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Eltrombopag diethanolamine salt and preparation method thereof

A technology of ethanolamine salt and ethanolamine, which is applied in the field of eltrombopag diethanolamine salt and its preparation, can solve the problems that solvent residues do not meet the ICH guidelines, the amount of tetrahydrofuran is too much, and it is difficult to industrialize production, so as to reduce the amount of solvent residues and equipment The effect of low requirements and simple operation

Pending Publication Date: 2020-09-29
WUHAN WUYAO SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The object of the present invention is to provide a kind of eltrombopag diethanolamine salt and preparation method thereof, solve the problem that solvent residue in eltrombopag diethanolamine salt does not meet the ICH guideline, the regulation of Chinese Pharmacopoeia, and the excessive amount of tetrahydrofuran in the preparation process Many, cumbersome operation and difficult to industrialized production

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  • Eltrombopag diethanolamine salt and preparation method thereof
  • Eltrombopag diethanolamine salt and preparation method thereof

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preparation example Construction

[0022] The embodiment of the present invention provides a preparation method of eltrombopag diethanolamine salt. The preparation method comprises the following steps: dissolving ethanolamine in an organic solvent, heating up, stirring and dissolving, adding the tetrahydrofuran solution of eltrombopag free acid to into the ethanolamine solution, keep warm and stir, cool down after the dropwise addition, filter to obtain a wet product, and dry the wet product to obtain Eltrombopag diethanolamine salt. Wherein, preferably, the ratio of the volume of tetrahydrofuran: mass of Eltrombopag free acid: volume of organic solvent is 6-11:1:12-24. The method comprises: dissolving ethanolamine in an organic solvent, raising the temperature to 60-75° C., stirring and dissolving to obtain a dissolved ethanolamine solution, and slowly adding the prepared eltrombopag free acid solution dropwise to the ethanolamine solution. Both tripopopag free acid solution and ethanolamine solution are clear...

Embodiment 1

[0041] Add 13.7g (0.22mol) of ethanolamine (analytical grade, the same below) and 235mL of ethanol (industrial grade, the same below) into a 500mL three-necked flask, stir magnetically, and heat up the oil bath to 65°C; Eltrombopag free acid (Ⅰ ) 10g (0.023mol) was added into 90mL of tetrahydrofuran (technical grade, the same below) and slightly heated (40°C) to dissolve, and the obtained solution of Eltrombopag free acid (I) was slowly added dropwise into the above-mentioned ethanol solution and kept stirring; After 2 hours of dripping, the temperature was lowered to 20-30°C in a water bath, suction filtered, and the filter cake was dried in a vacuum oven at 45°C for 8 hours to obtain 12.0 g of Eltrombopag diethanolamine (II), with a yield of 93.6%. GC detection solvent residual ethanol < 0.07%, tetrahydrofuran < 0.02%, the dissolved residue is qualified.

Embodiment 2

[0043] Add 13.7g (0.22mol) of ethanolamine and 235mL of ethanol to a 500mL three-necked flask, stir magnetically, and heat up the oil bath to 67°C; ℃) was dissolved, and the obtained solution of Eltrombopag free acid (I) was slowly added dropwise to the above-mentioned ethanol solution and kept stirring; after about 2 hours, the temperature was cooled to 20-30°C in a water bath, suction filtered, and the filter cake was put into Baked in a vacuum oven at 45° C. for 8 hours, and obtained 12.1 g of Eltrombopag diethanolamine (II), with a yield of 94.3%. GC detection of solvent residual ethanol <0.05%, tetrahydrofuran <0.01%, qualified for dissolution.

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Abstract

The invention relates to the technical field of medicine preparation, and discloses an eltrombopag diethanolamine salt and a preparation method thereof. The preparation method comprises the followingsteps: dissolving ethanolamine in an organic solvent; heating to 60-75 DEG C, stirring to dissolve ethanolamine, dropwise adding a tetrahydrofuran solution of eltrombopag free acid into the ethanolamine solution, keeping the temperature, stirring, cooling after dropwise adding, and filtering, wherein the volume ratio of tetrahydrofuran to eltrombopag free acid to the organic solvent is (6-11): 1:(12-24). According to the method, in a homogeneous reaction system, sufficient salification is guaranteed, and the prepared eltrombopag diethanolamine salt is low in impurity content, simple in reaction operation, suitable for amplification and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, and in particular to an Eltrombopag diethanolamine salt and a preparation method thereof. Background technique [0002] Eltrombopag (eltrombopag) was developed by the British pharmaceutical giant GlaxoSmithKline. The drug is a once-daily oral thrombopoietin (TPO) receptor agonist. Platelet levels. At present, Eltrombopag has been approved by more than 100 countries around the world for the treatment of thrombocytopenia (thrombocytopenia) in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP), and has been approved by 43 countries. For the treatment of thrombocytopenia in patients with chronic hepatitis C (CHC), in order to initiate and maintain standard interferon-based therapy for liver disease. In August 2014, the FDA further approved Eltrombopag for the treatment of cytopenia (cytopenia) in patients with severe aplastic anemia (SAA) who had insufficient resp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/38
CPCC07D231/38
Inventor 黄猛翁飞李孝吴醇朱毅杨波
Owner WUHAN WUYAO SCI & TECH
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