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Synthetic method of valsartan

A synthetic method, the technology of valsartan, which is applied in the field of valsartan synthesis, can solve the problems of low yield and high manufacturing cost, and achieve the effects of high yield, thorough reaction and sufficient contact

Inactive Publication Date: 2013-02-06
苏州天绿生物制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In order to overcome the defects of lower yield and high manufacturing cost in the existing valsartan synthesis process, the purpose of the invention is to provide a kind of synthetic method of valsartan

Method used

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  • Synthetic method of valsartan

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Experimental program
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Effect test

Embodiment 1

[0025] (1) Add 200ml purified water, 60g potassium carbonate, 42g L-valine methyl ester hydrochloride to the reaction flask, stir until dissolved, then add 500ml ethyl acetate and 95g 4-bromomethyl-2′- Add 2.3g of 18-crown-6 to cyanobiphenyl, stir, and heat to about 60°C for reflux reaction. After 2 hours of reaction, the reaction is over, the temperature is reduced to room temperature, the layers are separated, the organic layer is washed twice with 50ml of saturated brine. After washing, the organic phase is evaporated under reduced pressure, 250ml of purified water is added, stirred, and hydrochloric acid is added dropwise to pH =1-2, precipitated crystals, filtered with suction, washed, and dried to obtain 82.7g of intermediate I, with a yield of 92%.

[0026] (2) Add 240ml purified water and 114g potassium carbonate to the reaction flask and stir to clear. Add 620ml xylene, 2.7g 18-crown-6 and 82.7g Intermediate I and stir. At room temperature, drop a mixture of 34 g of n-...

Embodiment 2

[0031] (1) Add 200ml purified water, 60g potassium carbonate, 42g L-valine methyl ester hydrochloride to the reaction flask, stir until dissolved, add 500ml ethyl acetate and 95g 4-bromomethyl-2′-cyanide Then add 1.7g of 12-crown-4, stir, heat to about 60°C and reflux for reaction. After 2.5 hours of reaction, the reaction is over, the temperature is reduced to room temperature, the layers are separated, the organic layer is washed twice with 50ml of saturated brine, after washing, the organic phase is evaporated under reduced pressure, 250ml of purified water is added, stirring, and hydrochloric acid is added dropwise to pH =1-2, precipitated crystals, filtered with suction, washed, and dried to obtain 80.0g of intermediate I, with a yield of 89%.

[0032] (2) Add 240ml purified water and 110g potassium carbonate to the reaction flask and stir to clear. Then add 620ml xylene, 1.8g 12-crown-4 and 80g intermediate I and stir. At room temperature, drop a mixture of 33 g of n-vale...

Embodiment 3

[0037] (1) Add 200ml purified water, 60g potassium carbonate, 42g L-valine methyl ester hydrochloride to the reaction flask, stir until dissolved, then add 500ml ethyl acetate and 95g 4-bromomethyl-2′- To cyanobiphenyl, add 3.2g [2.2.2]-cryptone, stir, and heat to about 60°C for reflux reaction. After 3 hours of reaction, the reaction was over, the temperature was reduced to room temperature, the layers were separated, the organic layer was washed twice with 50ml of saturated brine. After washing, the organic phase was evaporated under reduced pressure, 250ml of purified water was added, stirred, and hydrochloric acid was added dropwise to pH =1-2, precipitated crystals, filtered with suction, washed, and dried to obtain 81.7g of intermediate I with a yield of 91%.

[0038] (2) Add 240ml purified water and 113g potassium carbonate to the reaction flask and stir to clear. Add 620ml xylene, 3.8g [2.2.2]-cryptone and 81.7g Intermediate I and stir. At room temperature, drop a mixtu...

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Abstract

The invention relates to a synthetic method of valsartan, wherein the valsartan is obtained by adopting 4-brooethyl-2'-cyanobiphenyl and L-valine methyl ester hydrochloride as starting materials and synthetizing via steps of coupling, acylating, azidation and hydrolyzing; in the steps of coupling and acrylating, the proper phase transfer catalyst is added to catalyst. In the synthetic method, the phase transfer catalyst is applied to synthetic process of the valsartan, thus, the reactants can contact each other fully; the reaction activity of the reactants is improved; the method has fast reaction speed, thorough reaction and high yield; compared with the method without the phase transfer catalyst, the yield of the target product valsartan can be improved by more than one time; the reaction time is notably shortened so as to further reduce manufacturing cost.

Description

Technical field [0001] The invention relates to the field of medical synthesis, in particular to a method for synthesizing valsartan. Background technique [0002] Valsartan is a specific angiotensin II (AT1) receptor antagonist. It is also another non-skin AT1 receptor antagonist used clinically after Losartan. It regulates systemic blood pressure and maintains electrolyte fluids. The balance plays a key role. It selectively acts on the AT1 receptor subtype and blocks the binding of AngII to the AT1 receptor (its specific antagonistic effect on the AT1 receptor is about 20,000 times greater than that of the AT2 receptor), thereby inhibiting vasoconstriction and the release of aldosterone. Antihypertensive effect, but does not inhibit potassium ion (K + ) The release of aldosterone. The antihypertensive effect of valsartan is better than enalapril. It is suitable for the treatment of hypertension, mild to moderate primary hypertension, especially for secondary hypertension caus...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04
Inventor 陆其华秦笃伟
Owner 苏州天绿生物制药有限公司
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