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A purification method of a Sakubaquat Sandan sodium intermediate

The technology of a sacubitril-valsartan and a purification method is applied in the field of purification of an intermediate of sacubitril-valsartan sodium, and can solve the problems of incomplete acid removal, low purity and yield, corrosiveness of instruments and equipment, and the like, Achieve the effect of overcoming corrosive problems and simple operation

Active Publication Date: 2020-11-24
ZHUZHOU QIANJIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The purpose of the present invention is to overcome the defects of the prior art that the purity and yield of intermediate 1 are low, the acid removal is not complete, and the acid removal method is corrosive to instruments and equipment, and to provide a more effective method for significantly improving the purity and yield of intermediate 1. Acid removal, and can avoid the purification method of sacubitril valsartan sodium intermediate that is more corrosive to instruments and equipment

Method used

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  • A purification method of a Sakubaquat Sandan sodium intermediate
  • A purification method of a Sakubaquat Sandan sodium intermediate
  • A purification method of a Sakubaquat Sandan sodium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1 Preparation of intermediate 1 ((2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride)

[0054] The intermediate 1 was prepared and isolated by the following method:

[0055] S1. Dissolve 50 g of the starting material (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (1eq) in 380 mL of anhydrous In ethanol (50eq), cool down to 4°C, add 31.0g of thionyl chloride (2eq) dropwise at a rate of 1mL / min, keep the temperature below 10°C, raise the temperature to reflux after dropping, and stir at 75°C for 1.5h , get the reaction liquid;

[0056] S2. Cool the reaction solution obtained in step S1 to 50°C, concentrate under reduced pressure until no obvious liquid droplets flow out, then add 500mL of ethyl acetate, raise the temperature to 75°C, stir for 60min, and add 250mL of n-heptane after the system is clear, Cool down to below 5°C, stir and crystallize for 60 min, filter with suction, wash the filter cake w...

Embodiment 2

[0057] Example 2 Preparation of intermediate 1 ((2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride)

[0058] The intermediate 1 was prepared and isolated by the following method:

[0059] S1. Dissolve 50 g of the starting material (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (1eq) in 380 mL of anhydrous In ethanol (50eq), lower the temperature to 4°C, add 31.0g of thionyl chloride (2eq) dropwise, keep the temperature below 10°C, raise the temperature to reflux after dropping, reflux at 75°C and stir for 1.5h to obtain a reaction solution;

[0060] S2. Cool the reaction solution obtained in step S1. to 50°C, concentrate under reduced pressure until no obvious liquid droplets flow out, add 500mL of ethyl acetate, raise the temperature to 75°C, stir for 60min, and add 375mL of n-heptane until the system is clear, Cool down to below 5°C, stir and crystallize for 60 min, filter with suction, wash the filter cake with...

Embodiment 3

[0061] Example 3 Preparation of intermediate 1 ((2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride)

[0062] The intermediate 1 was prepared and isolated by the following method:

[0063] S1. Dissolve 50 g of the starting material (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (1eq) in 380 mL of anhydrous In ethanol (50eq), lower the temperature to 4°C, add 31.0g of thionyl chloride (2eq) dropwise, keep the temperature below 10°C, raise the temperature to reflux after dropping, reflux at 75°C and stir for 1.5h to obtain a reaction solution;

[0064] S2. Cool the reaction solution obtained in step S1 to 50°C, concentrate under reduced pressure until no obvious liquid drops flow out, then add 500mL of ethyl acetate, raise the temperature to 75°C, stir for 60min, and add 500mL of n-heptane after the system is clear, Cool down to below 5°C, stir and crystallize for 60 min, filter with suction, wash the filter cake wit...

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Abstract

The invention discloses a purification method of a sacubitril valsartan sodium intermediate. According to the method, a certain amount of specific lower fatty acid ester and a low-polarity solvent areadopted; the method comprises the following steps: recrystallizing and purifying an intermediate 1: ((2R, 4S)-4-amino-5-biphenyl-4-yl-2-methyl ethyl valerate hydrochloride) crude product prepared from a thionyl chloride / ethanol system, and removing acidic substances in the crude product. The method has characteristics of simple operation; corrosion on instrument equipment due to the use of the n-heptane repeated reduced pressure concentration method in the prior art is avoided, and the yield of the intermediate 1 is increased obviously. The purification method provided by the invention is more beneficial to subsequent preparation of sacubitril valsartan sodium, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis. More specifically, it relates to a purification method of sacubitril-valsartan sodium intermediate. Background technique [0002] Sacubitril valsartan sodium is a combination compound of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, suitable for patients with chronic heart failure (NYHA class II-IV) Its advantage is that it can reduce the probability of cardiovascular death and hospitalization for heart failure. It is the first and only drug that has significantly surpassed the standard treatment drug enalapril in clinical trials, and has shown higher safety Sex, has a broad market prospect. [0003] The current method for synthesizing sacubitril-valsartan sodium is basically prepared by co-crystallization of sacubitril, valsartan and sodium hydroxide aqueous solution, such as WO2008 / 083967 discloses a method for preparing sacubitril-valsartan The pr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/44C07C227/42C07C227/18C07C229/34
CPCC07C227/18C07C227/42C07C227/44C07C229/34
Inventor 朱维君邹斌彬朱婧郑希冬侯岳华陈雪兰
Owner ZHUZHOU QIANJIN PHARMA
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