盐酸普环替尼(CY03529B)候选药物合成工艺优化研究  

Study on Optimization of Synthetic Process of Candidate Drugs of Procyclitinib Hydrochloride(CY03529B)

作　　者：周云鹏[1] 周利航 唐明锐 徐丹 陈烨[1] 沈继伟 ZHOU Yun-peng;ZHOU Li-hang;TANG Ming-rui;XU Dan;CHEN Ye;SHEN Ji-wei(School of Pharmaceutical Sciences,Liaoning University,Shenyang 110036,China)

机构地区：[1]辽宁大学药学院,辽宁沈阳110036

出　　处：《辽宁大学学报(自然科学版)》2024年第4期298-314,共17页Journal of Liaoning University:Natural Sciences Edition

摘　　要：慢性粒细胞性白血病(Chronic myeloid leukemia,CML)属于造血干细胞获得性基因突变而引起的骨髓增殖性疾病.随着酪氨酸激酶抑制剂伊马替尼被美国食品药品监督管理局批准作为该病临床治疗药物,获得性耐药问题愈发明显,其中基因T315I突变最难攻克.第二代Bcr-Abl酪氨酸激酶抑制剂对该突变体无效,第三代抑制剂治疗效果良好但毒副作用大.因此,本课题组通过查阅文献以及对TypeⅡ型酪氨酸激酶抑制剂和Bcr-Abl激酶蛋白共晶结构分析,设计并合成了以四氢化萘为母核的普环替尼,细胞活性以及体内活性研究表明,其对K562/G01耐药细胞有较好的抑制作用且优于伊马替尼.本文以6-甲氧基-1-萘满酮为起始原料,经亲核取代、还原、酰胺交换、成盐等反应得到盐酸普环替尼.在控制反应物料的基础上进一步考察并优化各步工艺参数,实现利于盐酸普环替尼放大生产的合成工艺,所得产品结构通过质谱(Mass specturm,MS)、核磁共振氢谱(Nuclear magnetic resonance hydrogen,1H-NMR)进行验证,结果表明结构正确.整个工艺耗时较短、操作简便、成本降低,总产率达到了26%以上.Chronic myeloid leukemia(CML)is a myeloproliferative disease caused by genetic mutations acquired from hematopoietic stem cells.As Tyrosine kinase inhibitors imatinib were approved by the Food and Drug Administration as clinical treatment of the disease,the problem of acquired drug resistance became more and more obvious,and the mutation of gene T315I was the most difficult to overcome.The second generation of Bcr-Abl tyrosine kinase inhibitors did not respond to the mutant,and the third generation inhibitors had good therapeutic effect but had great side effects.Therefore,by reviewing literatures and analyzing the eutectic structure of TypeⅡtyrosine kinase inhibitors and Bcr-Abl kinase proteins,this research group designed and synthesized procyclitinib with tetrahydronaphthalene as its parent nucleus.Studies on cell activity and in vivo activity showed that it had better inhibitory effect on K562/G01 resistant cells and was superior to imatinib.In this process,6-methoxy-1-naphthomanone was used as the starting material to obtain procyclitinib hydrochloride through nucleophilic substitution,reduction,amide exchange and salt formation.On the basis of controlling the reaction material,the process parameters of each step were further investigated and optimized to achieve the synthesis process of procyclitinib hydrochloride,which was beneficial to scale-up production.The structure of the obtained product was confirmed by mass specturm(MS)and nuclear magnetic resonance hydrogen(1H-NMR),and the results showed that the structure was correct.The whole process is short in time,simple in operation,low in cost,and the total yield is more than 26%.

关 键 词：伊马替尼耐药 盐酸普环替尼 工艺参数 化学合成 

分 类 号：R914.5[医药卫生—药物化学]