Reaction Steps
To a solution of triphenylphosphine (0.8 g, 3.0 mmol) in THF (20 mL) was added diethyl azodicarboxylate (4.7 mL, 3.0 mmol) at 0° C., and the mixture was stirred for 0.5 h. 1-t-butyloxycarbonyl-2-(R)-azetidinemethanol (0.51 g, 2.7 mmol, from Example 1c above) and 2-fluoro-5-hydroxypyridine (0.32 g, 2.8 mmol, Step 8e below) were then added. The mixture was allowed to warm slowly to room temperature and stirred overnight. The solvent was removed and the residue was chromatographed (silica gel; hexane/EtOAc, 9:1 to 7:3) to provide 0.80 g of the coupled product: MS (CI/NH3) m/z 283 (M+H)+, 300 (M+NH4)+; 1H NMR (CDCl3, 300 MHz) δ1.42 (m, 9H), 3.33 (m, 1H),3.89 (t, J=7.31 Hz,1H), 4.11 (m 1H), 4.31 (m, 1H), 4.51 (m, 1H), 6.85 (m, 1H), 7.38 (m, 1H), 7.87 (m, 1H). The 6-fluoro-3-(1-t-butyloxycarbonyl-2-(R)-azetidinylmethoxy)pyridine (760 mg, 2.70 mmol) was combined with TFA (2 mL) in methylene chloride (2 mL) at 0° C., and the solution was stirred for 30 minutes. The volatile components were then removed under vacuum. The residue was basified with saturated aqueous NaHCO3 and extracted with methylene chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel:methylene chloride:methanol:NH4OH 10:1:0.1) to afford of the free base of the title compound (240 mg, 49%). The base was converted to the dibenzoic acid salt by treatment with benzoic acid in ether to give the title compound (235 mg, 42%): mp 76-80° C.; [α]D2.9 (c 1, MeOH); MS (CI/NH3) m/z 183 (M+H)+; 1H NMR (D2O, 300 MHz) δ2.23 (m, 1H), 2.34 (m, 1H), 3.49(m, 1H), 3.66 (m, 1H), 4.14 (m, 1H), 4.35 (m, 1H), 7.12 (dd, J=2.44, 8.81 Hz, 1H), 7.45 (m, 4H), 7.56 (m, 2H), 7.63 (m, 1H), 7.93 (m, 3H); Anal. Calcd. for C9H11N2OF.2 C6H5COOH: C, 64.78 H, 5.44; N, 6.57. Found: C, 64.65; H, 5.48; N, 6.45.
