BrCCBr.C[Si](Cl)(C)C.[C:10]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Br[C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(Cl)Cl>CC(N(C)C)=O.[Zn].[Cu]I>[Br:29][C:28]1[C:23]([CH:19]2[CH2:20][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:18]2)=[N:24][CH:25]=[CH:26][CH:27]=1A 5 L 3-neck round bottom flask fitted with a magnetic stirrer under nitrogen was charged with zinc dust (138 g, preactivated according to the above Preparation 1, 2.11 mol, 2 eq.) and DMA (370 mL, anhydrous). 1,2-dibromoethane (13 mL, 0.158 mol, 0.15 eq, Aldrich) was then added over 5 min, followed by TMSCl (20 mL, 0.158 mol, 0.15 eq, Acros) over 5 min. The reaction mixture was stirred for 20 min at RT. A solution of N-Boc-3-iodoazetidine (2) (448 g, 1.583 mol, 1.5 eq, CNH Technologies) in DMA (925 mL, anhydrous) was added over 25 min 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 12 L 3-neck round bottom flask fitted with a mechanical stirrer was charged with 2,3-dibromopyridine (1) (250 g, 1.055 mol, 1.0 eq, Frontier Scientific), PdCl2dppf.CH2Cl2 (25.8 g, 31.65 mmol, 0.03 eq, Aldrich), CuI (12.5 g, 65.41 mmol, 0.062 eq, Aldrich), and DMA (925 mL, anhydrous). The solution was degassed with nitrogen. The clear zinc reagent solution above the residual solid zinc was poured into the 12 L flask under nitrogen. The brown solution was degassed with nitrogen and heated to 80° C. for 17 h at which point LCMS indicated complete conversion of 2,3-dibromopyridine (1). The reaction mixture was transferred to brine (2 L) in 22 L separatory funnel. Water (2 L) and EtOAc (4 L) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2×3 L). The combined organics were washed with water (3×3 L) and brine (2 L), dried over sodium sulfate and evaporated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 5:1) to obtain 289 g of impure tert-butyl 3-(3-bromopyridin-2-yl)azetidine-1-carboxylate (3) which was distilled under high vacuum to remove the impurity (N-Boc-azetidine) to give 281 g of pure tert-butyl 3-(3-bromopyridin-2-yl)azetidine-1-carboxylate. Yield: 85%.
Wird geladen…
