A kind of synthetic method of valsartan intermediate

A synthesis method and intermediate technology are applied in the field of synthesis of valsartan intermediates, can solve the problems of high consumption of n-valeryl chloride, large environmental pollution, increased consumption, etc., achieve improved purity and yield, reduced production cost, reduced The effect of pollution

Active Publication Date: 2022-04-05
ZHEJIANG MENOVO PHARMA
View PDF15 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Due to the presence of water in the reaction system, n-pentanoyl chloride will undergo hydrolysis reaction, which will lead to an increase in its dosage
And in the molar ratio of compound of formula II and n-valeryl chloride in the prior art, the amount of n-valeryl chloride is too high, which increases the residue of impurity n-valeric acid in the product, and needs to be washed with ammonia for many times, which is not only unfavorable for the quality control of the product , leading to lower product purity and yield, and also increased production costs and nitrogen-containing wastewater discharge, causing greater environmental pollution

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • A kind of synthetic method of valsartan intermediate
  • A kind of synthetic method of valsartan intermediate
  • A kind of synthetic method of valsartan intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The synthetic method of the valsartan intermediate of the present embodiment comprises the following steps:

[0030] (1) add 30g formula II compound and 200mL toluene in 500mL four-necked flask, stir; 21g sodium carbonate and 18g sodium chloride are added into 120mL water, after stirring and dissolving, add dropwise to the above-mentioned four-necked flask; The temperature is 20~28℃, slowly add 12g of n-valeryl chloride and 20mL of toluene mixture dropwise, after the drop is completed, keep stirring, and detect the residue of the compound of formula II by HPLC;

[0031] (2) After HPLC detects that the residue of the compound of formula II is less than or equal to 0.10%, 120 mL of water is added, the aqueous layer is separated, the organic phase is washed with 120 mL of 2.5% ammonia water, and the aqueous layer is separated; the organic phase is washed with 50 mL of 5% aqueous hydrochloric acid, and the water is separated. The organic phase was washed with 50 mL of 2% so...

Embodiment 2

[0033] The synthetic method of the valsartan intermediate of the present embodiment comprises the following steps:

[0034] (1) in 500mL four-necked flask, add 30g formula II compound and 200mL xylene, stir; 30g potassium carbonate and 20g sodium chloride are added in 150mL water, after stirring and dissolving clear, add dropwise in above-mentioned four-necked flask; Control The inner temperature is 20~28℃, slowly add 11g n-valeryl chloride and 20mL xylene mixed solution dropwise, after dripping, keep stirring under heat, HPLC detects the residue of the compound of formula II;

[0035] (2) After HPLC detects that the residual compound of formula II is less than or equal to 0.10%, 120 mL of water is added, and the water layer is removed; the organic phase is washed with 120 mL of 2.5% ammonia water, and the water layer is removed; the organic phase is washed with 50 mL of 5% aqueous hydrochloric acid, and the water is removed. The organic phase was washed with 50 mL of 2% sodiu...

Embodiment 3

[0037] The synthetic method of the valsartan intermediate of the present embodiment comprises the following steps:

[0038] (1) in 1000mL four-necked flask, add 50g formula II compound and 335mL methylene dichloride, stir; 35g sodium carbonate and 39g potassium chloride are added in 200mL water, after stirring and dissolving clear, add dropwise in above-mentioned four-necked flask; Controlling the internal temperature at 20-28°C, slowly adding 20 g of n-valeryl chloride and 33.5 mL of dichloromethane mixture dropwise, after dripping, stirring at a temperature, HPLC detects the residue of the compound of formula II;

[0039] (2) After HPLC detects that the residue of the compound of formula II is less than or equal to 0.10%, add 200 mL of water, and remove the water layer; wash the organic phase with 200 mL of 2.5% ammonia water, and remove the water layer; wash the organic phase with 85 mL of 5% aqueous hydrochloric acid, and remove the water The organic phase was washed with ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The present invention relates to a kind of synthetic method of valsartan intermediate, comprises the following steps: (1) first dissolving following formula II compound in organic solvent, adding acid-binding agent, sodium chloride or potassium chloride and water, stirring evenly , after adding n-valeryl chloride dropwise, carry out insulation reaction; (2) add water to quench after completion of the reaction, carry out alkali washing, pickling, and alkali washing successively, and finally obtain the following formula I compound of the target product by distillation under reduced pressure, i.e. N-[( 2'-cyanobiphenyl-4-yl)methyl]-N-(1-oxopentyl)-L-valine methyl ester. In the present invention, by adding an appropriate amount of sodium chloride or potassium chloride to the reaction system, the occurrence of the hydrolysis reaction of n-valeryl chloride is suppressed by using the same ion effect, thereby reducing the amount of n-valeryl chloride, which is beneficial to improving the purity and yield of the product , reduces production cost, reduces environmental pollution, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparation, in particular to a method for synthesizing a valsartan intermediate. Background technique [0002] Valsartan, chemical name: N-(1-oxopentyl)-N-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]-L-valine , is an angiotensin II receptor antagonist developed by Novartis, which has the characteristics of stable blood pressure reduction, strong curative effect, long duration of action and good patient tolerance. [0003] The compound N-[(2'-cyanobiphenyl-4-yl)methyl]-N-(1-oxopentyl)-L-valine methyl ester is a key intermediate in the synthesis of valsartan, Its structure is shown in formula I. [0004] [0005] Preparation of valsartan intermediate N-[(2'-cyanobiphenyl-4-yl)methyl]-N-(1-oxopentyl)-L-valine methyl ester in the prior art, It is N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester hydrochloride (structure shown in formula II) and n-valeryl chloride in aqueous solution of inorganic...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(China)
IPC IPC(8): C07C253/30C07C253/34C07C255/60
CPCC07C253/30C07C253/34C07C255/60
Inventor 余奎唐雪松黄勤张富荣黄想亮曹倩
Owner ZHEJIANG MENOVO PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap