C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])=[O:38])([CH3:35])([CH3:34])[CH3:33].[Cl:45][C:46]1[CH:47]=[C:48](O)[CH:49]=[N:50][C:51]=1[Cl:52]>C1COCC1>[Cl:45][C:46]1[CH:47]=[C:48]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:49]=[N:50][C:51]=1[Cl:52]
A solution of triphenylphosphine (2.6 g, 9.94 mmol) and diethyl azodicarboxylate (1.6 mL, 9.94 mmol) in THF (16 mL) was stirred at 0° C. for 15 minutes. 1-t-Butyloxycarbonyl-2-(S)-azetidinemethanol (1.55 g, 8.28 mmol, from step 7c above) and 5,6-dichloro-3-pyridinol (1.5 g, 9.1 mmol) were then added. The reaction mixture was allowed to warm slowly to room temperature and stir overnight. The solvent was removed, and the residue was redissolved in methylene chloride. The solution was washed with saturated aqueous K2CO3 and brine, dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; ethyl acetate:hexane, 1:5) to afford the 5,6-dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine (1.08 g): MS (CI/NH3) m/z 333 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.22-2.42 (m, 2H), 3.85-3.92 (m, 2H), 4.12 (dd, J=2.7, 10.1 Hz, 1H), 4.30-4.40 (m, 1H), 4.48-4.56 (m, 1H), 7.41 (d, J=2.8 Hz, 1H), 7.97 (d, J=2.8 Hz, 1H). To a solution of 5,6-dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)-pyridine (1.06 g, 3.11 mmol) in CH2Cl2 (10 mL) at 0° C. was added TFA (10 mL). The solution was allowed to warm to room temperature while stirring for 45 minutes. The volatile components were then removed under vacuum. The residue was treated with saturated K2CO3 solution, then extracted with methylene chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; MeOH/CHCl3/NH4OH, 1:10:0 to 1:10:0.05) to afford the free base of the title compound (475 mg, 64% yield): mp 59-60° C.; MS (CI/NH3) m/z 233 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ2.21-2.44 (m, 2H), 3.45 (m, 1H), 3.73 (dd, J=8.4, 15.8 Hz, 1H), 3.98-4.08 (m, 2H), 4.28 (m, 1H), 7.37 (d, J=2.8 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H). The base (336 mg) was slurried in ether and converted to the hydrochloride salt by treatment with saturated HCl in ether. Recrystallization from methanol/ether gave the title compound (317 mg, 81% yield): mp 181-182° C.; MS (CI/NH3) m/z 233 (M+H)+; 1H NMR (D2O, 300 MHz) δ2.65-2.74 (m, 2H), 4.03-4.21 (m, 2H), 4.44 (d, J=4.4 Hz, 1H), 4.95 (m, 1H), 7.79 (d, J=2.9 Hz, 1H), 8.13 (d, J=2.9 Hz, 1H). Anal. Calcd. for C9H11N2OCl2.1.0 HCl: C, 40.10; H, 4.11; N, 10.39. Found: C, 39.89; H, 4.08; N, 10.25.
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