合成路线1

Dapagliflozin can be synthesized as follows: 2-Chloro-5-bromobenzoic acid (I) is chlorinated with oxalyl chloride and catalytic DMF in CH2Cl2 to afford the benzoyl chloride derivative (II), which is subjected to Friedel-Crafts reaction with ethoxybenzene (III) in the presence of AlCl3 in CH2Cl2 to give the benzophenone derivative (IV). Subsequent decarbonylation of ketone (IV) employing triethylsilane and boron trifluoride etherate in acetonitrile yields 5-bromo-2-chloro-4’-ethoxydiphenylmethane (V). The lithiated derivative of bisarylmethane (V) (generated by treatment with BuLi in THF/toluene at –78 ºC) is coupled with the persilylated lactone (VII) (obtained from D-gluconolactone [VI] by treatment with trimethylsilyl chloride and NMM in THF) to yield the corresponding lactol adduct, which is deprotected in situ with methanesulfonic acid in MeOH to afford the desilylated ketal (VIII) (1-3). Polyol (VIII) is peracetylated with acetic anhydride and DIEA in THF resulting in the tetraacetate (IX). The glucosidic methoxy group of (IX) is then reductively removed using triethylsilane and boron trifluoride etherate in water/acetonitrile to give the glucoside (X) (1, 2), which is finally deacetylated by treatment with LiOH in aqueous MeOH (1-3).
Alternatively, intermediate (X) can be prepared by reduction of the glucosidic methoxy group of (VIII) with trethylsilane and boron trifluoride etherate in CH2Cl2/acetonitrite, and subsequent peracetylation with Ac2O, DMAP in CH2Cl2/pyridine (3).