依鲁替尼的合成  

Synthesis of Ibrutinib

作　　者：王雪娜 唐斌 马驰 范琳 林燕琴[2] 赵学清[2] WANG Xue-na;TANG Bin;MA Chi;FAN Lin;LIN Yan-qin;ZHAO Xue-qing(Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China;Fujian Institute of Microbiology,Fuzhou 350007,China)

机构地区：[1]福建中医药大学,福建福州350122 [2]福建省微生物研究所,福建福州350007

出　　处：《海峡药学》2024年第6期58-60,共3页Strait Pharmaceutical Journal

摘　　要：目的解决依鲁替尼关键合成工艺中副产物Ph_(3)PO的去除问题,更高效合成依鲁替尼。方法关键工艺中由Mitsunobu反应在吡唑并嘧啶中间体1-位上引入3-S-N-Boc保护的哌啶环,通过加入ZnCl_(2)与该反应副产物Ph_(3)PO络合沉淀,从而去除Ph 3PO,再经酸性水解脱Boc保护基,最后经丙烯酰氯酰胺化得依鲁替尼。结果ZnCl_(2)可除去副产物Ph_(3)PO。结论ZnCl_(2)有效的去除了关键工艺中副产物Ph_(3)PO,使得该合成工艺更简洁高效。OBJECTIVE To get rid of the side-product Ph_(3)PO in the key synthetic process of ibrutinib,and to prepare ibrutinib more efficiently.METHODS The 3-S-N-Boc-protected piperidine ring was introduced into the 1-position of the pyrazolopyrimidine intermediate via Mitsunobu reaction.The side-product Ph_(3)PO could be removed by means of the precipitation of its complexation with additive ZnCl_(2),subsequently Boc group was deprotected under acidic codition,and finally ibrutinib was obtained by acryloyl amidation.RESULTS The side-product Ph_(3)PO of Mitsunobu reaction was able to be removed by additive ZnCl_(2).CONCLUSION The side-product Ph_(3)PO can be efficiently removed and a more economic and brief process for the synthesis of ibrutinib has been developed.

关 键 词：布鲁顿酪氨酸激酶 依鲁替尼 ZnCl_(2) MITSUNOBU反应 

分 类 号：R914[医药卫生—药物化学]