反应详情

To a solution of (1S,2R)-(+)-N-methylephedrine (31.1 g, 0.174 mol) in ether (208 mL) was added lithium aluminum hydride (1M/diethylether, 1.5 eq., 174 mL) dropwise at 0° C. under argon. The reaction was refluxed for 1.5 h. turning from a clear solution to a white milky solution. The reaction was cooled to room temperature and then −78° C. The intermediate obtained in Step A (39.53g, 0.116 mmol) was dissolved in 400 mL of dry diethyl ether and cooled to 0° C. for a dropwise addition to the reaction mixture (˜2 mL/min., the temperature should not rise above −60° C.). The reaction was kept at −78° C. for 4.0 hours and then allowed to warm overnight. The reaction was quenched at 0° C. with isopropanol (70 mL) and diluted with ether (700 mL), washed with water (4×500 mL), 10% HCl (2×500 mL), brine (2×500 mL) and dried with MgSO4. Filtration and concentration afforded a residue which was filtered through a pad of silica (600 g, 10% diethyl ether/hexane) to give the title compound (97% e.e.) as a white solid (36.67 g, 107 mmol, 92%). 1H NMR (300 MHz, CDCl3): δ 7.11 (m, 4H), 4.67 (dq, J=3.3, 6.6 Hz, 1H), 3.74 (septet, J=6.6 Hz, 1H), 3.20 (septet, J=6.6 Hz, 1H), 2.17 (m, 2 H), 1.61 (d, J=2.9 Hz, 1H), 1.40 (d, J=7.0 Hz, 3H), 1.30 (m, 14H), 0.741 (t, J=7.4 Hz, 3H). FAB-MS: calcd for (C22H30NOF) 343, found 344 (M+H). mp 102-104° C. Rf=0.2 (60% CH2Cl2/hexane).

1. temperatureThe reaction was refluxed for 1.5 h.
2. custom−78° C
3. temperaturecooled to 0° C. for a dropwise addition to the reaction mixture (˜2 mL/min.
4. customrise above −60° C.
5. temperatureto warm overnight
6. customThe reaction was quenched at 0° C. with isopropanol (70 mL)
7. additiondiluted with ether (700 mL)
8. washwashed with water (4×500 mL), 10% HCl (2×500 mL), brine (2×500 mL)
9. dry with materialdried with MgSO4
10. filtrationFiltration and concentration
11. customafforded a residue which
12. filtrationwas filtered through a pad of silica (600 g, 10% diethyl ether/hexane)