Ammonium Chloride → N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

Participants

Reaction Conditions

Reaction Steps

N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (21.0 g, 0.519 mol, 1.0 equiv.) was dissolved in dry THF (105 mL) under a nitrogen atmosphere and the solution was cooled at 0° C. N,N-diisopropylethylamine (40.7 mL, 0.234 mol, 4.50 equiv.), triethylamine trihydrofluoride (14.0 mL, 0.0857 mol, 1.65 equiv.) and perfluorobutanesulfonyl fluoride (22.4 mL, 0.125 mol, 2.40 equiv.) were added while maintaining temperature under 5° C. The reaction was stirred for 3 h at 0° C. then slowly warmed to RT and stirred for 11 h. To the reaction mixture was charged sat.NH4Cl (100 mL) followed by 2-methoxy-2-methylpropane (100 mL). The organic phase was isolated and washed with aq. HCl (1.0 M, 100 ml), concentrated and redissolved in 2-methoxy-2-methylpropane (301 ml). The organic phase was then washed with aq.HCl (1M, 63 mL), sat aq.NaHCO3 (100 mL). The last aqueous layer was extracted with 2-methoxy-2-methylpropane. The combined organic phase was washed with 18% aq.NaCl (63 mL) and concentrated under reduced pressure to afford title compound (19.40 g) as a foam. 1H NMR (500 MHz, DMSO) δ ppm 8.02 (s, 2H), 7.61-7.51 (m, 1H), 7.51-7.38 (m, 3H), 7.39-7.18 (m, 2H), 4.72-4.49 (m, 2H), 4.48-4.37 (m, 1H), 4.41 (d, J=9.1 Hz, 21H), 3.04 (s, 2H); 13C NMR (125 MHz, DMSO) δ ppm 150.92 (dd, JCF=245.5, 13.3 Hz), 148.11 (dd, JCF=248.2, 13.4 Hz), 132.40, 128.99, 128.63, 125.16, 124.94, 117.61, 83.64 (d, JCF=170.2 Hz), 79.51 (d, JCF=18.4 Hz), 76.17, 66.27, 23.67.

Provenance & Evidence