Trifluoromethanesulfonic anhydride → N-((4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

Participants

Reaction Conditions

Reaction Steps

Trifluoromethanesulphonic acid anhydride (0.40 mL, 2.35 mmol) was added slowly to a stirred solution of N-(((3S,4R,5S)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (1.3 g, 1.96 mmol) in dry pyridine (4 mL) under nitrogen such that the internal temperature remained below −20° C. Upon complete addition, the reaction was stirred at −20° C. for a further 10 minutes and then transferred to an ice bath. After 2 hours at 0° C. the reaction was quenched with saturated aqueous NH4Cl (20 mL) and then the mixture was partitioned between EtOAc (50 mL) and water (25 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (50 mL×1). The combined extracts were washed with half saturated brine (2×50 mL) and brine (50 mL×1), then dried (Na2SO4), filtered and evaporated. The residue was azeotroped with toluene (×2) to give 1.6 g (oil). The reaction was repeated starting with 5.0 g of N-(((3S,4R,5S)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide and the crude product from the two experiments was combined for purification by column chromatography (normal phase, 100 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 20% to 30% EtOAc in n-hexane) to give the title compound. (3.99 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.71 (dd, J=13.76, 3.97 Hz, 1 H) 3.02-3.17 (m, 1 H) 3.19-3.28 (m, 1 H) 3.31-3.35 (m, 1 H) 3.40 (dd, J=10.27, 4.28 Hz, 1 H) 4.00-4.07 (m, 1 H) 4.38-4.47 (m, 1 H) 4.54 (d, J=9.17 Hz, 1 H) 6.96-7.13 (m, 2 H) 7.17-7.39 (m, 9 H) 7.42-7.58 (m, 10 H) 8.03 (br. s., 2 H).

Provenance & Evidence