Improved Synthesis Of Antidiabetic Drug, Dapagliflozin

Dapagliflozin is a kind of sodium dependent glucose transporter(SGLT2) inhibitor used for treatment of type Ⅱ diabetes mellitus(T2DM), As a selective inhibitor of the SGLT2 in the kidney, dapagliflozin is expected to normalize plasma glucose levels by enhancing the excretion of glucose in the urine, thereby delaying the development of diabetic complications which was not associated with significant hypoglycemic episodes or weight gain.This article briefly reviews the pathogenesis of diabetes, the common drugs used in clinical and of its pathogenesis, and as well as the research progress of SGLT2 inhibitors. This paper also reviews the synthesis of dapagliflozin, the third synthetic route was determined and optimizied.Dapagliflozin was prepared via δ-Gluconolactone derivative and diphenylmethane derivative. δ-Gluconolactone derivative was prepared from glucolactone which was protected by trimethylsilyl chloride. The intermediate product diphenylmethane derivative, 5-bromo-2-chloro-4’-ethoxybenzophenene, was prepared via Friedel-Crafts acylation of 5-bromo-2-chlorobenzoyl chloride with phenetole, which was reduced with polymethylhydrosiloxane(PMHS),diphenylmethane derivative was condensed with δ-Gluconolactone derivative, followed by the etherification,removal of the methoxy. The obtained crude product via esterification and recrystallization to remove the epimer of anomeric carbon. Finally, the target product was obtained from alkaline hydrolysis with an overall yield of 44 % and a purity of 99.093 %. The target compound was confirmed by MS, 1H NMR and 13 C NMR. The route of the improved process is easily to operate with more mild reaction conditions, the total yield of which was improved obviously. Based on all the advantages above, the process can be provided reference value to industrial-scale production.