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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。
Objective To study the synthesis of Btk inhibitor Ibrutinib. Methods Starting from 4-phenoxybenzoic acid, the intermediate 3- (4-phenoxyphenyl) -1H-pyrazolo [ 3,4-d] pyrimidin-4-amine, followed by Mitsunobu reaction, de Boc, acylation reaction to give the desired product Ibrutinib. RESULTS AND CONCLUSION The chemical structures of the target compounds and some intermediates were confirmed by MS, IR, ~ 1H-NMR and 13C-NMR. Purity was determined by HPLC. The overall yield was 28.5% (as 4-phenoxybenzoic acid) with a purity of 99.7%. The raw materials used in this route are cheap and easy to obtain, the reaction conditions are mild, the yield and purity are high, the impurities are less, the environment pollution is less, which is good for industrialized production.