Thionyl Chloride → HCID 67117253, compound

Participants

Reaction Conditions

Reaction Steps

A solution of (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(hydroxymethyl)pyrrolidin-2-one a12R (0.281 g, 1.32 mmol, 1.5 eq) in dichloromethane (25 ml) is treated with thionyl chloride (382 μl, 5.27 mmol, 6 eq). The mixture is stirred for 1 h at 22° C. and concentrated in vacuo to obtain (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(chloromethyl)pyrrolidin-2-one a18R. The resulting liquid is then added to a solution of anhydrous zinc chloride (0.239 g, 1.76 mmol, 2 eq) and 2-[methoxy(2H2)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a44 (0.210 g, 0.88 mmol, 1 eq) in dioxane. The mixture is stirred at 80° C. for 4 days. Some more (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(hydroxymethyl)pyrrolidin-2-one a12R (1.5 eq) are then added and the mixture is stirred for another 24 h. (4R)-4-(2-chloro-2,2-difluoroethyl)-1-(hydroxymethyl)pyrrolidin-2-one a12R (2 eq) is added again and the mixture stirred for another 3 days. The mixture is then diluted with dichloromethane and washed with water (2×25 ml). The organic layer is dried over magnesium sulphate and concentrated under reduced pressure to afford 1.28 g of a brown oil. The mixture is purified by reverse phase HPLC (X-bridge C18, eluent: MeCN/H2O/NH3) to afford (4R)-4-(2-chloro-2,2-difluoroethyl)-1-({2-[methoxy(2H2)methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl}methyl)pyrrolidin-2-one 31 as a yellow oil.

Provenance & Evidence