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Novel method for preparing valsartan

A new method and technology of valsartan, applied in the field of preparation of antihypertensive drug valsartan, can solve the problems of low chemical purity and low optical purity of valsartan, and achieve simplified post-processing process, high product purity, and high yield. high rate effect

Inactive Publication Date: 2013-04-03
Jiangsu Shimeikang Pharmaceutical Co Ltd
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The technical problem to be solved by the present invention is to provide a new method for preparing valsartan, so as to solve the problem that the valsartan produced by the existing technology has low chemical purity and low optical purity, and needs multiple recrystallizations to reach the pharmacopoeia standard

Method used

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  • Novel method for preparing valsartan
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  • Novel method for preparing valsartan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: Preparation of the cyclization reaction solution of valsartan methyl ester.

[0031] Add 150ml toluene and 40.65g (0.1mol) N-(1-pentanoyl)-N-[4-[2-(5-cyano)phenyl]benzyl]-L-valline to a 500ml four-neck flask Acid methyl ester (1), stirring, heating up (about 30 ℃) to the compound (1-pentanoyl)-N-[4-[2-(5-cyano)phenyl]benzyl]-L-valline The acid methyl ester is completely dissolved. After the dissolution is complete, add 6.5g (0.1mol) sodium azide, 13.75g (0.1mol) triethylamine hydrochloride and 4g (0.03mol) zinc chloride to it, and heat up to 100°C Left and right, reflux reaction for 20 hours, HPLC tracking sample, after the reaction, start to drop the temperature, add 200ml water to it for washing, separate the lower water layer, wash the organic layer with 100ml saturated saline, separate the brine layer, and obtain the organic layer Be the toluene solution 160g of valsartan methyl ester crude product, contain valsartan methyl ester 22%.

Embodiment 2

[0032] Embodiment 2: Preparation of valsartan methyl ester sodium salt.

[0033] In a 3000ml four-neck flask, add 1000g of valsartan methyl ester toluene solution (cyclization reaction solution prepared in Example 1, containing 22% of valsartan methyl ester), then add the solution made of 60g sodium bicarbonate and 540g water , stirred at room temperature to form a salt for 4 hours, filtered, washed with 100g of toluene, and then washed with 100g of water, and dried in vacuum at 80°C to constant weight to obtain 220g of white valsartan methyl ester sodium salt.

[0034] As detected by HPLC, the chemical purity is 99.4%.

[0035] Chiral HPLC detection, the optical purity is 99.2%.

[0036] 1 In HNMR analysis, there was no peak corresponding to the proton on the tetrazole ring.

[0037] Elemental analysis: C, 63.49%, H, 6.45%, N, 14.80%, Na, 4.85% (theoretical value: C, 63.68%, H, 6.41%, N, 14.85%, Na, 4.88%)

Embodiment 3

[0038] Embodiment 3: Preparation of valsartan methyl ester potassium salt.

[0039] Add 1000g valsartan methyl ester ethyl acetate solution (cyclization reaction solution, containing 25% valsartan methyl ester) in a 3000ml four-necked flask, then add a solution made of 80g sodium bicarbonate and 600g water, and stir at room temperature to form salt for 6 hours, filtered, washed with 100 g of toluene, and then washed with 100 g of water, and vacuum-dried at 80° C. to constant weight to obtain 260 g of white valsartan methyl ester potassium salt.

[0040] As detected by HPLC, the chemical purity is 99.5%.

[0041] Chiral HPLC detection, the optical purity is 99.1%.

[0042] 1 In HNMR analysis, there was no peak corresponding to the proton on the tetrazole ring.

[0043] Elemental analysis: C, 61.33%, H, 6.31%, N, 14.28%, K, 7.99% (theoretical value: C, 61.58%, H, 6.20%, N, 14.36%, K, 8.02%)

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Abstract

The invention discloses a novel method for preparing valsartan. The method comprises the following steps in sequence: carrying out cyclization reaction on N-(1-valeryl)-N-[4-[2-(5-cyan) phenyl] benzyl]-L-valine alkyl ester and sodium azide in the presence of ammonium salt, so as to obtain the valsartan methyl ester; mixing the cyclization reaction liquid of the prepared valsartan methyl ester with inorganic aqueous alkali I containing the sodium ion or potassium ion; stirring and reacting to obtain the salt; filtering again; washing; drying to obtain the pure valsartan methyl ester alkali metal salt; mixing and hydrolyzing the pure valsartan methyl ester alkali metal salt and the inorganic aqueous alkali II; acidifying again; extracting; recrystallizing at one time; and drying to obtain the valsartan, wherein the valsartan methyl ester alkali metal salt is provided with the following structural formula.

Description

technical field [0001] The invention belongs to the field of organic and pharmaceutical synthesis, in particular to a preparation method of antihypertensive drug valsartan. Background technique [0002] Valsartan (Valsartan) is a non-peptide angiotensin II receptor antagonist (ARB), clinically used to treat hypertension, the Chinese name is: N-(1-pentanoyl)-N-[4-[2- (1H-tetrazol-5-yl)phenyl]benzyl]-L-valine, the structural formula is as follows: [0003] [0004] U.S. Patent US5399578A discloses the preparation method of valsartan crude drug: N-(1-pentanoyl-N-[4-[2-(5-cyano)phenyl]benzyl]-L-valine benzyl ester Carry out cyclization reaction with sodium azide in the presence of organotin compounds to obtain valsartan benzyl ester, which is prepared by catalytic hydrogenolysis to valsartan. [0005] [0006] This method uses expensive and highly toxic organotin compounds to participate in the cyclization reaction, and the last step needs to use Pd to catalyze hydrogeno...

Claims

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Application Information

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IPC IPC(8): C07D257/04
Inventor 刘一超王晓维王秀云王俊华
Owner Jiangsu Shimeikang Pharmaceutical Co Ltd
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