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Preparation method of small-particle-size Levetiracetam

A particle and particle size technology, applied in the field of medicinal chemistry, can solve the problems of many process operation steps, low tap density, limited production capacity, etc., and achieve the effects of good process reproducibility, high yield and simple operation.

Inactive Publication Date: 2018-07-27
ZHEJIANG HUAHAI PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The particle size of the obtained levetiracetam is relatively large, the crystals are lumpy, and the tap density of the product is small. Usually, it is necessary to use means such as jet milling to break the product particles before performing the preparation work. The process operation steps are many and complicated, and at the same time The broken levetiracetam crystals have poor morphology, and the solvent agglomerates and absorbs water during storage and transportation, which leads to higher commercial production costs and limited production capacity

Method used

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  • Preparation method of small-particle-size Levetiracetam
  • Preparation method of small-particle-size Levetiracetam
  • Preparation method of small-particle-size Levetiracetam

Examples

Experimental program
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Effect test

Embodiment 1

[0037] Add 100g of levetiracetam and 500ml of acetone to the reaction bottle, and stir at a temperature of 50-60°C until it dissolves; add 2000ml of cyclohexane to the crystallization bottle, and cool to 10°C. Add levetiracetam acetone solution dropwise to cyclohexane under temperature control at 0-10°C, keep warm and crystallize at -10-0°C for 2 hours after the dropwise addition, after the crystallization is complete, filter, and dry the filter cake at 30°C to obtain 94g levetiracetam, yield 94.0%; D90=108.9μm, D50=36.5μm; tap density 0.63g / cm 3 .

Embodiment 2

[0039] Add 100g of levetiracetam and 400ml of acetone in the reaction flask, and stir at 50-60°C with temperature control until it dissolves; add 1500ml of n-heptane in the crystallization flask, and cool to 0°C. Add levetiracetam acetone solution dropwise to n-heptane under temperature control at -10-10°C, heat and crystallize at -10-0°C for 1 hour after dropping, after crystallization is complete, filter, and dry the filter cake at 60°C. Obtain 93g levetiracetam, yield is 93.0%; D90=101.2μm, D50=37.4μm; Tap density 0.63g / cm 3 .

Embodiment 3

[0041] Add 100 g of levetiracetam and 300 ml of ethyl acetate to the reaction bottle, and stir at a temperature of 70 to 80 ° C until it dissolves; add 1000 ml of methyl tert-butyl ether to the crystallization bottle, and cool to -5 ° C. Add levetiracetam ethyl acetate solution dropwise to methyl tert-butyl ether under temperature control -10~10°C, keep warm and crystallize at -10~0°C for 0.5 hours after the dropwise addition, after crystallization is complete, filter, filter cake Dry at 50°C to obtain 93g of levetiracetam with a yield of 93.0%; D90=90.1μm, D50=40.2μm; tap density 0.67g / cm 3 .

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Abstract

The invention provides a preparation method of small-particle-size Levetiracetam. The method comprises the following steps: dissolving Levetiracetam in a benign solvent, and dropwisely adding the solution into a poor solvent; and after the dropwise addition is completed, keeping the temperature for crystallization, and performing filtration and drying to obtain the target product. The method of the invention is simple to operate; and the prepared Levetiracetam has the advantages of small particle size, high tap density, easy tableting and the like.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of levetiracetam. Background technique [0002] Levetiracetam, known in English as Levetiracetam, is an antiepileptic drug developed by UCB Company in Belgium. It was approved by the FDA in April 2000 and marketed in the United States. It is mainly used for the treatment of localized and secondary generalized epilepsy. Levetiracetam is a derivative of pyrrolidone. Compared with other epilepsy drugs, the drug shows stronger anti-epileptic properties and can effectively control epileptic seizures. Its chemical structural formula is as follows: [0003] [0004] The crystalline form of levetiracetam, which was originally developed by UCB, is the crystalline form I, and the maximum marketed dosage form of the preparation reaches 3000 mg. At present, there are many patent reports on the synthesis and preparation of levetiracetam, and the crystallization and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/27
CPCC07B2200/07C07D207/27
Inventor 钱刚张文灵
Owner ZHEJIANG HUAHAI PHARMA CO LTD