Method for preparing Sacubitril intermediate of anti-heart-failure medicine

An intermediate and anti-heart failure technology, applied in the preparation of organic compounds, cyanide reaction preparation, carbamic acid derivatives preparation, etc., can solve the explosive decomposition of lithium aluminum hydride, the danger of large-scale production, and the cost of palladium catalyst High-level problems, to achieve the effect of mild reaction conditions, low cost, and simple post-treatment

Inactive Publication Date: 2016-07-13
CHANGZHOU PHARMA FACTORY
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Problems solved by technology

[0010] But the defective of above-mentioned method is, raw material (Ib) price is comparatively expensive, does not have cheap industrial product to buy at present in the market; The palladium catalyst cost that Suzuki reaction uses is higher, and recovery is difficult; Explosive decomposition occurs, which poses a danger to large-scale production

Method used

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  • Method for preparing Sacubitril intermediate of anti-heart-failure medicine
  • Method for preparing Sacubitril intermediate of anti-heart-failure medicine
  • Method for preparing Sacubitril intermediate of anti-heart-failure medicine

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Embodiment 1

[0050] Step 1: the compound of formula (I) obtains the compound of formula (II) through iodination reaction

[0051] 85.2g of compound (I) was dissolved in 470mL of acetic acid and 62mL of concentrated sulfuric acid, and 52.4g of iodine and 20.4g of sodium iodate were added under stirring, accompanied by exothermic phenomena. After the addition, heat to 70°C and keep warm for 20 hours, the solution is wine red. Add 4g of sodium periodate, and continue stirring at 70°C until the reaction solution turns orange. The acetic acid was evaporated, 800ml of water was added, and impurities were extracted with 500mL of ether and 500mL of dichloromethane. The water phase was decolorized with 11 g of activated carbon, filtered, and the filtrate was adjusted to pH 5 with sodium hydroxide, a large amount of white solids were precipitated, and filtered with suction. Rinse the filter cake with 1700 mL of water and 650 mL of ethanol, and dry the filter cake to obtain 118 g of white solid, na...

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Abstract

The invention discloses a method for preparing a Sacubitril intermediate of anti-heart-failure medicine as indicated in the formula (VII).The method comprises the following steps of taking D-phenylalanine which is low in price and easy to obtain as the raw material, and conducting an iodination reaction, an esterification reaction, a Boc protection reaction, a negishi coupling reaction, a DIBAL-H reduction reaction and a wittig reaction, so that the Sacubitril intermediate is obtained through preparation.The method for preparing the Sacubitril intermediate is mild in reaction condition and environmentally friendly, compared with existing preparation methods, the yield is higher, and the method is economical, effective and suitable for large-scale industrialized production.

Description

technical field [0001] The invention relates to a preparation method of an anti-heart failure drug Sacubitril intermediate. Background technique [0002] In July 2015, FDA approved the launch of Novartis' most exciting anti-heart failure drug Sacubitril / Valsartan (Sacubitril / Valsartan), trade name Entresto, which will challenge the most successful cardiovascular drugs currently on the market. [0003] Entresto is the first ARNI inhibitor drug to be tested successfully. ARNI inhibitors are angiotensin inhibitors, but at the same time they can enhance the action of endogenous natriuretic peptides (vasodilators). The drug is a dual-acting angiotensin receptor neprilysin inhibitor with a unique mode of action thought to reduce strain in failing hearts. Entresto combines Novartis' Diovan (generic name: valsartan) with the experimental drug AHU-377 (Sacubitril). AHU377 (Sacubitril) can block the mechanism of action of two polypeptides that are responsible for lowering blood pre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/06C07C271/22C07C269/04C07C227/18C07C227/16C07C229/36
CPCC07C269/06C07B2200/07C07C227/16C07C227/18C07C269/04C07C271/22C07C229/36
Inventor 张云然孙光祥王兵陶琪孙海江王敏峰都瑜峰
Owner CHANGZHOU PHARMA FACTORY
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