Scalable, Chromatography-Free Synthesis of 1,7-dimethylxanthine

Abstract: 1,7-dimethylxanthine is a critical intermediate in the pharmaceutical industry. In this paper, a scalable route for the synthesis of 1,7-dimethylxanthine was developed. The method included two steps: (1) acylation reaction of ethyl 4-amino-1-methyl-1H-imidazole-5- carboxylate was carried out by using commercially available methylcarbamoyl chloride as the starting material; (2) through cyclization of pyrimidine ring with aqueous sodium hydroxide, 1,7- dimethylxanthine was obtained with a total yield of 80%, and its HPLC purity was 99% by area. The method is very efficient and readily adaptable to kilogram scale, and because of the cyclization reaction process in aqueous conditions, this route is worthy of exploration for industrial application.