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Preparation method and application of sacubitril intermediate

A technology for sacubitril and intermediates, which is applied in the field of medicine and chemical industry, can solve the problems of repeated protection of carboxyl groups and amino groups, numerous reaction steps, unfavorable industrial production and the like, and achieves the effects of easy availability of raw materials, cheap raw materials and simple process.

Active Publication Date: 2021-07-16
浙江来益生物技术有限公司
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  • Application Information

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Problems solved by technology

[0014] The above-mentioned methods for preparing Shakubiqu, although the starting materials and reaction routes are different, all have the difficulties of obtaining chiral starting materials, numerous reaction steps, expensive chiral reduction catalysts or expensive chiral inducing reagents, and the need for carboxyl and amino groups. Shortcomings such as repeated protection and deprotection are not conducive to industrial production

Method used

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  • Preparation method and application of sacubitril intermediate
  • Preparation method and application of sacubitril intermediate
  • Preparation method and application of sacubitril intermediate

Examples

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Embodiment

[0041] 1. Preparation of R-methylsuccinic anhydride (1)

[0042]

[0043] Add itaconic anhydride (50g, 446.4mmol) and ethyl acetate (250ml) in a 500ml hydrogenation kettle, blow with argon for 10min, add (S,S)-Me-Duphos (136.6mg, 0.45mmol) and paracyme Hydrocarbon ruthenium dichloride (275.6mg, 0.45mmol), pressurized hydrogen to 5MPa, reacted at 35°C for 24h, TLC detected that the reaction was complete, concentrated to 100ml, a white solid was precipitated, filtered and dried to obtain a white solid 1( 49.3g%, yield 96.9%).

[0044] 1 HNMR (500MHz, CDCl3) δ3.25–3.14 (m, 2H), 2.68–2.59 (m, 1H), 1.45 (d, J=9.0Hz, 3H). MS (ESI) m / z: 115.1 [M+ H]+.

[0045] 2. Synthesis of ethyl R-methylsuccinate (2)

[0046]

[0047] Add R-methylsuccinic anhydride (49.3g, 432.5mmol) and ethanol (200ml) into a 500ml single-necked bottle, add 5ml of concentrated sulfuric acid, heat to reflux for 24h, and TLC detects that the reaction is complete. The solvent was spin-dried, ethyl acetate...

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Abstract

The invention discloses a preparation method and application of a sacubitril intermediate. The sacubitril intermediate disclosed by the invention is obtained by taking itaconic anhydride as a raw material, performing chiral reduction, esterification, selective hydrolysis and carboxyl activation, and finally conducting coupling with 4-biphenylacetic acid. The invention also provides a method for preparing sacubitril by using the sacubitril intermediate. The preparation method provided by the invention has the advantages of easily available raw materials, simple process, economy, environmental protection and the like, and is more suitable for industrial production compared with other routes.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation method of a sacubitril intermediate and an application of the sacubitrah intermediate. Background technique [0002] Sacubitril, the chemical name is 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl- 5-oxopentane-2-yl)amino)-4-oxobutanoic acid, its structural formula is as follows: [0003] [0004] Entresto's Chinese generic name is Sacubitril Valsartan Sodium Tablets, which was first approved by the FDA in July 2015 for adult patients with chronic heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure. It is considered to be the most important new drug launched by Novartis in recent years. Entresto is a new type of anti-heart failure drug with double inhibitory effect of enkephalinase / angiotensin receptor, including ARB (valsartan) and enkephalinase inhibitor (sacubitril...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/343C07C69/738C07C231/02C07C235/78
CPCC07D307/60C07C67/08C07C67/27C07C67/343C07C227/06C07C227/18C07C231/02C07C69/34C07C69/738C07C229/34C07C235/78Y02P20/55
Inventor 王涛杜良栋万定建程思远李佳霖
Owner 浙江来益生物技术有限公司
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