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Improved method for synthesizing valsartan

A compound, the technology of valine alkyl ester, applied in the direction of organic chemistry, can solve the problems of low yield, difficult to reduce the content of optical isomers, difficult to control, etc.

Active Publication Date: 2010-09-01
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the use of tin-containing reagents, the residual tin will always be carried into the final product, and the organotin compound is a highly toxic compound. According to the requirements of the drug ICH, the organotin compound in the finished product should be within 1ppmm, very hard to control
[0004] Chinese Patent Publication No. CN101270096A mentions that the above method has been improved, canceling the use of halogenated alkyl tin compounds to participate in the reaction, and instead using the reaction of compound 5 with the metal salt of azide in the presence of triethylamine hydrochloride. In the final product , does not have tin compound, but also produces a series of problems at the same time, as the product quality of this triethylamine hydrochloride process is not as good as the tributyl tin chloride process, and the yield is also low, especially the high optical isomers in the product , it is difficult to reduce the content of optical isomers

Method used

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  • Improved method for synthesizing valsartan
  • Improved method for synthesizing valsartan
  • Improved method for synthesizing valsartan

Examples

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Effect test

example 1

[0025] Example 1: Synthesis of Valsartan

[0026] Add 200ml of water, 25g of sodium carbonate, 350ml of toluene and 28g of condensate hydrochloride into the reaction bottle, stir to dissolve, cool down to 10°C, add 18g of valeryl chloride dropwise, and keep it warm at 10°C for 2 hours. After the reaction is complete, let it stand The layers were separated, and the lower aqueous layer was separated. The organic layer was washed with sodium bicarbonate solution and dilute hydrochloric acid, dried over magnesium sulfate, and filtered to obtain a pentanoylation reaction solution. Add 11 g of sodium azide and 23.5 g of triethylamine hydrochloride to the valerylation reaction solution, and react under reflux for 30 hours, cool down to 50°C, add 200ml of 8% sodium hydroxide solution, and react at 25°C for 4 hours, statically Separate the layers, separate the organic layer, use 6M dilute hydrochloric acid to adjust the pH of the reaction solution to 1-2, add 200ml of isopropyl acetate...

example 2

[0027] Example 2: Synthesis of Valsartan

[0028] Add 200ml of water, 25g of sodium carbonate, 350ml of toluene and 28g of condensate hydrochloride into the reaction bottle, stir to dissolve, cool down to 10°C, add 18g of valeryl chloride dropwise, and keep it warm at 10°C for 2 hours. After the reaction is complete, let it stand The layers were separated, and the lower aqueous layer was separated. The organic layer was washed with sodium bicarbonate solution and dilute hydrochloric acid, dried over magnesium sulfate, and filtered to obtain a pentanoylation reaction solution. Add 11g of sodium azide and 23.5g of triethylamine hydrochloride to the valerylation reaction solution, reflux for 25 hours, cool down to 50°C, add 200ml

[0029] 8% sodium hydroxide solution, reacted at 20°C for 4 hours, let stand to separate layers, separated the organic layer, adjusted the pH of the reaction solution to 1-2 with 6M dilute hydrochloric acid in the alkaline aqueous layer, added 200ml of ...

example 3

[0030] Example 3: Synthesis of Valsartan

[0031] Add 200ml of water, 25g of sodium carbonate, 350ml of toluene and 28g of condensate hydrochloride into the reaction bottle, stir to dissolve, cool down to 10°C, add 18g of valeryl chloride dropwise, and keep it warm at 10°C for 2 hours. After the reaction is complete, let it stand The layers were separated, and the lower aqueous layer was separated. The organic layer was washed with sodium bicarbonate solution and dilute hydrochloric acid, dried over magnesium sulfate, and filtered to obtain a pentanoylation reaction solution. Add 11g of sodium azide and 23.5g of triethylamine hydrochloride to the valerylation reaction solution, reflux for 25 hours, cool down to 50°C, add 200ml of 8% sodium hydroxide solution, react at 20°C for 4 hours, and let stand Separate the layers, separate the organic layer, adjust the pH of the reaction solution to 1-2 with 6M dilute hydrochloric acid in the alkaline aqueous layer, add 200ml of isopropy...

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Abstract

The invention provides an improved method for synthesizing valsartan. The valsartan synthesized by the method can be further purified to give high-purity valsartan. In the method, tin compounds are not used, N-[(2'-cyano-1,1'-biphenyl-4-yl)alkyl]-ester L-valine monohydrochloride is used as a raw material, pentaacylation, diazotization and saponification are performed to obtain the valsartan, a crystallization process is controlled and thus the high-purity valsartan is obtained. The method has the advantages that: the operation is simple; the yield is high; the product purity is high; and the industrial production is easy.

Description

(1) Technical field [0001] The invention relates to an improved method for synthesizing valsartan, belonging to the fields of chemical industry and chemical medicine. (2) Background technology [0002] Valsartan (Valsartan), Chinese name (S)-N-(1-pentanoyl)N-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]-L-valerian Amino acid, a non-peptide angiotensin II receptor antagonist (ARB), was first launched in Germany after being successfully developed by Swiss Novartis. It was approved by the US FDA in December 1996 and launched in the US in 1997 under the product name Diovan. In 1998, Novartis’ valsartan was registered in China under the product name Diovan. Valsartan's US patent will expire on March 12, 2012. [0003] The preparation method mentioned in U.S. Patent US5399578A is: compound 4 (N-[(2'-cyano-1,1'-biphenyl-4-yl) alkyl]-L-valine methyl ester hydrochloride) Mixed with dichloromethane and triethylamine, and then reacted with valeryl chloride to obtain compound 5 (N-(1-pentan...

Claims

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Application Information

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IPC IPC(8): C07D257/04
Inventor 陈为人龚道新
Owner ZHEJIANG MENOVO PHARMA
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