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Ibrutinib purification method

A technology of ibrutinib and purification method, applied in the field of compound purification, can solve the problems of long operation time, cumbersome operation, high operator requirements, etc., and achieve the effect of simple operation and high yield

Inactive Publication Date: 2016-03-30
ZHEJIANG JINGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The silica gel column chromatography method needs to consider the column efficiency to achieve different adsorption, desorption, re-adsorption, and re-desorption capabilities of different substances, and the separation process needs to continuously add elution solvents and detect the outflow of products in real time, not only requires a large amount of elution solvents, It is easy to introduce new impurities; and the amount of each purification is small, the operation time is long, and the operation is cumbersome, which requires high requirements for operators, so it is difficult to apply to industrial production

Method used

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Examples

Experimental program
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Effect test

Embodiment 1～4

[0025] Embodiment 1~4 Silica gel adsorption purification Lutinib crude product

[0026] Put the crude ibrutinib into the reaction bottle, add dichloromethane, stir to dissolve, add 200-300 mesh silica gel for column chromatography, raise the temperature to 30-40°C, stir for half an hour, filter while hot, and use the filter cake Rinse with ethyl acetate at 70-77°C, and concentrate the obtained filtrate to dryness to obtain the semi-finished product of ibrutinib.

[0027] Examples 1-4 were purified by column chromatography with silica gel adsorption to obtain semi-finished products of ibrutinib.

[0028] Table 1 Silica gel adsorption purification parameter table

[0029]

[0030]

Embodiment 5～11

[0033] Put the semi-finished product of ibrutinib into the reaction bottle, add a medium-strong polar organic solvent to raise the temperature to reflux, stir until clarification, add the anti-solvent dropwise, after the addition is completed, stir at T°C for half an hour, cool down to crystallize, and cool down to 0-20 °C, filter and dry to obtain the finished product of ibrutinib. The specific parameters are shown in Table 2.

[0034] Table 2 Examples 5-11 Ibrutinib Semi-finished Product Recrystallization Purification Parameters

[0035]

[0036]

[0037] In Examples 5-11, the semi-finished ibrutinib was used as the raw material to obtain the finished ibrutinib through further recrystallization and purification. The results are shown in Table 2, the purity of ibrutinib finished products were all increased to 99.8% and above.

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Abstract

The invention discloses an ibrutinib purification method. The ibrutinib purification method comprises the following steps: 1) dissolving a crude product of ibrutinib in a moderately polar organic solvent, adding silica gel used for column chromatography, mixing the materials, carrying out stirring and filtering and concentrating obtained filtrate until dryness, thus obtaining a semi-finished product of ibrutinib; carrying out impurity separation with a simple silica gel adsorption method and obtaining the semi-finished product of ibrutinib with purity of 99.5% after purification; 2) then carrying out separation by recrystallization, thus obtaining a finished product of ibrutinib with purity over 99.8%. The ibrutinib purification method can achieve the effect of effectively removing the impurities in the crude product of ibrutinib, is simple in purification operation and high in yield and can be applied to industrial production.

Description

technical field [0001] The present invention relates to a method for purifying compounds, in particular to a method for purifying ibrutinib. Background technique [0002] Ibrutinib, chemical name: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-D] Pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one, the molecular formula is: C 25 h 24 N 6 o 2 , the molecular weight is: 440.50, the CAS number is: 936563-96-1, and the structural formula is as follows: [0003] [0004] Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor jointly developed by Johnson & Johnson and Circular Pharma. In February 2013, the drug obtained the FDA's "breakthrough therapy" qualification, and was approved for marketing on November 13, 2013, as a single treatment for mantle cell lymphoma, suitable for mantle cells treated with other means before Patients with lymphoma, the brand name is "Imbruvca". [0005] There is no special report on the purification method of ibrutinib in the existing l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 钟宏班朱建荣马哲勇李喜安
Owner ZHEJIANG JINGXIN PHARMA
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