Reaction Steps
A solution of 2,2,3,3-tetrafluoropropanol (381 mg, 2.9 mmol) in anhydrous NMP (10 mL) was treated with NaH (55% in hexane, 126 mg, 2.9 mmol) for 10 min at room temperature. Once H2 ceased to evolve, (1R,2R)-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4triazol-1-yl)propyl]-7-fluoroquinazolin-4(3H)-one (400 mg, 0.96 mmol, obtained in example 12) was added and the mixture was stirred at 120° C. overnight. Once the reaction was completed, water and EtOAc were added. The aqueous phase was separated and reextracted with further EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography to give the title compound as an amorphous white solid (200 mg, 48%): 1H NMR (300 MHz, CDCl3) δ (TMS) 8.56 (s, 1H, N=CH--N), 8.29 (d, J=9.5, 1H, arom), 7.76 (s, 1H, triazole), 7.74 (s, 1H, triazole), 7.48 (dt, Jd =6.5, Jt =8.8, 1H, arom), 7.15 (m, 2H, arom), 6.9-6.7 (m, 2H, arom), 6.08 (tt, J=4.5, J=53, 1H, CHF2), 5.92 (dq, Jd =2, Jq =7.3, 1H, MeCH), 5.51 (d, J=1.5, 1H, OH), 5.16 (d, J=14.3, 1H, CH(H)), 4.49 (tt, J=1.5, J=12, 2H, CH2), 4.01 (d, J=14.3, 1H, CH(H)), 1.29 (d, J=7.3, 3H, CHMe); GC/MS 304 (N-ethylheterocycle group, C13H12F4N2O2), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =-16.7° (c 1, CHCl3). Analysis calculated for C23 H19F6N5O3 : C 52.38; H 3.63; N 13.28. Found: C 51.84; H 3.68; N 12.29.
