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Preparation method of levetiracetam

A technology of triethylamine and inert solvent, applied in the field of preparation of antiepileptic drug levetiracetam, can solve the problems of difficult industrialized operation, expensive reagents, low total yield and the like, and achieves easy control of the operation process, optical The effect of ideal purity and lower raw material cost

Inactive Publication Date: 2013-06-19
PEKING UNIV FOUNDER GRP CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this technology has the following disadvantages: 1. Use a large amount of inorganic strong alkali potassium hydroxide and water-absorbing agent anhydrous sodium sulfate, cause a large amount of solid waste residues, be difficult for realizing industrialization; Potassium hydroxide used needs to be ground into fine powder on the other hand, industrialization Difficult to operate
3. The product yield is low, only about 74%
This technology has the following disadvantages: 1. The reaction needs to be completed in two steps, and the more expensive base catalyst 2-hydroxypyridine will be used
2. The reaction time is long and the total yield is low
This technology has the following disadvantages: the required reagents are expensive, and the total yield of the product obtained is low

Method used

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  • Preparation method of levetiracetam
  • Preparation method of levetiracetam
  • Preparation method of levetiracetam

Examples

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preparation example Construction

[0038] The preparation method of levetiracetam provided by the invention comprises: 1) in an inert solvent, under a suitable organic base environment, make (S)-2-aminobutyramide hydrochloride and 4-chlorobutyryl chloride directly carry out one-step reaction Make levetiracetam, its reaction formula is as shown in following reaction formula (I):

[0039]

[0040] Reaction formula (I)

[0041] Wherein, the organic base of the present invention may be trimethylamine, triethylamine, tripropylamine or diisopropylethylamine, preferably tripropylamine or diisopropylethylamine. The yield of levetiracetam obtained by the method of the invention is ideal and the optical purity is high.

[0042] According to one embodiment of the present invention, the inert solvent in the present invention may be an inert organic solvent, such as benzene, toluene, xylene, methylene chloride, 1,2-dichloroethane, chloroform, preferably chloroform. The amount of the inert solvent can be 3 to 20 times t...

Embodiment approach

[0043] According to another embodiment of the present invention, the molar ratio of (S)-2-aminobutyramide hydrochloride, 4-chlorobutyryl chloride and the preferred organic base of the present invention can be 1: (1~5): (3~15). In the method of the present invention, if the molar ratio of 4-chlorobutyryl chloride and the organic base is too high, the cost of raw materials will be increased; if the molar ratio is too low, the reaction will be incomplete, resulting in reduced product yield and purity. Preferably, the molar ratio of (S)-2-aminobutyramide hydrochloride, 4-chlorobutyryl chloride and the preferred organic base is 1:(1.1-3):(2-6).

[0044] According to another embodiment of the present invention, the reaction temperature in the present invention may be -15°C to 15°C. In the method of the present invention, if the reaction temperature is too high, the product will racemize and reduce the optical purity of the product; if the reaction temperature is too low, the reacti...

Embodiment 1

[0066] With (S)-2-aminobutyramide hydrochloride (69.3 grams, 0.5mol), chloroform (831.6 grams), tripropylamine (300.7g, 2.1mol), join in the three-necked reaction flask that cryogenic thermometer is housed, stir After 10 minutes, start to cool down after uniformity. When it drops to -5°C, start to drop 4-chlorobutyryl chloride (141g, 1mol). , keep warm at 0~5 ℃ and continue to react for 4 hours, the raw material controlled in HPLC disappears, the product purity is 95.52%, stop the reaction, remove the solid in the reaction solution by suction filtration, and the filtrate is evaporated to dryness under reduced pressure (0.09MPa) at 50 ℃ to obtain Pale yellow solid, add 600ml of ethyl acetate to reflux until clarified, cool down naturally, refreeze (-5°C) for crystallization for 5 hours, filter with suction, wash the filter cake with glacial ethyl acetate (-5°C) until white, bake at 60°C After drying, 72.25 g of levetiracetam was obtained, with a yield of 84.9%, a liquid chromat...

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Abstract

The invention provides a preparation method of levetiracetam. The method comprises the steps that: (1) in an inert solvent, an organic alkali is adopted as a catalyst, and (S)-2-amino butanamide hydrochloride and 4-chloroprene chloride are subjected to a reaciton, such that levetiracetam is prepared. The reaction formula (I) is shown below. In the reaction formula (I), the organic alkali is selected from trimethylamine, triethylamine, tripropylamine and diisopropylethylamine ethylamine. Compared with prior arts, the method provided by the invention has the advantages that: according to the invention, the applications of a large amount of inorganic strong alkali and water absorbent are avoided, such that the production of a large amount of strong-alkaline solid waste is avoided; the method has the advantages of short reaction time, easy-to-control operation process, reduced raw material cost, and suitability for large-scale industrial production; with the method, levetiracetam yield is improved, and the obtained levetiracetam has ideal optical purity.

Description

technical field [0001] The invention belongs to the field of pharmacy, and in particular relates to a preparation method of an antiepileptic drug levetiracetam. Background technique [0002] Levetiracetam is a high-efficiency broad-spectrum antiepileptic drug developed by UCB Company in Belgium. It has been registered in the European Medicines Evaluation Agency (EMEA) and the US Food and Drug Administration (FDA) and has been used clinically. Levetiracetam has a unique mechanism of action, long duration of curative effect, less adverse reactions, good safety and tolerability, and can be used for addition therapy, adjuvant therapy or monotherapy of various types of epileptic seizures, and has a wide range of clinical applications. Application prospect. [0003] The chemical name of levetiracetam is: (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide; its English name is: (S)-α-Ethyl-2-oxo-1- pyrrolidineacetamide; its molecular formula is: C 8 h 14 N 2 o 2 , the molecular weight i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
Inventor 张铮王威
Owner PEKING UNIV FOUNDER GRP CO LTD
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