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Preparation method of eltrombopag olamine

A technology of eltrombopag and alkyl acetoacetate, which is applied in the field of preparation of the therapeutic drug eltrombopag, can solve problems such as many reaction steps, high cost, and high pressure on environmental protection, and achieve easy availability of raw materials and high product yield And the effect of high product purity

Active Publication Date: 2014-05-28
山东佰盛能源科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Analyzing the disclosed preparation methods of Eltrombopag and its intermediates, there are generally disadvantages such as many reaction steps, high environmental protection pressure, and high cost. Therefore, a simpler, more convenient, environmentally friendly and cost-controllable process route is sought. The economic and technological development of medicine is very important

Method used

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  • Preparation method of eltrombopag olamine
  • Preparation method of eltrombopag olamine
  • Preparation method of eltrombopag olamine

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Experimental program
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Embodiment 1

[0027] Add 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid (II) (2.29 g, 10 mmol) and 50 mL of 1N hydrochloric acid into the reaction flask, and stir to dissolve. Add 25mL aqueous solution of sodium nitrite (0.76g, 11mmol) dropwise under ice bath, after dropping, add ethyl acetoacetate (1.63g, 12.5mmol) and sodium acetate (8.2g, 0.1mol) ethanol 75mL solution under stirring , raised to room temperature, and reacted for 10 hours, and TLC detected that the reaction was complete. Filtration, the crude product was recrystallized with methanol to obtain a light yellow solid (Z)-2-[3'-(2'-hydroxy-3-carboxylic acid biphenyl)hydrazono]-3-oxobutanoic acid ethyl ester (III ) 2.7g, yield 73.0%.

Embodiment 2

[0029] At room temperature, add 3,4-dimethylphenylhydrazine (0.75 g, 5.5 mmol) and glacial acetic acid (25 mL) into the reaction flask, and stir to dissolve. Add (Z)-2-[3'-(2'-hydroxyl-3-carboxybiphenyl)hydrazono]-3-oxobutanoic acid ethyl ester (III) (1.85g, 5mmol) and heat up to 100° C., stirred for 24 hours, and TLC detected that the reaction was complete. The solvent was removed under reduced pressure. The crude product was recrystallized from methanol to obtain 1.8 g of off-white solid Eltrombopag (I), with a yield of 81.4%.

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Abstract

The invention discloses a preparation method of eltrombopag olamine (Eltrombopag). The preparation method comprises the following steps: carrying out azo coupling reaction by using 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid (II) and acetoacetic acid alkyl ester to obtain (Z)-2-[3'-(2'-hydroxyl-3-hydroxy-biphenyl) hydrazono]-3-oxo acid alkyl ester (III); carrying out condensation cyclization reaction on an intermediate (III) and 3,4-dimethyl benzene hydrazine to prepare the eltrombopag olamine (I). The method is concise in process, available in raw material, economical and environmental friendly, and beneficial to achievement of industrialization, and economic and technological development of the eltrombopag olamine crude drug can be facilitated.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of Eltrombopag, a therapeutic drug for thrombocytopenic purpura. Background technique [0002] Eltrombopag (Eltrombopag) is an oral thrombopoietin drug developed by GlaxoSmithKline. Produces a signaling cascade that induces the proliferation and differentiation of bone marrow megakaryocytes. The drug was approved by the U.S. Food and Drug Administration (FDA) for marketing in the U.S. in November 2008. It is used for the treatment of chronic idiopathic thrombocytopenic purpura ( Thrombocytopenia in patients with ITP). The trade name is Promacta. Eltrombopag is the first oral non-peptide thrombopoietin receptor agonist approved for the treatment of adults with chronic ITP, and its approval for the treatment of ITP patients is an important milestone. Currently, the drug is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/46
CPCC07D231/46A61K31/4152
Inventor 许学农
Owner 山东佰盛能源科技有限公司
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