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Synthesis process of valsartan

A synthesis process and valsartan technology are applied in the field of valsartan synthesis technology, can solve the problems of high pollution and high risk, and achieve the effects of improving product purity, improving production efficiency and mild reaction conditions

Active Publication Date: 2021-11-30
安徽美诺华药物化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the traditional preparation process, the tetrazole ring is prepared by high-temperature reaction between cyano group and azide, which is highly polluting and dangerous, and the Chinese Pharmacopoeia stipulates that the R-configuration content of valsartan should not exceed 1.0%. During the production process of this drug In valsartan, the content of R-enantiomer must be controlled. Since the chiral center in the molecular structure of valsartan is connected to three special groups, namely carboxyl group, isopropyl group and polyaromatic ring group, according to the "three-point action" chiral The carboxyl group in the valsartan structure can provide ion exchange sites, the isopropyl group can provide steric hindrance sites, and the polyaromatic ring groups can increase the π-π interaction sites, through cation exchange , steric hindrance, and π-π interaction as the starting point, design a chiral stationary phase to selectively adsorb R-type and S-type valsartan, increase the content of S-enantiomer in valsartan, and simplify Synthetic process, improving production efficiency is a technical problem that needs to be solved at present

Method used

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  • Synthesis process of valsartan
  • Synthesis process of valsartan
  • Synthesis process of valsartan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] The chiral fixation is made by the following steps:

[0029] Step S1, 1.0 g Quinin is dispersed in 60 ml of toluene, reflux reaction for 3 h, after the reaction is completed, cooled to room temperature, add 0.63 g of 4-nitrophenyl chloroformate, at room temperature, rotation speed 60R / min stirring reaction 24h After the reaction, filtered, filter cake was washed with toluene, n-hexane was washed, and then dried in vacuo to constant weight at 40 ° C to give intermediate 1;

[0030]Step S2, 0.63 g of intermediate 1, 0.3 g of iron powder and 68 ml of anhydrous ethanol were added to the reactor, and after refluxing for 3 h, a hydrochloric acid solution was added, and the reaction liquid pH was 7, continued to react 1 h, and the reaction was completed, filtered After extraction of ethyl acetate, evaporation, to give intermediate 2, hydrochloric acid solution mass fraction of 17%;

[0031] Step S3, 5.8 g of intermediate 2, 1.1 g of chloroacetrazine and 68.7 ml of tetrahydrofura...

Embodiment 2

[0035] The chiral fixation is made by the following steps:

[0036] Step S1, 1.0 g Quinnin is dispersed in 62 ml of toluene, reflux reaction for 3 h, after the reaction is completed, cooled to room temperature, add 0.64 g of 4-nitrophenyl chloroformate, at room temperature, rotational speed 70R / min stir stock 24 h After the reaction, filtered, filter cake was washed with toluene, n-hexane was washed, and then dried in vacuo to constant weight at 40 ° C to give intermediate 1;

[0037] Step S2, 0.64 g of intermediate 1, 0.3 g of iron powder and 70 ml of anhydrous ethanol were added to the reactor, and after refluxing for 4 h, a hydrochloric acid solution was added, and the reaction liquid pH was 7, continued to react 1 h, and the reaction was completed, filtered After extraction of ethyl acetate, evaporation, to give intermediate 2, hydrochloric acid solution mass fraction of 17%;

[0038] Step S3, 6.1 g of intermediate 2, 1.1.2 g of chloroacetamic chloride and 72.3 ml of tetrahy...

Embodiment 3

[0042] The chiral fixation is made by the following steps:

[0043] Step S1, 1.0 g Quinnon is dispersed in 65 ml of toluene, reflux reaction for 3 h, after the reaction, cool to room temperature, add 0.65 g of 4-nitrophenyl chloroformate, at room temperature, rotation speed 80R / min stirring reaction 24h After the reaction, filtered, filter cake was washed with toluene, n-hexane was washed, and then dried in vacuo to constant weight at 40 ° C to give intermediate 1;

[0044] In step S2, 0.65 g of intermediate 1, 0.3 g of iron powder and 74 ml of anhydrous ethanol were added to the reactor, and after refluxing reaction for 5 h, a hydrochloric acid solution was added, and the reaction liquid pH was 8, and the reaction was continued for 1 h, and the reaction was completed, filtered After extraction of ethyl acetate, evaporation, to give intermediate 2, hydrochloric acid solution mass fraction of 17%;

[0045] Step S3, 6.3 g of intermediate 2, 1.3 g of chloroacetyl chloride and 74.1 ...

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Abstract

The invention relates to a synthesis process of valsartan, belonging to the technical field of medicine synthesis. The synthesis process comprises the following steps: mixing DMF, L-valine methyl ester hydrochloride and N,N-diisopropylethylamine, carrying out magnetic stirring at 5 DEG C, dropwise adding n-valeryl chloride, and conducting stirring at a room temperature for a reaction for 1.5 hours after dropwise adding to obtain an intermediate product a; producing an intermediate product b from the intermediate product a and N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl)tetrazole under the action of a hydrogen pulling agent and a condensing agent; and subjecting the intermediate product b to protection group removal and ester group hydrolysis to obtain a crude valsartan product, and finally, carrying out chiral separation to obtain the valsartan target product with a high S-enantiomer content. According to the invention, an existing raw material is used as a substrate, so generation of impurities is reduced, a synthesis route is shortened, product purity is improved, and production efficiency is improved; and moreover, reaction conditions are mild, and the process is an efficient valsartan synthesis process.

Description

Technical field [0001] The present invention belongs to the field of medical synthesis, and in particular, to a synthetic process of valsartan. Background technique [0002] Valsartan, the chemical name is (S) -N-pentyl-N - [[2 '- (1H-5-tetrazole) [1,1'-biphenyl] -4-yl] methyl 】 Valine, trade name (Diovan), has a chiral center, a pair of optical enantiomers, wherein the S-enantiomer has biological activity, while the R-enantiomer has no biological activity. [0003] In the conventional preparation process, tetrazolic ring is prepared with the azide of the azide, the contamination is high, the risk is high, and the China Pharmaceutical specification is not more than 1.0% in the proliferation of valsartan, in the pharmaceutical process In the middle, the content of the R-enantiomer must be controlled, and three special groups are connected in the histacological center of the valsia, which are carboxyl groups, isopropyl and multi-aromatic cyclists, respectively, according to "three ...

Claims

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Application Information

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IPC IPC(8): C07D257/04B01D15/38
CPCC07D257/04B01D15/3833
Inventor 孙海涛龚道新刘俊刘琳梅贤军郭伟云陈军李望
Owner 安徽美诺华药物化学有限公司
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