反应详情

3.4-dimethoxy-2-(trifluoromethyl)-(N-methylamino)ethanol (12) was made according to methods known in the art. See Kirk et al. (2000). Specifically, a solution of (1S or 1R)-2-amino-1-(3,4-dimethoxy-2-trifluoromethylphenyl)ethanol (10) (MW=265.23, 3.00 g, 11.3 mmol) in ethyl formate (140 ml) was heated to reflux under an atmosphere of Ar for 3 hours with stirring. The suspension eventually goes into solution during the first hour of reflux. Upon completion, the reaction was allowed to cool to room temperature. Volatiles were removed in vacuo to afford 1-N-[2-(3,4-dimethoxy-2-trifluoromethylphenyl)-2-hydroxyethyl]formamide (11) as a low melting yellowish solid. To a cold (0° C.) suspension of LiAlH4 (MW=37.95, 95%, 2.4 g, 63.2 mmol) in THF (30 ml) under Ar a solution of formamide (11) (MW=293.24, 13.0 mmol, 3.81 g) in THF (70 ml) was added dropwise. The mixture was heated to reflux for 3 hours and then cooled to 0° C. and quenched by the addition of 2.4 ml H2O, 2.4 ml 15% NaOH and 7.2 ml H2O. The mixture was stirred at room temperature until all of the unreacted LAH has reacted. The solid was filtered and washed 5 times with 50 ml of hot EtOAc. The filtrate was concentrated and the residue was recrystallized from hex/EtOAc. For S isomer: mp=121-128° C. 1H NMR for S in CDCl3 (300 MHz) δ 7.53 (m, 1H, J=8.8), 7.06 (m, 1H, J=8.8), 5.16 (m, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 2.80 (m, 1H), 2.56 (m, 1H), 2.42 (s, 3H). 13C NMR in CDCl3 (75 MHz) 152.5, 148.1, 133.8, 124.5 (q, J=274 Hz), 122.8, 121.3, 115.5, 66.8, 61.5, 59.2, 55.9, 35.5. 19F (282.8 Mz) −53.4. For R isomer: mp=125-127° C. 1H NMR for R in CDCl3 (300 MHz) δ 7.55 (m, 1H, J=8.8), 7.06 (m, 1H, J=8.8), 5.22 (m, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 2.83 (m, 1H), 2.62 (m, 1H), 2.47 (s, 3H). 13C NMR in CDCl3 (75 MHz) 152.3, 148.1, 133.6, 124.5 (q, J=274 Hz), 122.9, 121.3, 115.5, 66.6, 61.6, 58.9, 56.0, 35.2. 19F (282.8 Mz) −53.4.

1. temperatureto reflux under an atmosphere of Ar for 3 hours
2. temperatureof reflux
3. customVolatiles were removed in vacuo