反应详情

To a solution of 5-bromo-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (400 mg, 1.20 mmol, Step 12a above) in THF (10 mL) at 0° C. was added a catalytic amount of [1,3-bis(diphenylphosphino)-propane]nickel(II) chloride (3.8 mg) followed by MeMgBr (0.8 mL of a 3.0 M solution in THF, Aldrich). The mixture was refluxed for 3 hours, cooled to ambient temperature, and quenched with saturated aqueous ammonium chloride. The volatile components were evaporated and the residue was diluted with CH2Cl2 and saturated aqueous ammonium chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; CH2Cl2 /MeOH, 10:0.2 to 10:0.5) to afford the 5-methyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethyloxy)pyridine as an oil (177 mg, 53%): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.20-2.40 (m, 2H), 3.90 (t, J=8.33 Hz, 2H), 4.14 (m, 1H), 4.31 (m, 1H), 4.51 (m, 1H), 7.04 (s, 1H), 8.06 (s, 1H), 8.18 (d, J=3.33 Hz, 1H); MS (CI/NH3) m/z 279 (M+H)+. To a solution of the above product (170 mg, 0.6 mmol) in CH2Cl2 (2 mL) at 0° C. was added TFA (1.0 mL). After stirring for 30 minutes the solution was basified with 15% aqueous NaOH and extracted with CH2Cl2. The combined organic extracts were dried over MgSO4 and concentrated. The crude product was chromatographed (silica gel; CH2Cl2 /MeOH, 10:1) to afford 5-methyl-3-(azetidinyl-(2S)-methoxyl)pyridine as an oil (93 mg, 64%): 1H NMR (CDCl3, 300 MHz) δ 2.28 (m, 1H), 2.36 (s, 3H), 2.39 (m, 1H), 3.43 (m, 1H), 3.65 (q, J=3.33 Hz, 1H), 3.98-4.02 (m, 2H), 4.22 (m, 1H), 7.12(m, 1H), 8.04 (s, 1H), 8.14 (d, J=3.33 Hz, 1H); MS (CI/NH3) m/z: 179 (M+H)+. The above product was slurried in Et2O and HCl in Et2O was added dropwise. The solvent was removed and the resultant solid was recrystallized from MeOH/Et2O to afford the title compound as a light yellow, very hygroscopic solid: 1H NMR (D2O, 300 MHz) δ 2.36 (s, 3H), 2.67 (q, J=8.33 Hz, 2H), 4.04-4.21 (m, 2H), 4.40 (d, J=3.40 Hz, 2H), 4.90 (m, 1H), 7.40 (s, 1H), 8.04 (s, 1H), 8.14 (s, 1H). MS (CI/NH3) m/z: 179 (M+H+)+. Anal. Calcd. for C10H14N2.1.5 HCl: C, 51.57; H, 6.71; N, 12.03. Found: C, 51.53; H, 6.86; N, 12.03.

1. temperatureThe mixture was refluxed for 3 hours
2. customquenched with saturated aqueous ammonium chloride
3. customThe volatile components were evaporated
4. additionthe residue was diluted with CH2Cl2 and saturated aqueous ammonium chloride
5. extractionThe organic extract
6. dry with materialwas dried over MgSO4
7. concentrationconcentrated
8. customThe residue was chromatographed (silica gel; CH2Cl2 /MeOH, 10:0.2 to 10:0.5)