盐酸纳呋拉啡的合成工艺改进  

Improved synthetic process of nalfurafine hydrochloride

作　　者：丁军 李娜 张仲奎 张乃华 张贵民 DING Jun;LI Na;ZHANG Zhongkui;ZHANG Naihua;ZHANG Guimin(Lunan Pharmaceutical Group Co.,Ltd.,Linyi 273400,China;National Engineering and Technology Research Center of Chirality Pharmaceutical,Shandong New Time Pharmaceutical Co.,Ltd.,Linyi 273400,China)

机构地区：[1]鲁南制药集团股份有限公司,山东临沂273400 [2]山东新时代药业有限公司国家手性制药工程技术研究中心,山东临沂273400

出　　处：《中国药物化学杂志》2024年第2期99-104,共6页Chinese Journal of Medicinal Chemistry

摘　　要：目的 优化盐酸纳呋拉啡的合成工艺。方法 以14-羟基二氢降吗啡酮(2)为起始原料,与溴甲基环丙烷经取代反应生成纳曲酮(3),3与N-甲基苄胺在氰基硼氢化钠作用下经还原胺化反应得到6β-(N-苄基)甲氨基-17-环丙甲基-4,5α-环氧-3,14β-二羟基吗啡喃(4),4经钯炭催化氢解脱苄基得到6β-甲氨基-17-环丙甲基-4,5α-环氧-3,14β-二羟基吗啡喃(5),5与(E)-3-(3-呋喃基)丙烯酰氯经酰化反应得到纳呋拉啡(6),6与盐酸成盐制得盐酸纳呋拉啡。结果 目标产物结构经质谱、核磁共振谱以及红外光谱确证,总收率52%(以2计),纯度99.971%(HPLC法)。结论 优化后的合成工艺反应条件温和,操作简便,生产成本较低,已经过中试放大实验验证,适合工业化生产。In this study,the synthetic process of nalfurafine hydrochloride(1)was improved.A substitution reaction of 14-hydroxydihydromorphinone(2)with bromomethylcyclopropane provided naltrexone(3),which was reacted with N-methylbenzylamine in the presence of sodium cyanoborohydride to generate 6β-(N-benzyl)methylamino-17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxymorphopyran(4)through reductive amination.Compound 4 was hydrogenated and de-benzylated to give 6β-methylamino-17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxymorphin(5)on exposure to Pd/C.Compound 5 was acylated with(E)-3-(3-furanyl)acryloyl chloride to generate nalfurafine(6).At last,compound 6 salted with hydrochloric acid to give nalfurafine hydrochloride with a purity of 99.971%(HPLC)and an overall yield of 52%(based on compound 2).The improved process with mild reaction conditions,reduced cost and convenient reaction operation,has been validated in pilot scale up and is suitable for industrial production.

关 键 词：盐酸纳呋拉啡 尿毒症瘙痒 合成 工艺改进 

分 类 号：R914[医药卫生—药物化学]