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A kind of method for preparing olanzapine crystal form Ⅱ

A technology of olanzapine and crystal form, applied in organic chemistry and other directions, can solve the problems of prolonging drying time, high acetonitrile residue, reducing residual solvent, etc., to achieve the goal of reducing residual amount, good product purity, and conducive to market competition. Effect

Active Publication Date: 2016-06-01
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In summary, the current method for preparing crystal form II of olanzapine has the following problems: (1) A product with a purity of 99.5% can be obtained by direct recrystallization with acetonitrile, but the residue of acetonitrile is very high. The residual solvent of the obtained olanzapine is still about 1200ppm, and prolonging the drying time has no effect on reducing the residual solvent, while the residual amount of acetonitrile needs to be controlled below 410ppm to meet the pharmacopoeia standard

Method used

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  • A kind of method for preparing olanzapine crystal form Ⅱ
  • A kind of method for preparing olanzapine crystal form Ⅱ
  • A kind of method for preparing olanzapine crystal form Ⅱ

Examples

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Effect test

Embodiment 1

[0023] Example 1: Preparation of Olanzapine Form II

[0024] Add 10 g of crude olanzapine into 120 ml of acetonitrile, heat until dissolved, add 0.5 g of activated carbon, heat to reflux and keep stirring for 30 min under reflux. Filtrate while hot, slowly cool down the filtrate to 70°C and keep it warm at 65-70°C for 2 hours, then slowly cool it down to 55°C and keep it at 50-55°C and stir for 1.5 hours, then lower the temperature to 35°C within 1 hour and keep it warm for 30 Stir at ~35°C for 0.5 hours, finally cool down to 0-5°C and keep stirring for 1.5 hours, then filter. Add 30ml of ethyl acetate to the filter cake, heat to 60°C, stir and wash for 3 hours, then slowly cool down to 0-5°C and keep stirring for 1.5 hours, then filter. After the filter cake was dried, 9.1 g of solid was obtained, which was tested as olanzapine crystal form II, with a HPLC purity of 99.96%, 217 ppm of ethyl acetate and 255 ppm of acetonitrile.

Embodiment 2

[0025] Example 2: Preparation of Olanzapine Form II

[0026] Add 10 g of crude olanzapine into 120 ml of acetonitrile, heat until dissolved, add 0.5 g of activated carbon, heat to reflux and keep stirring for 30 min under reflux. Filtrate while hot, slowly cool down the filtrate to 70°C and keep it warm at 65-70°C for 2 hours, then slowly cool it down to 55°C and keep it at 50-55°C and stir for 1.5 hours, then lower the temperature to 35°C within 1 hour and keep it warm for 30 Stir at ~35°C for 0.5 hours, finally cool down to 0-5°C and keep stirring for 1.5 hours, then filter. Add 30ml of toluene to the filter cake, heat to 60°C, stir and wash for 3 hours, then slowly cool down to 0-5°C and keep stirring for 1.5 hours, filter, and dry the filter cake to obtain 9.2g of solid, which is olanzapine crystal form after inspection II, HPLC purity 99.95%, residual toluene 209ppm, residual acetonitrile 305ppm.

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Abstract

The invention discloses a method for preparing Zyprexa crystal form II. The method for preparing the Zyprexa crystal form II comprises the following steps of: dissolving a Zyprexa crude product into acetonitrile; cooling and crystallizing; washing the obtained crystal with ethyl acetate or methylbenzene; and drying to obtain the Zyprexa crystal form II. Compared with the prior art, the method has the advantages of effectively controlling residual quantity of the solvent acetonitrile and contributing to market competition, along with high purity in products.

Description

(1) Technical field [0001] The present invention relates to a kind of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (the present invention It is called olanzapine) preparation method of crystal form II. (2) Background technology [0002] Olanzapine is an antipsychotic drug with the chemical name 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] Benzodiazepines have the following structural formula: [0003] [0004] For the preparation method of olanzapine, please refer to US5229382, which is cited in its entirety as a reference in the present invention. US5229382 mentions that the crude product of olanzapine is recrystallized with acetonitrile. [0005] US5736541 characterized the crystal form of olanzapine for the first time. In this patent, the crude product of olanzapine was dissolved in ethyl acetate under anhydrous conditions, and the crystal form II was precipitated from the formed solution, and US5229382 The product obtained...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04
Inventor 王磊吕志宠王鹏
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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