Preparation method of Ibrutinib intermediate

Abstract

The invention discloses a preparation method of an Ibrutinib intermediate shown as a formula 4. The method comprises the following steps: in a organic solvent, under effect of an acid-binding agent, a compound shown as a formula 2 and a compound shown as a formula 3 are subjected to a nucleophilic substitution reaction, and the Ibrutinib intermediate shown as the formula 4 is prepared. The acid-binding agent is one or more of sodium carbonate, potash and sodium hydride; wherein, Y is C1-C6 alkyl, phenyl or C1-C6 alkyl-substituted phenyl; and Z is halogen, or 4-phenoxyl-phenyl. The preparation method has the advantages of simple operation, low cost, less reagent amount, less three wastes, environmental pollution, simple post-treatment, high yield, and high optical purity, and is suitable for industrial production.

Description

technical field

[0001] The present invention specifically relates to a preparation method of an ibrutinib intermediate. Background technique

[0002] Antineoplastic drug Ibrutinib (Ibrutinib), its chemical name is 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 indications are mantle cell lymphoma and chronic lymphocytic leukemia, the structural formula is as follows:

[0003]

[0004] ibrutinib

[0005] US Patent US20080108636 discloses ibrutinib and its preparation method. The synthetic route is as follows:

[0006]

[0007] This patent discloses an ibrutinib intermediate (R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3, 4-d] The preparation method of pyrimidin-1-yl)piperidine: take intermediate (3) and (S)-1-Boc-3-hydroxypiperidine as raw materials, and undergo Mitsunobu reaction to obtain the intermediate (4), the yield is only 34...

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