反应详情

Diethyl azodicarboxylate (1.2 mL, 7.9 mmol) was added to a stirred solution of triphenylphosphine (2.1 g, 7.9 mmol) in THF (60 mL) at 0° C. After 15 minutes, (R)-1-(benzyloxycarbonyl)-2-azetidinemethanol (1.46 g, 6.6 mmol, Step 1e above) in THF (6.6 mL) was added to the reaction vessel followed by 3-hydroxypyridine (690 mg, 7.3 mmol, Aldrich). After stirring for 18 h at ambient temperature the solvent was removed and the residue was dissolved in CH2Cl2 and washed with saturated K2CO3, dried (MgSO4), concentrated and chromatographed (silica gel; EtOAc/hexane, 1:2) to afford a mixture (2.8 g) of (R)-1-(benzyloxycarbonyl)-3-((2-azetidinylmethyl)oxy)pyridine and triphenylphosphine oxide: MS (CI/NH3) m/z: 299 (M+H)+. A sample (1.6 g) of this mixture was dissolved in EtOH (25 mL) and stirred in the presence of 10% Pd/C (320 mg) under an atmosphere of H2 (1 atm) for 4 h. The reaction was filtered, concentrated and chromatographed (silica gel; CHCl3 /MeOH/NH4OH, 90:10 to 90:10:0.5) to afford the free base of the title compound as an amber oil (465 mg, overall yield 75%): [α]D20 +5.8 (c 1.6, CHCl3); MS (CI/NH3) m/z: 165 (M+H)+ ; 1H NMR (CDCl3, 300 MHz) δ 2.22-2.46 (m, 2H), 3.45-3.51 (m, 1H), 3.73 (dd, J=7.7, 8.5 Hz, 1H), 4.00-4.10 (m, 2H), 4.26-4.35 (m, 1H), 7.21-7.24 (m, 2H), 8.22 (dd, J=2.9, 3.0 Hz, 1H), 8.33 (dd, J=1.5, 2.2 Hz, 1H). The (R)-3-((2-azetidinylmethyl)oxy)pyridine (450 mg, 2.74 mmol) was slurried in Et2O (20 mL) and MeOH (~2 mL), then Et2O saturated with HCl gas was added at ambient temperature. The solvent was removed and the remaining solid recrystallized from MeOH/Et2O to afford the title compound as a deliquescent white solid (206 mg, 31%): mp 138-140° C.; [α]D20 +9.8 (c 0.5, MeOH). MS (CI/NH3) m/z: 165 (M+H)+ ; 1H NMR (D2O, 300 MHz) δ 2.71 (dd, J=8.5, 17.3 Hz, 2H) 4.05-4.21 (m, 2H), 4.57 (d, J=4.4 Hz, 2H), 4.96-5.03 (m, 1H), 7.99 (dd, J=5.7, 9.0 Hz, 1H), 8.21 (ddd, J=1.2, 2.8, 9.0 Hz, 1H), 8.46 (d, J=5.7 Hz, 1H), 8.59 (d, J=2.8 Hz, 1H); Anal. Calcd for C9H12N2O.2 HCl.0.2 H2O: C, 44.90; H, 6.03; N, 11.64. Found: C, 44.90; H, 5.98; N, 11.54.

1. customwas removed
2. dissolutionthe residue was dissolved in CH2Cl2
3. washwashed with saturated K2CO3
4. dry with materialdried (MgSO4)
5. concentrationconcentrated
6. customchromatographed (silica gel; EtOAc/hexane, 1:2)