Method for separation and purification of LCZ696 intermediate diastereoisomer

A technology for separation and purification of diastereomers, applied in organic chemistry methods, chemical instruments and methods, organic chemistry, etc., and can solve problems such as excessive product impurities

Inactive Publication Date: 2019-03-01
CHONGQING SANSHENG IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The generated diastereomer impurity formula (I-b) will be derived into related isomer impurities in the final product during the preparation of Sacubitril, resulting in excessive impurities in the product

Method used

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  • Method for separation and purification of LCZ696 intermediate diastereoisomer
  • Method for separation and purification of LCZ696 intermediate diastereoisomer
  • Method for separation and purification of LCZ696 intermediate diastereoisomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Preparation of (R, E)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpent-2-enoic acid (1), reaction formula as follows:

[0031]

[0032] According to Example 1 of patent CN101516831, ethyl (R,E)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpent-2-enoate (2) Hydrolysis with lithium hydroxide in ethanol gave white solid (R,E)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentane -2-enoic acid (1).

Embodiment 2

[0033] Embodiment 2 prepares diastereomer formula (I-a) and formula (I-b) mixture, and reaction formula is as follows:

[0034]

[0035] Add (R,E)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpent-2-enoic acid 10g into 150ml ethanol, and then add 10 % palladium carbon 1g, hydrogenation at 40-50°C for 6 hours at a pressure of 0.5 MPa. The catalyst was filtered off, and the solvent was removed from the filtrate under reduced pressure to obtain a mixture of diastereoisomers of formula (I-a) and formula (I-b). As determined by HPLC, (I-a):(I-b) was about 80:20.

Embodiment 3

[0036] Example 3 Preparation of (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (formula I-a)

[0037] Add 5 g of the mixture of formula (I-a) and formula (I-b) obtained in Example 2 into 10 ml of tetrahydrofuran, heat to reflux to dissolve completely, cool to below 40 ° C, add 100 ml of n-heptane, continue cooling to below 10 ° C, filter, filter The cake was washed with 20 ml of tetrahydrofuran / n-heptane (5:1), and dried to obtain a white powder. Dissolve the white powder with 8ml of tetrahydrofuran under reflux, cool to below 40°C, add 80ml of n-heptane, continue cooling to below 10°C, filter, wash the filter cake with 10ml of tetrahydrofuran / n-heptane (5:1), and dry A white powder was obtained.

[0038] As determined by HPLC, the formula (I-a): formula (I-b) in the white powder is higher than 95:5.

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PUM

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Abstract

A method for separation and purification of LCZ696 intermediate diastereoisomer includes the following steps: (1) placing the mixture of the diastereoisomer (I-a) and (I-b) in an organic solvent untilthe mixture is completely dissolved, cooling to 0-10 DEG C, recrystallizing until the crystal is stable, filtering, taking a filter cake, and drying to obtain a product mixture, and (2) taking the filtrate, removing the solvent under reduced pressure, and drying the solute to obtain an impurity mixture. The method for separation and purification can efficiently and conveniently separate and purify the diastereomers (I-a) and(I-b) and the purity of the resulting product mixture (I-a) is as high as 95 percent, which can be directly used for preparing a high-purity Sacubitril intermediate to finally synthesize LCZ696 so as to ensure the product quality.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a method for separating and purifying diastereomers of LCZ696 intermediates. Background technique [0002] LCZ696 is a dual inhibitor of angiotensin II receptor and neprilysin developed by Novartis. It is a complex composed of Valsartan and Sacubitril linked by sodium ions. Its structural formula as follows: [0003] [0004] Patent US5217996 discloses the preparation method of Sacubitril. Using (R,E)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpent-2-enoic acid ethyl ester (2) in the presence of palladium carbon There is no selectivity for hydrogenation under conditions, and the generated (4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methyl-2-pentanoic acid ethyl ester (3) is a mixture of diastereoisomers (2R,4S):(2S,4S) in a ratio of 80:20. [0005] [0006] Patent CNN101516831 first used (R, E)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/08C07C271/22
CPCC07B2200/07C07C269/08C07C271/22
Inventor 何伟宋世戈代广会彭磊李杰柳玲
Owner CHONGQING SANSHENG IND CO LTD
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