反应详情

1.0 N LiOH (0.74 mL, 0.74 mmole) was added all at once to a solution of ethyl (±)-10,11-dihydro-3-[3-(4-amino-2-pyridylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate (216.3 mg, 0.49 mmole) in THF (2.5 mL) and H2O (1.8 mL) at RT. The two-phase mixture was warmed for 1 hr in an oil bath set at 40° C., then absolute EtOH (ca. 1 mL) was added to combine the phases. The reaction was kept at 40° C. for 19.5 hr, then was concentrated, and the residue was dissolved in 1:1 CH3CN/H2O (5 mL). The solution was acidified with TFA (0.11 mL, 1.47 mmole) and concentrated. ODS chromatography (40% CH3CN/H2O containing 0.1% TFA) followed by concentration to remove CH3CN left an oily, aqueous solution, which was made homogeneous by addition of a little CH3CN. The pH was adjusted to 7 with 1.0 N NaOH, and an oily semisolid precipitated. The mixture was concentrated to remove the CH3CN, and the resulting solid was collected. This was dissolved in aqueous NaOH, and the pH was adjusted to 7. The solid was collected, washed with plenty of H2O, and dried in high vacuum at 45° C. to afford the title compound (133.3 mg, 61%) as an off-white solid: HPLC (Hamilton PRP-1®, 35% CH3CN/H2O containing 0.1% TFA) k′=3.0; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=6.3 Hz, 1H), 7.04-7.22 (m, 4H), 6.95 (d, J=8.2 Hz, 1H), 6.88-7.02 (m, 1H), 6.82 (d, J=2.4 Hz, 1H), 6.67 (dd, J=8.2, 2.4 Hz, 1H), 6.27 (br s, 2H), 5.95 (dd, 1H), 5.65 (narrow d, 1H), 4.18 (d, J=14.7 Hz, 1H), 4.00 (t, J=6.1 Hz, 2H), 3.88 (d, J=14.7 Hz, 1H), 3.59-3.70 (m, 1H), 3.13-3.30 (m, 3H), 2.82 (dd, J=15.2, 10.0 Hz, 1H), 2.46 (dd, J=15.8, 8.8 Hz, 1H, partially obscured by residual solvent signal), 2.58 (dd, J=15.8, 5.2 Hz, 1H), 1.86-2.01 (m, 2 H); MS (ES) m/e 418 (M+H)+. Anal. Calcd for C25H27N3O3 .1.67 H2O: C, 67.09; H, 6.83; N, 9.39. Found: C, 66.99; H, 6.59; N, 9.34.

1. temperatureThe two-phase mixture was warmed for 1 hr in an oil bath
2. customset at 40° C.
3. concentrationwas concentrated
4. dissolutionthe residue was dissolved in 1:1 CH3CN/H2O (5 mL)
5. concentrationconcentrated
6. concentrationODS chromatography (40% CH3CN/H2O containing 0.1% TFA) followed by concentration
7. customto remove CH3CN
8. waitleft an oily, aqueous solution, which
9. additionwas made homogeneous by addition of a little CH3CN
10. customan oily semisolid precipitated
11. concentrationThe mixture was concentrated
12. customto remove the CH3CN
13. customthe resulting solid was collected
14. dissolutionThis was dissolved in aqueous NaOH
15. customThe solid was collected
16. washwashed with plenty of H2O
17. customdried in high vacuum at 45° C.