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Post-treatment method of sacubitril valsartan sodium intermediate

A technology of sacubitrilvaler and sartan sodium, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve problems such as corrosion, incomplete acid removal, and unsatisfactory purity, and achieve simple operation , reducing the corrosive effect

Inactive Publication Date: 2020-02-21
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 incomplete acid removal, unsatisfactory purity, and corrosiveness to equipment in the prior art, provide a more effective acid removal, improve the purity of intermediate 1, and avoid damage to equipment. The post-processing method of the relatively corrosive sacubitril-valsartan sodium intermediate

Method used

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  • Post-treatment method of sacubitril valsartan sodium intermediate
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  • Post-treatment method of sacubitril valsartan sodium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1 Preparation of intermediate 1 ((2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride)

[0049] The intermediate 1 was prepared and isolated by the following method:

[0050]S1. Dissolve 100g of starting material (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (1eq) in 600g of anhydrous In ethanol (50eq), lower the temperature to 4°C, add 62g 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 solution;

[0051] S2. Add 35.5g imidazole (2eq) to the reaction solution obtained in step S1, stir for 10min, concentrate under reduced pressure until there are no obvious droplets, add 600g ethyl acetate, stir for 10min, filter with suction, and concentrate the filtrate under reduced pressure to obtain 81.6g intermediate Body 1.

Embodiment 2

[0052] Example 2 Preparation of intermediate 1 ((2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride)

[0053] The intermediate 1 was prepared and isolated by the following method:

[0054] S1. Dissolve 100g of starting material (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (1eq) in 600g of anhydrous In ethanol (50eq), lower the temperature to 4°C, add 62g 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 solution;

[0055] S2. Add 41.3g of pyridine (2eq) to the reaction solution obtained in step S1, stir for 10min, concentrate under reduced pressure until there are no obvious droplets, add 600g of ethyl acetate, stir for 10min, filter with suction, and concentrate the filtrate under reduced pressure to obtain 77.3g of intermediate Body 1.

Embodiment 3

[0056] Example 3 Preparation of intermediate 1 ((2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride)

[0057] The intermediate 1 was prepared and isolated by the following method:

[0058] S1. Dissolve 100g of starting material (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (1eq) in 600g of anhydrous In ethanol (50eq), lower the temperature to 4°C, add 62g 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 solution;

[0059] S2. Add 168.1g tetrabutylammonium bromide (2eq) to the reaction solution obtained in step S1, stir for 10min, concentrate under reduced pressure until there are no obvious droplets, add 600g ethyl acetate, stir for 10min, filter with suction, and concentrate the filtrate under reduced pressure , to obtain 78.5g of intermediate 1.

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Abstract

The invention discloses a post-treatment method of a sacubitril valsartan sodium intermediate. According to the method, a proper acid-binding agent is adopted; by removing acidic substances in an intermediate 1 ((2R, 4S)-4-amino-5-biphenyl-4-yl-2-methyl ethyl valerate hydrochloride) crude product prepared by a thionyl chloride / ethanol system, a high purity intermediate 1 can be obtained; and the method is simple to operate, and overcomes the problem of corrosivity of instruments and devices caused by repeated reduced pressure concentration of n-heptane in the prior art. The post-treatment 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 post-processing 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C227/40C07C227/44C07C229/34
CPCC07C227/18C07C227/40C07C227/44C07C229/34
Inventor 郑希冬邹斌彬谭鑫强吴超男陈雪兰龙承基
Owner ZHUZHOU QIANJIN PHARMA
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