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Synthesis process of anti-heart-failure medicine sacubitril

A synthetic process, the technology of sacubitril, which is applied in the preparation of organic compounds, organic chemistry, carboxylic acid amide preparation, etc., can solve the problems of unfavorable scale-up production and high cost, and achieve low pollution, low cost, and cumbersome preparation The effect of steps

Pending Publication Date: 2022-05-06
无锡双启科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is currently the main process route for the synthesis of sacubitril. The starting material cost of this route is expensive, and high-risk reactions such as oxidation and hydrogenation are required, which is not conducive to industrial scale-up production

Method used

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  • Synthesis process of anti-heart-failure medicine sacubitril
  • Synthesis process of anti-heart-failure medicine sacubitril
  • Synthesis process of anti-heart-failure medicine sacubitril

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] A synthesis process of anti-heart failure drug sacubitril, the specific steps of the synthesis process are:

[0039] (1) Preparation of compound V

[0040] S1, add 266g (1mol) of compound II, 1000ml of dichloromethane, 143g (1.2mol) of thionyl chloride to the reaction flask, heat up to 40°C under reflux and stir for 4 hours, follow the reaction by HPLC until the reaction of compound II is complete; concentrate In the reaction solution, 298 g of compound III was obtained, and the molar yield was 105%.

[0041] S2, add 1000ml of dichloromethane, 298g (1mol) of compound III, 121g (1.2mol) of triethylamine to the reaction flask, add 121g of R-phenylethylamine (1mol) dropwise at 20°C, stir for 2 hours after dropping, follow the reaction by HPLC Until the reaction of compound III is complete; the organic layer is washed with 1M dilute hydrochloric acid, washed with saturated sodium chloride, concentrated, and 147 g of compound IV is obtained by adding 1000 ml of toluene for ...

Embodiment 2

[0052] A synthesis process of anti-heart failure drug sacubitril, the specific steps of the synthesis process are:

[0053] (1) Preparation of compound V

[0054] S1, add 266g (1mol) compound II, 1000ml dichloromethane, 131g (1.1mol) sulfur oxychloride in the reaction flask, add temperature and reflux and stir for 6 hours, HPLC follows reaction until compound II reacts completely; Concentrate the reaction solution, 297.8 g of compound III was obtained, molar yield: 105%.

[0055] S2, add 1000ml dichloromethane, 297.8g (1mol) compound III, 101g (1.0mol) triethylamine to the reaction flask, add 121g R-phenylethylamine (1mol) dropwise at 30°C, stir for 6 hours after dropping, HPLC Track the reaction until the reaction of compound III is complete; wash the organic layer with 1M dilute hydrochloric acid, wash with saturated sodium chloride, concentrate, add 1000ml of toluene for beating to obtain 146.5g of compound IV, racemize the mother liquor with aqueous sodium hydroxide solut...

Embodiment 3

[0064] A synthesis process of anti-heart failure drug sacubitril, the specific steps of the synthesis process are:

[0065] (1) Preparation of compound V

[0066] S1, add 266g (1mol) compound II, 1000ml dichloromethane, 131g (1.1mol) sulfur oxychloride in the reaction bottle, add temperature and reflux and stir for 2 hours, HPLC follows reaction until compound II reacts completely; Concentrate the reaction solution, 298g of compound III was obtained, molar yield: 105%.

[0067] S2, add 1000ml dichloromethane, 298g (1mol) compound III, 111g (1.1mol) triethylamine to the reaction flask, add 121g R-phenylethylamine (1mol) dropwise at 40°C, stir for 4 hours after dropping, follow by HPLC React until the reaction of compound III is complete; wash the organic layer with 1M dilute hydrochloric acid, wash with saturated sodium chloride, concentrate, add 1000ml of toluene for beating to obtain 147g of compound IV, add aqueous sodium hydroxide solution to racemize the mother liquor, ex...

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Abstract

The invention discloses a synthesis process of an anti-heart failure drug sacubitril, which comprises the following specific steps: (1) reacting a compound V with ethanol in the presence of concentrated sulfuric acid to generate a compound VI; (2) carrying out Michael addition reaction on the compound VI and succinimide in the presence of alkali to generate a compound VII; (3) hydrolyzing the compound VII to generate a compound I; the Sacubabu is the Sacubabu. In the synthesis process, starting materials are easy to obtain, operation is simple, the whole synthesis process is small in pollution and easy to separate and purify, dosage amplification is facilitated, industrial production is achieved, the yield of target products is higher, and the synthesis cost is lower.

Description

technical field [0001] The invention relates to the field of pharmaceutical chemical synthesis, in particular to a synthesis process of sacubitril, an anti-heart failure drug. Background technique [0002] Sacubitril / valsartan (Entresto) is a salt complex formed by combining sacubitril and valsartan at a molar ratio of 1:1. In July 2015, sacubitril / valsartan sodium was approved by the US FDA Approved; in May 2016, Europe and the United States updated their heart failure guidelines respectively, and both considered sacubitril / valsartan as a class I recommendation for heart failure. In 2017, sacubitril / valsartan sodium was launched in my country, and in 2018, it was included in my country's anti-heart failure guidelines. [0003] Sacubitril is one of the main components of sacubitril valsartan (Entresto), the chemical name is 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl )-5-ethoxy-4-methyl-5-oxopropan-2-yl)amino)-4-oxobutanoic acid. [0004] There have been many research reports on ...

Claims

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Application Information

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IPC IPC(8): C07C231/08C07C233/47C07D207/404C07C231/02C07C233/11
CPCC07C231/08C07D207/404C07C231/02C07B2200/07C07C233/47C07C233/11Y02P20/55
Inventor 顾喜丰秦英张国强
Owner 无锡双启科技有限公司
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