2-氨基-9-(3-乙酰氧甲基丁基)嘌呤的合成

Synthesis of 2-amino-9-(3-acetoxymethylbutyl)purine

2-氨基-9-(3-乙酰氧甲基丁基)嘌呤(1)是美国药典USP39-NF34版本所收载的抗病毒药物泛昔洛韦(Famciclovir)的一个有关物质(也称为杂质)。目前还没有文献报道过该有关物质的合成。以甲基丙二酸二乙酯和1,2-二溴乙烷为原料,通过亲核取代反应首先制备得到侧链2-甲基-2-(2-溴乙基)丙二酸二乙酯(4)。4接着和2-氨基-6-氯嘌呤缩合生成关键前体2-氨基-6-氯-9-[3,3-二(乙氧羰基)丁基]嘌呤(6),然后依次通过脱酯反应、还原反应、酯化反应和还原脱氯反应首次合成得到目标产物1。六步合成路线的总产率为24%。提供了一种新的合成方法用于合成1。制备的样品可用于生产中泛昔洛韦的质量控制。

2-amino-9-（3-acetoxymethylbutyl）purine（1）is one of the related substances（impurities）of antiviral drug Famciclovir recorded in US Pharmcopoeia（USP39-NF34edition）.A synthetic route for target product 1 was developed.Starting from readily available diethyl methylmalonate and 1,2-dibromoethane,side chain diethyl 2-methyl-2-（2-bromoethyl）malonate was first smoothly synthesized.The condensation of the side chain with 2-amino-6-chloropurine provided the key precursor 2-amino-6-chloro-9-[3,3-bis（ethoxycarbonyl）butyl]purine（6）.Next 6 underwent consecutive decarbethoxylation,reduction,acetylation and reductive dechlorination offering the target molecule 1.The six-step overall yield is 24%.The target product obtained can be used as reference sample in the quality control of Famciclovir in industrial manufacturing.