盐酸纳呋拉啡的合成工艺改进Improved synthetic process of nalfurafine hydrochloride
丁军,李娜,张仲奎,张乃华,张贵民
摘要(Abstract)：
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。
关键词(KeyWords)： 盐酸纳呋拉啡;尿毒症瘙痒;合成;工艺改进
基金项目(Foundation):
作者(Author): 丁军,李娜,张仲奎,张乃华,张贵民
DOI: 10.14142/j.cnki.cn21-1313/r.2024.02.003
参考文献(References)：
- [1] KUMAGAI H,EBATA T,TAKAMORI K,et al.Effect of a novel kappa-receptor agonist,nalfurafine hydrochloride,on severe itch in 337 haemodialysis patients:a phase Ⅲ,randomized,double-blind,placebo-controlled study[J].Nephrol Dial Transpl,2010,25(4):1251-1257.
- [2] KUMAGAI H,EBATA T,TAKAMORI K,et al.Efficacy and safety of a novel κ-agonist for managing intractable pruritus in dialysis patients [J].Am J Nephrol,2012,36(2):175-183.
- [3] NAKAO K,MOCHIZUKI H.Nalfurafine hydrochloride:a new drug for the treatment of uremic pruritus in hemodialysis patients [J].Drugs Today,2009,45(5):323-329.
- [4] WIKSTROM B,GELLERT R,LADEFOGED S D,et al.κ-Opioid system in uremic pruritus:multicenter,randomized,double-blind,placebo-controlled clinical studies [J].Am Soc Nephrol,2005,16(12):3742-3747.
- [5] 国家药品监督管理局.国药准字HJ20230091 [EB/OL].[2023-11-7].https://www.nmpa.gov.cn/datasearch/search-result.html.
- [6] 陈本顺，石利平，何伟，等.一种纳呋拉啡中间体的生物合成方法及生物酶：中国，112575011B [P].2021-03-30.CHEN B S,SHI L P,HE W,et al.A method of biosynthesis of nalfurafine intermediates and a biological enzyme:CN,112575011B [P].2021-03-30.
- [7] 周晓雯，刘欢，马铮，等.一种纳呋拉啡中间体的制备方法：中国，114437089A [P].2022-05-06.ZHOU X W,LIU H,MA Z,et al.Preparation method of nalfurafine intermediate:CN,114437089A [P].2022-05-06.
- [8] 丁军，鹿晓东，刘忠.一种制备纳呋拉啡的方法：中国，114621238A [P].2022-06-14.DING J,LU X D,LIU Z.Method for preparing nalfurafine:CN,114621238A [P].2022-06-14.
- [9] 张贵民，丁军，郭新亮.一种制备纳呋拉啡中间体的方法：中国，115521317A [P].2022-12-27.ZHANG G M,DING J,GUO X L.Method for preparing nalfurafine intermediate:CN,115521317A [P].2022-12-27.
- [10] HIROSHI N,KOJI K,KUNIAKI K,et al.Morphinan derivative and its pharmaceutical applications:US,6277859B1 [P].2001-08-21.
- [11] CASHMAN J R.Synthesis of metabolically stable agents for alcohol and drug abuse:WO,2010006119A [P].2010-01-14.
- [12] BROCK U,HUDLICKY T,CARROLL R,et al.Processes for the preparation of morphinane and morphinone compounds:WO,2010121369A [P].2010-10-28.
- [13] 长濑博，内海润，远藤孝，等.止痒药物：中国，1214634A [P].1999-04-21.HIROSHI N,OTSUMI J,TAKASHI E,et al.Antipruritic agent:CN,1214634A [P].1999-04-21.