泛昔洛韦中两种脱羟基杂质的合成

Synthesis of two impurities of famciclovir

目的为加强泛昔洛韦药物的质量控制,本文合成了泛昔洛韦的两个杂质。方法方法以(±)-α-甲基-γ-丁内酯为原料,经开环溴化、甲酯化、还原、乙酰化得到侧链(±)-2-甲基-4-溴丁醇乙酸酯,再与2-氨基-6-氯嘌呤(ACP)偶联,合成了杂质(±)-4-(2-氨基-6-氯-9H-9-嘌呤基)-2-甲基丁基乙酸酯(BRL48951),经加氢脱氯得到杂质(±)-4-(2-氨基-9H-9-嘌呤基)-2-甲基丁基乙酸酯(BRL45145)。结果与结论产物的结构经~1H-NMR、^(13)C-NMR、HRMS确证,合成的杂质可以作为泛昔洛韦药物质量控制的杂质对照品,该合成方法路线短,反应稳定可靠,原料易得,操作简单。

To improve the quality control of famciclovir, two related substances were synthesized in this paper. Starting from （ ± ）-α-methyl-γ-butyrolactone＇ a convenient synthetic route was designed including ring-opening bromination, methyl esterification, reduction with LiBH4 and acetylation to afford side chain （±）-4-bromo-2-methylbutyl acetate, which could be coupled with 2-amino-6-chloropurine （ACP） to synthesize 4-（ 2-amino-6-chloro-9H-purin-9-yl ） -2-methylbutyl acetate （ BRIA8951 ）. Another related sub- stance 4- （2-amino-9H-purin-9-yl） -2-methylbutyl acetate （ BRIA5145 ） could be synthesized from BRL48951 via catalytic hydrogenation. The structures of the target compounds were verified by ^1H-NMR,^ 13 C-NMR and HRMS. The target compounds can be used as the reference substance of the related substances in the quality control of famciclovir and the starting materials were cheap and easy to obtain, and the reaction conditions were mild.