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Preparation method of Sacubitril key intermediate

A technology of sacubitril and intermediates, applied in the field of drug synthesis, can solve the problems of difficult purification and removal, low reaction yield and the like

Inactive Publication Date: 2018-10-19
CHANGZHOU YABANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0026] In addition, this method adopts a low-temperature-controlled Grignard reaction, a coupling reaction catalyzed by cuprous chloride, and the reaction yield is low. At the same time, a large amount of waste liquid containing copper salts is generated, and the bromination reaction of the aromatic ring is prone to polybromination. And the formation of brominated positional isomer impurities, which are difficult to purify and remove once formed

Method used

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  • Preparation method of Sacubitril key intermediate
  • Preparation method of Sacubitril key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Embodiment 1: the synthetic preparation of intermediate II

[0085] In the reaction flask, add 500ml of water, heat up to 60°C, add hydantoin (100.1g, 1.0mol) and ethanolamine (12.2g, 0.2mol) in turn under stirring, heat up to reflux, drop 4-linked Benzaldehyde (182.2g, 1.0mol) in ethanol (500ml) solution, after the dropwise addition, continue to maintain reflux reaction, TLC detection reaction, until the raw material point of 4-biphenyl formaldehyde disappears; then add 20% sodium hydroxide aqueous solution ( 200ml), continue the reflux reaction for 4 hours; cool the reaction solution to below 5°C, adjust the pH to 4~5 with concentrated hydrochloric acid, evaporate about 600ml of solvent under reduced pressure, filter the precipitated solid, and dry to obtain the intermediate Compound II (229.6g, 0.956mol), the molar yield is 95.6%.

Embodiment 2

[0086] Embodiment 2: the synthetic preparation of intermediate II

[0087] In the reaction flask, add 500ml of water, heat up to 50°C, add hydantoin (100.1g, 1.0mol) and ethanolamine (30.6g, 0.5mol) in turn under stirring, heat up to reflux, drop 4-linked Benzaldehyde (182.2g, 1.0mol) in ethanol (500ml) solution, after the dropwise addition, continue to maintain reflux reaction, TLC detection reaction, until the raw material point of 4-biphenyl formaldehyde disappears; then add 20% sodium hydroxide aqueous solution ( 200ml), continue the reflux reaction for 5 hours; cool the reaction solution to below 5°C, adjust the pH to 4~5 with concentrated hydrochloric acid, evaporate about 600ml of solvent under reduced pressure, filter the precipitated solid, and dry to obtain the intermediate Compound II (231.1 g, 0.962mol), the molar yield is 96.2%.

Embodiment 3

[0088] Embodiment 3: the synthetic preparation of intermediate II

[0089] In the reaction flask, add 4-biphenylformaldehyde (182.2g, 1.0mol), hydantoin (100.1g, 1.0mol) and ammonium acetate (77.1g, 1.0mol) into 800ml of acetic acid, heat up to reflux reaction , TLC detects the reaction until the raw material point of 4-biphenyl formaldehyde disappears. After the solvent is evaporated under reduced pressure, 500ml of ethanol and 20% sodium hydroxide solution (200ml) are added, and the stirring and reflux reaction is continued for 6 hours; the reaction solution is cooled to Below 5°C, use concentrated hydrochloric acid to adjust the pH to 4~5, evaporate the solvent under reduced pressure, dissolve the residue with 1L ethyl acetate, wash with water (300ml×2), dry the organic phase, filter, and concentrate the filtrate to obtain Intermediate II represented by formula II (211.2 g, 0.879 mol) has a molar yield of 87.9%.

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Abstract

The invention discloses a synthesis and preparation method of Sacubitril key intermediate N-[(1R)-2-(1,1'-biphenyl)-4-yl-1-(hydroxymethyl)ethyl]carbamic acid tert-butyl ester. The preparation method comprises the steps of adopting 4-biphenylcarboxaldehyde and hydantoin as starting materials; carrying out condensation and hydrolysis 'one-pot method' reaction, esterification reaction, dissymmetricaltransamination reaction, and Boc protection and reduction reaction to synthesize and prepare the target product. The preparation method has the characteristics of easiness in obtaining the reaction raw materials, short path, high reaction stereoselectivity, mild conditions, simple and convenient process operation, and the like, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing and preparing a key intermediate of sacubitril, which belongs to the field of drug synthesis. Background technique [0002] Sacubitril Valsartan Sodium (Sacubitril Valsartan Sodium) is a breakthrough innovative drug in the field of global chronic heart failure treatment in the past two decades. It can simultaneously inhibit neprilysin and block AT1 receptors (angiotensin II type 1 receptor). The drug was developed by Novartis Pharma Schweiz AG of Switzerland and was approved by the US FDA on July 7, 2015. The trade name is Entresto ® . On September 24, 2015, the European Commission for Human Medicine recommended that the European Union approve its treatment of heart failure in Europe. In 2017, China's CFDA approved its listing, the product name is Nuoxinto ® . The marketing specifications and dosage forms of sacubitril valsartan sodium tablets are: 50mg, 100mg, 200mg tablets. The chemical name of...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/16
CPCC07C51/00C07C67/08C07C227/08C07C269/04C07C269/06C07C271/16C07C59/84C07C69/738C07C229/36C07C271/22Y02P20/55
Inventor 陈再新于水涛吴茂诚王勇军朱峰李春伢
Owner CHANGZHOU YABANG PHARMA