Methyl morpholine oxide → (3R,4R)-benzyl 3-(((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate

Participants

Reaction Steps

To a solution of (R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropan-1-amine (2.55 g, 7.15 mmol) in CH2Cl2 (59 mL) was added the crude (3R,4S)-benzyl 3-fluoro-4-formylpyrrolidine-1-carboxylate (obtained from 1.4 equiv. of (3R,4R)-benzyl 3-fluoro-4-vinylpyrrolidine-1-carboxylate) in CH2Cl2 (10 mL) and NaBH(OAc)3 (2.3 g, 10.7 mmol). The reaction mixture was then stirred for 16 h at room temperature. After quenched with saturated NaHCO3 aqueous solution, the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude reductive amination product was contaminated by the HF eliminated alkene product, which was not separable on either silica column chromatography or preparative reverse phase HPLC. Therefore, the crude mixture (3.0 g) was dissolved in acetone and water (5:1, 120 mL). 4-Methylmorpholine N-oxide (715 mg, 6.1 mmol) and OsO4 (2.15 mL of a 4% w/v solution) were added to this reaction mixture, which was then stirred for over the weekend at room temperature. After removal of acetone in vacuo, the remaining aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The desired (3R,4R)-benzyl 3-(((R)-1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate was obtained on silica column chromatography (35% to 80% EtOAc in Hexanes, 1.5 g, 35%). LC/MS (uplc) MH+ 592.3, 0.97 min.

Provenance & Evidence