反应详情

温度

50 °C

A stirred mixture of compound 1 (418 mg, 1.2 mmol) and (R)—P-Phos RuCl2(R)-DAIPEN (5.4 mg, 0.0048 mmol) at room temperature was subjected to five cycles pressurizing with nitrogen to 40 psi and then depressurizing. Then KOtBu/tBuOH (1 M, 14.4 μL, 0.0144 mmol) in 9:1 i-PrOH/H2O (4 mL) was added and the mixture was subjected to five cycles of pressurizing with nitrogen to 40 psi and then depressurizing. The stirred mixture was then subjected to ten cycles of pressurizing with hydrogen to 435 psi and then depressurizing. The mixture was then stirred at 900 rpm under hydrogen (435 psi) at 50° C. for 18 hrs. The mixture was allowed to cool to room temperature and vented carefully. MeOH (8 mL) was added, and a sample (0.2 mL) was analyzed by chiral HPLC and LCMS (Phenomenex Luna C18) eluted with a gradient of CH3CN in 0.1% aq. HOAc. The above procedure was carried out in analogous fashion in an additional 12 runs. Samples of the required specification (>98%, >95% enantiomeric excess) were combined and filtered through celite, washing with MeOH. The filtrate was concentrated to dryness and further dried under high vacuum overnight to afford compound I as an off-white solid (4.48 g, 12.8 mmol). 1H NMR (300 MHz, DMSO-d6) δ 12.13 (br s, 1H), 10.38 (br s, 1H), 8.59 (d, J=7.7 Hz, 1H), 7.70-7.98 (m, 2H), 7.45-7.64 (m, 3H), 7.06-7.24 (m, 2H), 6.45 (s, 1H), 5.80 (s, 1H), 5.67 (s, 1H), 2.26 (s, 3H); LC-MS (ESI) m/z: 350 (M+H)+. Analysis by chiral HPLC showed a 96.7% enantiomeric excess of the earlier eluting enantiomer.

1. temperatureto cool to room temperature
2. washeluted with a gradient of CH3CN in 0.1% aq. HOAc
3. filtrationfiltered through celite
4. washwashing with MeOH
5. concentrationThe filtrate was concentrated to dryness
6. customfurther dried under high vacuum overnight