反应详情

To a room temperature solution of INTERMEDIATE 5a (250 mg; 0.54 mmol) in DMF (5 mL) was added cyclohexyl acetic acid (92 mg; 0.65 mmol), DIPEA (0.38 mL; 2.16 mmol) and HATU (0.31 g; 0.81 mmol). The reaction mixture was stirred for 22 hours then was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with sodium hydroxide (2N) then with HCl (1M). The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and TFA (1.5 mL) was added. The reaction mixture was stirred for 4 hours then was washed with saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Column chromatography eluting with 5% methanol in dichloromethane gave COMPOUND 77 (242 g; 92% for two steps). Purity (HPLC-215 nm): >99%; Optical purity (Chiral HPLC-215 nm): >99%. 1H NMR (400 MHz, CD3OD) δ 0.87-0.93 (m, 2H), 0.98 (t, J=7.13 Hz, 3H), 1.08-1.14 (m, 3H), 1.20-1.23 (m, 2H), 1.52-1.71 (br s, 6H), 1.72-1.77 (m, 1H), 2.12 (d, J=7.03 Hz, 2H), 3.09-3.14 (m, 2H), 3.18-3.23 (m, 6H), 3.26-3.33 (br s, 3H), 3.48-3.52 (m, 1H), 5.08 (s, 1H), 7.20 (d, J=4.49 Hz, 2H), 7.24-7.31 (m, 3H), 7.57 (d, J=7.81 Hz, 2H), 7.83 (s, 1H). Found: C, 58.11; H, 8.99; N, 7.46. C30H42N4O2×0.4HCl×6.5H2O has C, 57.90; H, 8.97; N, 9.00%. [α]D17=+4.6 deg [c 0.46, MeOH].

1. concentrationthen was concentrated under reduced pressure
2. dissolutionThe residue was dissolved in dichloromethane
3. washwashed with sodium hydroxide (2N)
4. dry with materialThe organic phase was dried over anhydrous sodium sulphate
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. dissolutionThe residue was dissolved in dichloromethane (10 mL)
8. additionTFA (1.5 mL) was added
9. stirringThe reaction mixture was stirred for 4 hours
10. washthen was washed with saturated sodium bicarbonate
11. dry with materialThe organic phase was dried over anhydrous sodium sulphate
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure
14. washColumn chromatography eluting with 5% methanol in dichloromethane