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A kind of purification method of bosutinib

A purification method, the technology of bosutinib, which is applied in the field of medicine, can solve the problems of being unsuitable for industrial production, difficult to remove impurities in crude products, cumbersome column chromatography operation, etc., and achieve the benefits of industrial production, high purification yield and product purity , post-processing convenient effect

Inactive Publication Date: 2021-05-07
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the prior art, column chromatography has a good purification effect and can remove most of the impurities. However, in large-scale production, column chromatography is not only cumbersome to operate, but also requires the use of a large amount of solvents, resulting in high cost of waste liquid treatment, which is not suitable for industrial production. ; and if the crude product of bosutinib is directly recrystallized without column chromatography, some impurities in the crude product are difficult to remove

Method used

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  • A kind of purification method of bosutinib
  • A kind of purification method of bosutinib
  • A kind of purification method of bosutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the preparation of bosutinib benzoate

[0044] Add 1.00g bosutinib crude product, add 2mL DMF, stir and heat to 40-45°C under nitrogen protection, the yellow color dissolves; slowly add dropwise the benzoic acid solution containing 3.78mmol benzoic acid and 10mL MTBE, the solution is yellow and clear during the dropping process ; Stir slowly to cool down to -10-0°C, stir for 2 hours, filter with suction, and dry; 0.94g of bosutinib benzoate is obtained respectively, with a yield of 76.4% and a purity of 96.88%.

Embodiment 2

[0045] Embodiment 2: the preparation of bosutinib benzoate

[0046] Add 1.00g bosutinib crude product, add 2mL DMA, stir and heat to 40-45°C under nitrogen protection, the yellow color dissolves; slowly add dropwise the benzoic acid solution containing 3.78mmol benzoic acid and 10mL MTBE, the solution is yellow and clear during the dropping process Slowly stir and cool down to -10-0°C, stir for 2 hours, filter with suction, and dry; 0.77g of bosutinib benzoate is obtained respectively, with a yield of 62.6% and a purity of 96.03%.

Embodiment 3

[0047] Embodiment 3: the preparation of bosutinib benzoate

[0048] Add 2.12mL of 1-methyl-2-pyrrolidone to 2.12g of bosutinib crude product, stir and heat to 40-45°C under nitrogen protection, and the solution will turn into a yellow solution; slowly add 8mmol of benzoic acid and 10.6mL of n-hexane Benzoic acid solution, the solution was yellow and clear during the dropwise addition; slowly stirred and cooled to 0-5°C, stirred for 2 hours, suction filtered, and dried; 2.18g of bosutinib benzoate was obtained, with a yield of 83.5% and a purity of 96.93% .

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Abstract

The invention provides a purification method of bosutinib, comprising: (1) the crude compound of formula I is dissolved in solvent A, and reacted with a benzoic acid solution containing benzoic acid and solvent B to obtain the compound of formula II; (2) any Optionally, the compound of formula II obtained in step (1) is dissolved in solvent C, reacts with the benzoic acid solution containing benzoic acid and solvent D to obtain the compound of formula II; (3) step (1) or step (2) obtains formula II Compounds are hydrolyzed in the presence of base, water and optionally other solvents to obtain pure compounds of formula I. The purification method of the present invention avoids the use of column chromatography or preparative chromatographic purification, and can greatly reduce the potential genotoxic impurities that are difficult to remove in conventional crystallization methods without column chromatography or preparative chromatographic purification, The purification method of the invention uses a small amount of solvent, is convenient for aftertreatment, has high purification yield and product purity, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine and relates to a purification method of bosutinib. Background technique [0002] Bosutinib is a potent protein kinase (Src-Abl) inhibitor, its chemical structural formula is shown in formula (I), and it can dual-specifically inhibit Src kinase and Abl kinase. Bosutinib was developed and marketed after the acquisition of Wyeth by Pfizer of the United States. It is approved in the United States for chronic myelogenous leukemia (CML) in the chronic phase, accelerated phase or blast phase of the chronic phase, accelerated phase or blast phase that is resistant or intolerant to previous treatment. ) for the treatment of adult patients, the trade name is Bosulif; approved in Europe for the treatment of adult patients with chronic phase, accelerated phase, and blast phase Ph+ CML, these patients have previously used one or more tyrosine kinase inhibitors Treatment, and these patients are not suitable f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/54
CPCC07D215/54
Inventor 陈程高鹏孟庆义张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD