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Preparation of ibrutinib intermediate

A technology of ibrutinib and intermediates, which is applied in the field of preparation of ibrutinib intermediates, can solve the problems of costing a lot of manpower and material resources, harmful to human body, etc.

Inactive Publication Date: 2019-01-04
WISDOM PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] This kind of synthetic method has 3 steps, but needs to use expensive palladium catalyst and corresponding boron or silicon reagent (XIII)
In the purification process, since palladium is a heavy metal, it is harmful to the human body, and the catalyst is a homogeneous catalyst, so it will take a lot of manpower and material resources to completely remove it.

Method used

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  • Preparation of ibrutinib intermediate
  • Preparation of ibrutinib intermediate
  • Preparation of ibrutinib intermediate

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Experimental program
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Embodiment

[0027]

[0028] 1. Preparation of 3-(4-phenoxyphenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine

[0029] Add 270.1 g (2.0 mol) of 4-aminopyrazolo[3,4-d]pyrimidine and 295.9 g (1.0 mol) of 4-iododiphenyl ether into 1 L of DMSO, followed by 448.8 g (4.0 mol) of tert potassium butoxide. After the addition, nitrogen replacement was carried out, and the mixture was heated to 120° C. and reacted for 24 hours. Controlled by HPLC, when 4-iododiphenyl ether is consumed, the reaction ends. After cooling down to room temperature, 5 L of methyl tert-butyl ether was added, followed by washing with 5 L of water three times. The organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The crude product obtained after conventional column chromatography was recrystallized with DMF solvent to obtain 3-(4-phenoxyphenyl)-4-amino-1H-pyrazolo [3,4-d]pyrimidine (248.5 g, 82%, HPLC purity 99.7%).

[0030] 2. Preparation of 3-(4-phenoxyphenyl)-4-amino-1H-py...

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Abstract

The invention relates to preparation of an ibrutinib intermediate, in particular to preparation of 3-(4-phenoxyphenyl)-4-amino-1H-pyrazole[3,4-d]pyrimidine. According to the method, the reaction stepsare few and use of expensive reagents is avoided.

Description

technical field [0001] The invention relates to the synthesis of an anticancer drug ibrutinib intermediate 3-(4-phenoxyphenyl)-4-amino-1H-pyrazolo[3,4-d]pyrimidine. This method can reduce the number of reaction steps and avoid the use of expensive reagents. Background technique [0002] The B-cell antigen receptor (BCR) signaling pathway is a key driver of the growth and dissemination of many tumors. BTK (Bruton's tyrosine kinase), as an indispensable participant of BCR signal peptide, is crucial for the formation, differentiation, information transmission and survival of B lymphocytes. BTK is a signal peptide molecule recognized by the BCR channel. When the signal peptide molecule passes through the surface receptor of B lymphocytes, the necessary channels for B lymphocytes to achieve translocation, chemotaxis and adhesion are activated, which is the basis for B cell malignancies. The formation provides convenience. [0003] Ibrutinib (ibrutinib) is a small molecule BTK ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 李延洁邱小龙邹平胡林陈俊曹雷
Owner WISDOM PHARM CO LTD