反应详情

温度

25 °C

A solution of 3-cyclohexyl-1-[2-(dimethylamino)-2-oxoethyl]-2-phenyl-1H-indole-6-carboxylic acid (from Step 6) in DMF (0.1 M) was treated with DIPEA (2 eq.), HATU (1.1 eq.) and ethyl (2E)-3-(4-{[(1-aminocyclopentyl)carbonyl]amino}phenyl)acrylate (from Step 7, 1.1 eq.). The solution was stirred at 25° C. for 12 h, then for 24 h at 50° C. The mixture was diluted with EtOAc, and then washed sequentially with HCl (2×, 1 N), NaOH (2×, 1N) and brine. The organic layer was dried over Na2SO4 and concentrated to afford an oil, which was dissolved in a mixture of THF and MeOH (0.5M, 2:1, v/v). NaOH (2 eq., 1 N) was added and the resultant mixture stirred at 50° C. for 1 h. The reaction mixture was diluted with EtOAc, and then washed with HCl (2×, 1 N), brine, and dried over Na2SO4. Evaporation gave an off-white foam, which was purified by RP-HPLC (column: Waters X-terra C18, 19×150 mm, 5 micron; flow 20 mL/min) to give the title compound (45%) as a white powder after lyophilization. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 1.11-1.39 (m, 3H), 1.60-1.96 (m, 11H), 2.03-2.17 (m, 2H), 2.28-2.40 (m, 2H), 2.61 (m, 1H), 2.81 (s, 3H), 2.88 (s, 3H), 4.84 (s, 2H), 6.40 (d, J 16.0, 1H), 7.32 (d, J 6.4, 2H), 7.46-7.55 (m, 4H), 7.59 (d, J 8.4, 2H), 7.65 (d, J 8.4, 2H), 7.71 (d, J 8.2, 1H), 7.80 (d, J 8.2, 1H), 7.86 (s, 1H), 8.27 (s, 1H), 9.67 (s, 1H), 12.1 (bs, 1H). MS (ES+) m/z 661 (M+H)+.

1. waitfor 24 h at 50° C
2. washwashed sequentially with HCl (2×, 1 N), NaOH (2×, 1N) and brine
3. dry with materialThe organic layer was dried over Na2SO4
4. concentrationconcentrated
5. customto afford an oil, which
6. washwashed with HCl (2×, 1 N), brine
7. dry with materialdried over Na2SO4
8. customEvaporation
9. customgave an off-white foam, which
10. customwas purified by RP-HPLC (column: Waters X-terra C18, 19×150 mm, 5 micron; flow 20 mL/min)