反应详情

温度

0 °C

1.0 N LiOH (0.32 mL, 0.32 mmole) was added dropwise to a solution of ethyl (±)-10,11-dihydro-3-[2-[2-(ethylamino)thiazol-4-yl]-1-ethoxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (145.0 mg, 0.32 mmole) in THF (2.4 mL) and H2O (0.48 mL) at 0° C. The resulting pinkish-orange two-phase mixture was stirred at 0° C. for 10 min, during which time the color faded to orangish-yellow, then was warmed to RT. After 1.5 hr, a little more H2O (5 drops) was added, and the reaction was stirred for 42 hr, then was cooled to 0° C. and neutralized with TFA (0.025 mL). The THF was removed on the rotavap, and the resulting oily residue was diluted with 0.1% TFA/CH3CN to give a homogeneous solution. ODS chromatography (gradient: 40% CH3CN/H2O containing 0.1% TFA, then 45% CH3CN/H2O containing 0.1% TFA) gave fractions containing the title compound. These were pooled, and the CH3CN was removed on the rotavap. The resulting aqueous mixture was made basic at 0° C. to afford a homogeneous solution. Careful acidification to pH 4-5 with 1.0 N HCl gave a solid precipitate, which was collected, washed with plenty of H2O, and dried to afford the title compound (80.9 mg, 51%) as an off-white solid: HPLC (Hamilton PRP-1®, 45% CH3CN/H2O containing 0.1% TFA) k′=0.89; 1H NMR (400 MHz, CD3OD) δ7.02-7.18 (m, 4 H), 7.00 (d, J=8.3 Hz, 1 H), 6.79 (d, J=2.6 Hz, 1 H), 6.68 (dd, J=8.3, 2.6 Hz, 1 H), 6.45 (s, 1 H), 4.26 (d, J=14.9 Hz, 1 H), 4.20 (t, J=6.4 Hz, 2 H), 3.87 (d, J=14.9 Hz, 1 H), 3.68-3.80 (m, 1 H), 3.34 (q, J=7.3 Hz, 2 H, partially obscured by residual solvent signal), 3.30 (dd, 1 H, obscured by residual solvent signal), 2.99 (t, J=6.4 Hz, 2 H), 2.92 (dd, J=15.0, 9.4 Hz, 1 H), 2.62 (dd, J=15.9, 5.0 Hz, 1 H), 2.47 (dd, J=15.9, 9.3 Hz, 1 H), 1.27 (t, J=7.3 Hz, 3 H); MS (ES) m/e 423 (M+H)+. Anal. Calcd for C24H26N2O3S.0.67 CF3CO2H: C, 61.03; H, 5.39; N, 5.62. Found: C, 61.21; H, 5.36; N, 5.60.

1. temperaturethen was warmed to RT
2. waitAfter 1.5 hr
3. stirringthe reaction was stirred for 42 hr
4. customThe THF was removed on the rotavap
5. additionthe resulting oily residue was diluted with 0.1% TFA/CH3CN
6. customto give a homogeneous solution