic method. React 500g of ammonia water and 60g of 2-bromobutyric acid at -5°C to 0°C for 3 to 5 days. After the reaction, concentrate to dryness, add 180ml of methanol to crystallize, and dry to obtain 33 grams of 2-aminobutyramide as a white solid. Molar yield ≥ 90%.

[0029] Step 2: the synthetic method of (S)-2-aminobutyramide tartaric acid

[0030] Dissolve 30 grams of 2-aminobutyramide in 200 ml of methanol, add 45 grams of L-(+)-tartaric acid, 0.3 grams of salicylaldehyde, heat up and reflux for 2 hours, cool and crystallize, and filter and dry the obtained S-(+)- 67 grams of 2-aminobutyramide tartaric acid, molar yield ≥ 90%

[0031] Step 3: the synthetic method of levetiracetam

[0032] 20 g of S-(+)-2-aminobutanamide tartaric acid was put into 120 ml of dichloromethane, 10 g of anhydrous sodium sulfate, 0.1 g of tetrabutylammonium bromide, and 25 g of p...

Embodiment 2

[0034] A preparation method of levetiracetam, comprising the steps of:

[0035] Step 1 is the same as Step 1 in Example 1.

[0036] Step 2: the synthetic method of (S)-2-aminobutyramide tartaric acid

[0037] Dissolve 30 grams of 2-aminobutyramide in 200 ml of methanol, add 45 grams of L-(+)-tartaric acid and 0.26 grams of benzaldehyde, heat up and reflux for 2 hours, cool and crystallize, and filter and dry the obtained S-(+)-2 - 67 grams of aminobutyramide tartaric acid, molar yield ≥ 90%

[0038] Step 3: the synthetic method of levetiracetam

[0039] 20 g of S-(+)-2-aminobutyramide tartaric acid was put into 120 ml of dimethyl tert-butyl ether, 10 g of anhydrous sodium sulfate, 0.1 g of tetrabutylammonium bromide, and 18 g of powdery sodium hydroxide were added. Control the temperature below 5°C, add 12g of 4-chlorobutyryl chloride dropwise, and keep warm at about 0°C for 5 hours after the drop is completed. After the reaction, filter, the filtrate is decompressed to re...

Embodiment 3

[0041] A preparation method of levetiracetam, comprising the steps of:

[0042] Step 1 and Step 2 are the same as Step 1 and Step 2 in Example 1.

[0043] Step 3: the synthetic method of levetiracetam

[0044] 20 g of S-(+)-2-aminobutyramide tartaric acid was put into 120 ml of acetonitrile, 10 g of anhydrous sodium sulfate, 0.1 g of tetrabutylammonium bromide, and 18 g of powdery sodium hydroxide were added. Control the temperature below 5°C, add 12g of 4-chlorobutyryl chloride dropwise, and keep warm at about 0°C for 5 hours after the drop is completed. After the reaction, filter, the filtrate is decompressed to recover the dichloromethane solvent, add acetone to the residue to recrystallize, and dry to obtain 12g of levetiracetam, the molar yield is ≥88%, the melting point is 116°C-120°C, and the purity is ≥99.9 %, single impurity ≤0.03%, total impurity ≤0.1%.

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Abstract

The invention provides a method for preparing levetiracetam, comprising the following steps of: taking 2-bromine butyric acid as a raw material, subjecting to ammonolysis reaction, concentrating till drying, adding carbinol, crystallizing and drying so as to obtain 2-amino butyramide solid; dissolving the 2-amino butyramide solid in the carbinol, resolving and salifying by utilizing L-(+) - tartaric acid under the existence of a catalyst so as to obtain S-(+)-2- amino butyramide tartrate; and putting the S-(+)-2- amino butyramide tartrate into an aprotic solvent, adding anhydrous sodium sulfate and tetrabutyl amonium bromide, reacting with 4-chlorobutyryl chloride under an alkaline condition, filtering, decompressing filtrate, recovering the aprotic solvent, adding acetone into the surplus filtrate, recrystallizing and drying so as to obtain levetiracetam solid. The preparation method provided by the invention has the advantages of short reaction step, mild reaction condition, low cost and high yield.

Description

technical field [0001] The invention relates to a preparation method of medicine, in particular to a preparation method of levetiracetam. Background technique [0002] Antiepileptic drugs are a class of drugs used to prevent and treat paroxysmal and temporary brain dysfunction caused by epileptic seizures. Levetiracetam is a unique pharmacological action developed by Belgian UCB Company for the treatment of localized and secondary generalized epilepsy, and does not affect the metabolism of other antiepileptic drugs in vivo. [0003] The synthetic route of levetiracetam can be roughly divided into the following two: [0004] The first one uses 2-pyrrolidone and methyl 2-bromobutyrate as raw materials to obtain levetiracetam through N-alkylation, hydrolysis, resolution and amidation. This route has simple steps, but under harsh or mild conditions, highly toxic dangerous goods need to be used. [0005] The second route passes through (S)-2-aminobutyramide; or uses 2-bromobut...

Claims

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Application Information

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IPC IPC(8): C07D207/27
Inventor 刘文山王高峰闻小俊李丽珍章金华陆康康刘汗荣
Owner ZHEJIANG JIANGBEI PHARMA
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