反应详情

温度

-15 °C

To a solution of (R)-tert-butyl 3-(5-fluoro-2-methylbenzoyl)piperidine-1-carboxylate (10.5 g, 0.0336 mol) in anhydrous THF (150 mL) at −15° C. under nitrogen was added dropwise a solution of 1 M R-CBS-oxazaborolidine in toluene (3 mL, 3 mmol, 0.09 eq). After stirring for 1 hr at −15° C., a solution of 10 M BH3 in THF (17 mL, 0.0336 mol, 1 eq) was added dropwise. After addition, the reaction mixture was stirred for 2 hr at −15° C. Methanol (80 mL) was added dropwise carefully at −15° C. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel eluting with AcOEt/hexane (1:30→1:15) to provide the light yellow oil (95 g, HPLC≧70%, ratio≧3:1). The mixture was dissolved in a minimum volume of EtOAc, the solvent was removed on the rotary evaporator until crystals appeared. The solution was cooled to rt and stood for 1-2 h. To the solution was added hexane and then filtered, the crystals were washed with cool hexane and re-crystallized an additional two times to afford the pure isomer (R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate (3.2 g, ee≧99%). 1H NMR (CDCl3) δ 7.1 (m, 2H), 6.85 (m, 1H), 4.7 (m, 1H), 2.3 (s, 3H), 1.45 (s, 9H), 1.25 (m, 4H).

1. additionAfter addition
2. stirringthe reaction mixture was stirred for 2 hr at −15° C
3. customThe solvent was removed under reduced pressure
4. customthe residue was purified by column chromatography on silica gel eluting with AcOEt/hexane (1:30→1:15)
5. customto provide the light yellow oil (95 g, HPLC≧70%, ratio≧3:1)
6. customthe solvent was removed on the rotary evaporator until crystals
7. temperatureThe solution was cooled to rt
8. waitstood for 1-2 h
9. additionTo the solution was added hexane
10. filtrationfiltered
11. washthe crystals were washed with cool hexane
12. customre-crystallized an additional two times