Boron Trichloride → N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-(hydroxymethyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide

Participants

Reaction Conditions

Reaction Steps

Boron trichloride (45.8 mL, 45.8 mmol) was added to a solution of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(5-bromo-2-fluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C32) (8.70 g, 15.3 mmol) in dichloromethane (76 mL) at 0° C., while maintaining the internal temperature below 5° C. The heterogeneous mixture was allowed to stir for 10 minutes at 0° C. and then at room temperature for 16 hours. The reaction mixture was then quenched by drop-wise addition of methanol (100 mL). The methanol solution was refluxed for 15 minutes and then concentrated under reduced pressure. The residue was re-dissolved in dichloromethane (100 mL) and washed sequentially with 1 N sodium hydroxide (2×100 mL) and with brine (100 mL), dried over sodium sulfate and filtered. Purification via silica gel chromatography (Gradient: 30% to 100% ethyl acetate in heptane) afforded the product as an off-white solid. Yield: 4.98 g, 68%. LCMS m/z 410 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 8.13 (d, J=6.8 Hz, 1H), 7.59-7.45 (m, 4H), 7.16 (dd, J=12.1, 8.6 Hz, 1H), 4.15-4.11 (m, 1H), 3.91 (d, J=11.9 Hz, 1H), 3.79-3.73 (m, 1H), 3.59 (d, J=5.1 Hz, 1H), 3.21 (br s, 1H), 2.96 (dd, J=13.0, 4.0 Hz, 1H), 2.76 (dd, J=13.2, 2.8 Hz, 1H), 1.81-1.90 (m, 1H), 1.72-1.68 (m, 1H).

Provenance & Evidence