反应详情

温度

100 °C

tert-Butyl 4-(2-(3-cyano-4-fluoro-2-methylphenyl)-2-hydroxyethyl)-3-(2-hydroxyethyl)piperazine-1-carboxylate (2.61 g, 6.41 mmol) and dissolved in benzene (60 mL) and added cyanomethylene tributyl phosphorane (2.78 g, 11.5 mmol). The mixture was placed into four separate 20 mL microwave tubes then heated at 100° C. overnight. The reaction mixtures were combined, concentrated then purified by MPLC chromatography using a 330 g ISCO Redi-Sep column and 5% acetone-95% DCM solvent system. Under these purification conditions was separated tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate cis diastereomers from the trans diastereomers LC-MS (IE, m/z): 334 [(M-56)+1]+; The cis-diastereomers were further separated to S,R and R,S diastereomers using the following conditions: Chiral IC column: 30×250 mm, 20% MeOH:/CO2, 70 mL/min, 100 bar, 50 mg/ml in MeOH, 35° C., 330 nm: cis-diastereomer A: 1H-NMR (600 MHz, CDCl3) δ ppm 7.88 (dd, J=8.7, 6.2 Hz, 1H), 7.04 (t, J=8.6 Hz, 1H), 4.83 (s, 1H), 4.03 (d, J=12.9 Hz, 1H), 3.86 (t, J=11.3 Hz, 1H), 3.79-3.96 (b, 2H), 2.93 (q, 2H), 2.83 (b, 1H), 2.56-2.63 (m, 4H), 2.53 (s, 3H), 1.78-1.87 (m, 2H), 1.49 (s, 9H).

1. customseparate 20 mL microwave tubes
2. customThe reaction mixtures
3. concentrationconcentrated
4. customthen purified by MPLC chromatography
5. customUnder these purification conditions
6. customwas separated tert-butyl 7-(3-cyano-4-fluoro-2-methylphenyl)-hexahydro-1H-pyrazino[1,2-d][1,4]oxazepine-2(9H)-carboxylate
7. customThe cis-diastereomers were further separated to S,R and R,S diastereomers
8. custom35° C., 330 nm