Process for refining valsartan

A purification method and valsartan technology are applied in the field of industrial purification of valsartan, can solve the problems of no industrial purification method of valsartan, few literature reports, low purification yield and the like, and achieve the advantages of being environmentally friendly and easy to operate. , the effect of high yield

Active Publication Date: 2012-08-01
浙江新赛科药业有限公司
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  • Summary
  • 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 refining method of valsartan, such as in patents ZL200710038346.0, ZL00115355.2, WO2004026847, US7741507, US7199144 The laboratory refining method of valsartan is simply mentioned, namely: dissolve the crude product of valsartan in an ester solvent, and then cool down to crystallize. The disadvantages of this method are: using this method requires multiple refining, low refining yield and high cost
At present, there is no bibliographical report on the industrial refining method of valsartan

Method used

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  • Process for refining valsartan

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Experimental program
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Effect test

Embodiment 1

[0025] The preparation of embodiment 1 valsartan crude product

[0026] Crude valsartan can be prepared by the existing preparation method, such as the existing 4-bromomethyl-2'-cyanobiphenyl as raw material and L-valine methyl ester condensation, and then valerylation, cyclization and the crude valsartan prepared by hydrolysis (see: US Patent No. 7,741,507), the quality of the crude valsartan: chromatographic purity 91%, chiral isomer: 4%.

Embodiment 2

[0027] The refining of embodiment 2 valsartan crude product

[0028] Add 100kg of crude valsartan in Example 1 (loss on drying: 20%) to a 500L reactor, then add 160kg of ethanol, stir and dissolve at 20°C, after dissolving, add 40kg of calcium hydroxide, and stir at 20°C for 2 hours , filter to get the calcium salt of valsartan, the calcium salt of valsartan is added in the reactor of 1000L, add 450kg ethyl acetate, then add the dilute hydrochloric acid aqueous solution that mass percent concentration is 9% to adjust pH=2, After the adjustment, separate layers, wash the ester solvent layer twice, evaporate to dryness under reduced pressure to recover the dry solvent, add 432kg ethyl acetate to dissolve, after dissolving, transfer to the special kettle for crystallization of valsartan (disclosed in Chinese patent ZL201020216357.0 A special kettle for valsartan crystallization) was stirred, slowly cooled to -2.5°C ± 2.5°C, centrifuged, and dried under reduced pressure to obtain ...

Embodiment 3

[0029] The refining of embodiment 3 valsartan crude product

[0030] Add 100kg of crude valsartan in Example 1 (loss on drying: 20%) to a 1000L reactor, then add 500kg of ethyl acetate, stir and dissolve at 30°C, after dissolving, add 40kg of calcium hydroxide, stir at 30°C After 2 hours, filter to obtain the calcium salt of valsartan, add the calcium salt of valsartan in a 1000L reaction kettle, add 450kg of ethyl acetate, then add a 9% dilute hydrochloric acid aqueous solution to adjust the pH= 2. After adjustment, separate layers, wash the ester solvent layer with water twice, evaporate to dryness under reduced pressure to recover the dry solvent, add 432kg of ethyl acetate to dissolve, after dissolving, transfer to the special kettle for valsartan crystallization (Chinese patent ZL201020216357.0 A disclosed special kettle for valsartan crystallization) was stirred, slowly cooled to -2.5°C ± 2.5°C, centrifuged, and dried under reduced pressure to obtain 68kg of valsartan, w...

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Abstract

The invention discloses a process for refining valsartan, which includes the following steps: dissolving crude products of the valsartan with an alcoholic solvent or an ester solvent; adding inorganic base to form salt, so that salt of valsartan is obtained through centrifugation; adding the obtained salt of the valsartan into the ester solvent; adding an aqueous solution of an inorganic acid for acidification; delaminating; recovering a drying solvent after the ester solvent layer is washed with water; adding the ester solvent to dissolve materials; and obtaining the valsartan through stirring, cooling crystallization, centrifugation and drying after dissolution. The process is simple in operation, high in yield, low in cost and good in quality of the obtained valsartan, all the reagents are common, cheap and easy to obtain, and simultaneously, the process is beneficial to environmental protection and suitable for industrial production. The quality of the obtained valsartan conforms to a standard of Chinese Pharmacopoeia 2010, and the refining mass yield exceeds 75%.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an industrial refining 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 refining method of valsartan, such as in patents ZL200710038346.0, ZL00115355.2, WO2004026847, US7741507, US7199144 The laboratory refining method of valsartan is si...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04
Inventor 杨和军胡宇宏郭拥政吕士华叶鑫杰朱汇锋许永平肖俊
Owner 浙江新赛科药业有限公司
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