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.
Abstract
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.
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