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Preparation method of Eltrombopag key intermediate 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid

A technology of hydroxybiphenyl and intermediates, applied in the field of organic and pharmaceutical synthesis, can solve the problems of inapplicability to mass production, high processing costs, and cumbersome steps, and achieve the effects of simple post-processing, low price, and convenient operation

Pending Publication Date: 2019-11-05
WUHAN INSTITUTE OF TECHNOLOGY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The steps for producing 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid in the prior art are cumbersome, the yield is low and the processing cost is high, so it is not suitable for mass production

Method used

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  • Preparation method of Eltrombopag key intermediate 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid
  • Preparation method of Eltrombopag key intermediate 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid
  • Preparation method of Eltrombopag key intermediate 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid

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Embodiment Construction

[0024] The following are specific examples of the present invention to further describe the technical solutions of the present invention, but the present invention is not limited to these examples.

[0025] The synthetic route of the present invention is as follows:

[0026]

[0027] Preparation of 2-bromo-6-nitrophenol

[0028] Take 5ml (0.078mol) of concentrated sulfuric acid and slowly add it into 16ml of water along the wall of the cup, add 6.6g (0.078mol) of sodium nitrate into the diluted sulfuric acid, stir well until it is completely dissolved. Under the condition of ice bath, slowly add 7.46g (0.043mol) of o-bromophenol dropwise to the above solution, and remove the ice bath after dropping. Reaction for 2 hours, followed by TLC until the reaction was complete, filtered, the filter cake was washed with water (5ml×4), dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting ...

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Abstract

The invention discloses a preparation method of an Eltrombopag key intermediate 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid. The preparation method comprises the following steps: (1) nitrating o-bromophenol with a nitrating reagent by using water as a solvent; (2) carrying out a Suzuki coupling reaction on 2-bromo-6-nitrophenol and 3-carboxyphenylboronic acid in the presence of an alkali by using metallic palladium or its metal salt as a catalyst; and (3) carrying out nitro reduction on obtained 3'-nitro-2'-hydroxybiphenyl-3-boronic acid in the presence of a proper hydrogen source by using the metallic palladium or its metal salt as the catalyst. The Eltrombopag key intermediate 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid is obtained through the preparation method of the nitration, Suzuki coupling and nitro reduction three-step reaction of the o-bromophenol used as the raw material. The Suzuki reaction uses the cheap and readily available palladium on carbon as the catalyst. The hydrogen source used in the reduction step is easy to operate. The preparation method has the advantages of simple reaction route in the whole process, mild conditions, simplicity in post-treatment operation, and suitableness for industrial production.

Description

technical field [0001] The invention relates to the technical field of organic and pharmaceutical synthesis, in particular to a method for preparing a key intermediate of Eltrombopag, 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid. Background technique [0002] The new hematopoietic drug eltrombopag olamine (trade name: Promacta) was developed by GlaxoSmithKline for the treatment of chronic idiopathic thrombocytopenia after glucocorticoids, immunoglobulin therapy or splenectomy Thrombocytopenia in patients with Henoch-Schonlein purpura was approved by the FDA in November 2008 for marketing in the United States. The Chinese chemical name of Eltrombopag: 3′-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5-dihydro-4H -pyridin-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid-2-aminoethanol salt (1:2), molecular formula: C25H22N4O4, relative molecular mass: 564.65, CAS registration number: 496775 -61-2. [0003] The steps for producing 3'-amino-2'-hydroxybiphenyl-3-carboxylic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C201/08C07C205/26C07C201/12C07C205/59C07C227/04C07C229/52
CPCC07C227/04C07C201/08C07C201/12C07C205/26C07C205/59C07C229/52
Inventor 陈云峰贾丽慧张元
Owner WUHAN INSTITUTE OF TECHNOLOGY
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