The regioselective bromine-lithium exchange reaction of alkoxymethyldibromobenzene: A new strategy for the synthesis of tofogliflozin as a SGLT2 inhibitor for the treatment of diabetes

Abstract The regioselective bromine-lithium exchange reaction of 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene ( 2 ), which resulted in optimized selectivity of 220:1, is described. Applying this method to the synthesis of tofogliflozin ( 1 ) as a SGLT2 inhibitor is also described. Selective and sequential metalation-functionalization of 2 led to the synthesis of 1 in 47% overall yield.