反应详情

A 12 L 3-neck round bottom flask fitted with a magnetic stirrer under nitrogen was charged with zinc dust (745 g, preactivated according to the above Preparation 1, 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 min, followed by TMSCl (108 mL, 0.855 mol, 0.15 eq, Acros) over 20 min. The reaction mixture was stirred for 25 min at RT. A solution of N-Boc-3-iodoazetidine (2) (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 h 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 (6) (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 h at which point LCMS indicated complete conversion of 2,3-dichloropyrazine (6). 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 obtain 536 g of pure tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (7) 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 (7).

1. customA 12 L 3-neck round bottom flask fitted with a magnetic stirrer under nitrogen
2. customthe internal temperature below 65° C.
3. stirringThe suspension was stirred for 1 h at RT at which point it
4. customwas degassed with nitrogen
5. stirringStirring
6. customA 22 L 3-neck round bottom flask fitted with a mechanical stirrer
7. customThe solution was degassed with nitrogen
8. additionThe clear zinc reagent solution above the residual solid zinc was poured into the 22 L flask under nitrogen
9. customThe brown solution was degassed with nitrogen
10. temperatureheated to 80° C. for 16 h at which point LCMS
11. customThe reaction mixture was transferred to brine (8 L) in 50 L reparatory funnel
12. additionWater (8 L) and EtOAc (15 L) were added
13. customthe layers were separated
14. extractionThe aqueous layer was extracted with EtOAc (2×10 L)
15. washThe combined organics were washed with water (3×10 L) and brine (5 L)
16. dry with materialdried over sodium sulfate
17. customevaporated
18. customThe resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=10:1)