Synthesis and purification process of ibrutinib intermediates

Abstract

The invention relates to a synthesis and purification process of ibrutinib intermediates, in particular to a process to obtain ibrutinib intermediates with the purity being greater than 97 percent by performing Mitsunobu reaction and Boc removal processes on 3-(4-phenoxyl phenyl)-1H-pyrazole[3,4-d]pyridine-4-amine and (s)-1-t-butyloxycarboryl-3-hydroxypiperidine, triphenylphosphine and DIAD to obtain intermediate mixing samples, using solvents for crystallization to obtain intermediate coarse products, and then recrystallizing the coarse products by a mixed solvent method. According to the process, a one-pot method is used for obtaining the ibrutinib intermediates; the reaction process is simple; the yield is high; meanwhile, an efficient refining method is also provided.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, specifically 3-(4-phenoxyphenyl)-1H-pyrazol[3,4-d]pyrimidin-4-amine and (s)-1-tert-butoxycarbonyl -3-Hydroxypiperidine, triphenylphosphine, and DIAD are obtained through the Mitsunobu reaction and de-Boc process to obtain ibrutinib intermediates and their recrystallization processes. Background technique [0002] Ibrutinib is a drug for the treatment of mantle cell lymphoma (MCL) jointly developed by pharmacyclics and Johnson & Johnson. The trade name is Imbruvica, which was approved by the FDA in October 2013. The specific structure is as follows: [0003] [0004] The original research patent US7514444 discloses a synthesis method of ibrutinib, the specific synthesis route is as follows: [0005] [0006] Patent CN104557945A discloses another synthesis method of ibrutinib, the specific synthesis route is as follows: [0007] [0008] Both of the above two methods for synthesi...

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Problems solved by technology

[0008] Both of the above two methods of synthesizing ibrutinib have gone through intermediate B, and the original research patent US7514444 uses the method of column chromatography to purify the intermediate, which is time-consuming and not suitable for large-scale production; patent CN104557945A does not involve To a clear intermediate purification method, and in the reaction process, self-made Grignard reagents are required, and expensive palladium and nickel catalysts are also required, the reaction process is difficult to control and the cost is high

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