Preparation method for intermediates of new medicine Lusutrombopag resisting to thrombopenia

An anti-platelet, intermediate technology, applied in the field of pharmaceutical intermediates, can solve the problems of poor control, uneconomical, unenvironmental protection, etc., and achieves the effects of simple operation, easy operation and easy repeatability

Active Publication Date: 2017-04-19
杭州天泽生物医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This route first uses diazotization reaction, which is not easy to control, and the yield can only be moderately low (35-45%, the diazonium salt needs to be prepared and used immediately, and it will decompose and release nitrogen when left for a long time)
Secondly, the ozonation reaction needs to be carried out at an extremely low temperature, which is neither economical nor environmentally friendly, and is not suitable for industrial production

Method used

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  • Preparation method for intermediates of new medicine Lusutrombopag resisting to thrombopenia
  • Preparation method for intermediates of new medicine Lusutrombopag resisting to thrombopenia
  • Preparation method for intermediates of new medicine Lusutrombopag resisting to thrombopenia

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Experimental program
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Effect test

Embodiment

[0043] The synthetic route of intermediate I is as follows:

[0044]

[0045] 1: Synthesis of Compound X

[0046]Compound XI (360g, 1.65mol) was added to the reaction kettle, acetone (1.8L) was added to dissolve, anhydrous potassium carbonate (552g, 4.0mol) was added, and dimethyl sulfate (443g, 3.50mol) was slowly added dropwise. After the addition was complete, reflux to TLC showed that the starting material disappeared. Filter, wash the solid with acetone, combine the organic phases, concentrate, dilute with ethyl acetate, wash with water, wash with saturated brine, and dry over anhydrous sodium sulfate. After filtration and concentration, the desired compound X (355 g, 94%) was obtained, which was directly put into the next reaction.

[0047] 2: Synthesis of compound IX

[0048] Compound X (355 g, 1.55 mol) was added to the reaction kettle, dissolved in toluene, and thionyl chloride was added, and concentrated under reflux for 2 hours to obtain a yellow oily liquid. ...

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Abstract

The invention discloses a preparation method for intermediates of a new medicine Lusutrombopag resisting to thrombopenia. According to the invention, column chromatography of each step is avoided through an effective method with regard to preparation for an intermediate I, and in addition, bromo-compounds are used for replacing chloro-compounds in the step of ring closure, thus the ring closure has a quantitative yield and is quite easy to operate. In addition, the second carbonyl group and bromine are introduced stepwise, thus the two steps achieve a yield of more than 80%, and are stable and easy to repeat. Compared with the yield of 25-30% of the last two steps of the original research document, the yield is greatly increased, and the preparation method is simple and convenient to operate, and easy to repeat. According to the invention, synthesis for an intermediate II is realized with a quite high yield (70-80%) and an extremely short route through two effective strategies with regard to the intermediate II.

Description

technical field [0001] The invention relates to a pharmaceutical intermediate, in particular to a preparation method of an antithrombocytopenia new drug Lusutrombopag intermediate. Background technique [0002] Lusutrombopag is a thrombopoietin receptor antagonist developed by Shionogi Corporation of Japan. It has a good curative effect on poor hemostatic clot formation and bleeding caused by decreased platelet count (thrombocytopenia) or decreased function (platelet insufficiency). The drug is currently on the market in Japan and is in phase II clinical trials in the United States and the European Union. [0003] However, due to its complex structure, its synthesis is difficult, and its source is greatly restricted. The existing synthesis of compounds and intermediates is developed by Shionogi Company (EP 2184279 A1). For the synthesis of intermediate I, the original research company adopts the following strategy. [0004] [0005] Starting from 2,6-dibromophenol, aft...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/40C07C69/65C07C67/343
CPCC07C51/363C07C51/373C07C67/343C07D277/40C07C69/65C07C65/30C07C63/70
Inventor 任国宝吴彦李传斌
Owner 杭州天泽生物医药有限公司
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