Btk抑制剂依鲁替尼的合成工艺改进

Improved synthesis of Btk inhibitor ibrutinib

目的研究Btk抑制剂依鲁替尼的合成工艺。方法以4-苯氧基苯甲酸为起始原料,经氯代、取代、吡唑环化、嘧啶环化反应得到中间体3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺,再经Mitsunobu反应、脱Boc、酰化反应得到目标产物依鲁替尼。结果与结论目标化合物及部分中间体的化学结构经MS、IR、~1H-NMR和13C-NMR确证,纯度经HPLC测定。总收率为28.5%(以4-苯氧基苯甲酸计),纯度为99.7%。此路线所用原料廉价易得,反应条件温和,收率与纯度均较高,杂质较少,对环境污染少,有利于工业化生产。

Ibrutinib is a newBtk inhibitor developed by Celera Genomics Corporation. Based on the literatures and patents,a synthetic route to ibrutinib was established and optimized thoroughly. Starting from 4-phenoxybenzoic acid,intermediate 3-（ 4-phenoxyphenyl）-1H-pyrazolo-[3,4-d]-pyrimidin-4-amine（ intermediate 5） was synthesized by chlorination,substitution,parazole cyclization and pyrimidine cyclization. After M itsunobu reaction,removing of Boc and amidation,ibrutinib was obtained. The total yield was 28. 5%（ calculated by 4-phenoxybenzoic acid） and the purity of the final product was 99. 7%. The process has several advantages over those reported procedures,such as the improved yield,high purity and in favor of industrial production. The structure of ibrutinib was confirmed by MS,IR,~1H-NMR and ^（13）C-NMR,and the structures of some intermediates were confirmed by MS and ~1H-NMR. The purity of compounds was determined by HPLC.