Dichloromethane → Tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate

Participants

Reaction Steps

A 12 L 3-neck round bottom flask fitted with a magnetic stirrer under nitrogen was charged with zinc dust (745 g, pre-activated, 11.4 mol, 2 eq.) and DMA (2 L, anhydrous). 1,2-dibromoethane (71 mL, 0.855 mol, 0.15 eq, Aldrich) was then added over 10 minutes, followed by TMSCl (108 mL, 0.855 mol, 0.15 eq, Acros) over 20 minutes. The reaction mixture was stirred for 25 minutes at room temperature. A solution of N-Boc-3-iodoazetidine (2420 g, 8.55 mol, 1.5 eq, CNH Technologies) in DMA (5 L, anhydrous) was added via a 2 L addition funnel over 2 h keeping the internal temperature below 65° C. using a water bath. The suspension was stirred for 1 hour at RT at which point it was degassed with nitrogen. Stirring was stopped and the suspension was allowed to stand. A 22 L 3-neck round bottom flask fitted with a mechanical stirrer was charged with 2,3-dichloropyrazine (850 g, 5.70 mol, 1.0 eq, AK Scientific), PdCl2dppf.CH2Cl2 (140 g, 171 mmol, 0.03 eq, Aldrich), CuI (67.3 g, 353 mmol, 0.062 eq, Aldrich), and DMA (5 L, anhydrous). The solution was degassed with nitrogen. The clear zinc reagent solution above the residual solid zinc was poured into the 22 L flask under nitrogen. The brown solution was degassed with nitrogen and heated to 80° C. for 16 hours at which point LCMS indicated complete conversion of 2,3-dichloropyrazine. The reaction mixture was transferred to brine (8 L) in 50 L reparatory funnel. Water (8 L) and EtOAc (15 L) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×10 L). The combined organics were washed with water (3×10 L) and brine (5 L), dried over sodium sulfate and evaporated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=10:1) to get 536 g of pure tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate and 121 g of mixed fractions. The impure material was distilled under high vacuum to remove the impurity (N-Boc-azetidine) to give 81 g of pure tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate.

Provenance & Evidence