Method for crystallizing valsartan

A technology of valsartan and crystallization, applied in the crystallization field of valsartan, can solve the problems of high cost, few literature reports, low yield and the like, and achieves the effects of simple operation, simple operation and good quality

Active Publication Date: 2013-05-08
浙江新赛科药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] There are many relevant documents about valsartan, especially the documents about the synthesis route of valsartan, but there are few reports about the crystallization method of valsartan, such as patents ZL200710038346.0, ZL001100115355.2, WO2004026847, WO2004026847, US7741507, The laboratory crystallization method of valsar...

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  • Method for crystallizing valsartan

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Embodiment 1

[0032] The preparation of embodiment 1 valsartan crude product

[0033] Crude valsartan can be prepared by existing preparation methods, such as the existing 4-bromomethyl-2'-cyanobiphenyl as raw material and L-valine methyl ester condensation, followed by valerylation and cyclization and hydrolysis to prepare crude valsartan (see: US Patent US7741507), quality: chromatographic purity 93%, chiral isomers: 3.7%, loss on drying: 20%.

Embodiment 2

[0034] The refining of embodiment 2 valsartan crude product

[0035] Add 400kg of crude valsartan to a 5000L reactor, then add 2000kg of ethyl acetate, stir and dissolve, wash twice with 200kg of drinking water, after washing, recover ethyl acetate from the ethyl acetate layer until dry, then add 1920kg Ethyl acetate, heated up to 40°C to dissolve, after dissolving, add 640kg cyclohexane, after adding, stir and cool down to 18°C, keep warm for 12 hours, then slowly cool down to 0°C at a cooling rate of 0.1°C / min, keep warm After 4 hours, centrifuge and dry to obtain 290kg of valsartan, with a total refined yield of 90.6%, quality: chromatographic purity of 99.88%, chiral isomers of 0.25%, and a single residual solvent of less than 100ppm.

Embodiment 3

[0036] The refining of embodiment 3 valsartan crude product

[0037] Add 400kg of crude valsartan to a 5000L reactor, then add 2000kg of ethyl acetate, stir and dissolve, wash twice with 200kg of drinking water, after washing, recover ethyl acetate from the ethyl acetate layer until dry, then add 2240kg Ethyl acetate, heated up to 40°C to dissolve, after dissolving, add 960kg cyclohexane, after adding, stir and cool down to 18°C, keep warm for 12 hours, then slowly cool down to 0°C at a cooling rate of 0.5°C / min, keep warm After 4 hours, centrifuge and dry to obtain 280kg of valsartan, with a total refined yield of 87.5%, quality: chromatographic purity of 99.78%, chiral isomers of 0.34%, and a single residual solvent of less than 100ppm.

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Abstract

The invention discloses a method for crystallizing valsartan. The method comprises the following steps of: dissolving a valsartan crude product by using an ester solvent; cleaning the ester solvent layer by using water to recover the dry solvent; adding an ester solvent for dissolving the material; adding an alkane solvent after dissolving; stirring and cooling to a first stage temperature of 15 to 20 DEG C, and preserving the heat; then cooling to a second stage temperature of -3 to 3 DEG C, and preserving the heat; centrifuging; and drying to obtain the valsartan. The method is simple to operate, high in yield and low in cost, the mass yield is over 85 percent, the obtained valsartan is high in quality, and the used reagents are common reagents which are cheap and easily obtained. Meanwhile, the method is an industrial crystallization method which is very suitable for industrial production and provides a technical support for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a crystallization method of valsartan. Background technique [0002] Valsartan, chemical name: N-(1-pentanoyl)-N-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]-L-valine, available It is suitable for various types of hypertension, and has a good protective effect on the heart, brain and kidney. Hypertensive patients such as myocardial infarction, heart failure, proteinuria, and diabetes can be used routinely, and can be used in combination with diuretics (such as hydrochlorothiazide). The structural formula of valsartan is as follows: [0003] [0004] There are many relevant documents about valsartan, especially the documents about the synthesis route of valsartan, but there are few reports about the crystallization method of valsartan, such as patents ZL200710038346.0, ZL001100115355.2, WO2004026847, WO2004026847, US7741507, The laboratory crystallization method of v...

Claims

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Application Information

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IPC IPC(8): C07D257/04
Inventor 李洪武杨和军肖俊朱汇锋周卫国
Owner 浙江新赛科药业有限公司
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