Synthesis Of Empagliflozin And Dapagliflozin

Empagliflozin and Dapagliflozin are both medicinally important SGLT-2 inhibotor which feature better tolerance, fewer side effects and are used primarily for the treatment of type II diabetes.The traditional synthesis of Empagliflozin is based on the reaction of aryllithiem or arylGrignard reagents with glucono lactone, to yield methyl glycopyranoside which need to be reduced in next step. However, low reaction temperature are required to avoid opening of the intermediate lactol. Due to the advantage of much improved chemo-selectivity and tolerance of functional groups of organozinc compounds, compared with organolithium and organomagnesium compounds, in this approach neighboring group participation is been utilized with the organozinc compounds as nucleophiles to achieve favorable selectivity.Two methods of synthesis danpgliflozin were reported in this paper. The key intermediate 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene can be prepared from commercially available 5-bromo-2-chlorobenzoic acids which was experienced Friedel-Crafts and reduction. In route I Dapagliflozin was successfully prepared by nucleophilic addition of lithium reagent and glucono lactone. In route II a general, transition-metal-free, highly stereoselective cross-coupling reaction between glycosyl bromides and arylzinc reagents leading to p-arylated glycosides is reported. The stereoselectivity of the reaction is explained by invoking anchimeric assistance via a bicyclic intermediate. This new method was applied to a short and efficient stereoselective synthesis of Dapagliflozin.