Improved synthetic process of nalfurafine hydrochloride
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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