反应详情

A solution of {3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetic acid TFA salt (228 mg, 0.42 mmol), EDCI (97 mg, 0.50 mmol) and HOBT (68 mg, 0.50 mmol) in THF (3 mL) was stirred for 20 minutes. 1-Amino-2-methyl-propan-2-ol (42 mg, 0.47 mmol) and diisopropylethylamine (0.18 mL, 1.05 mmol) in THF (2 mL) were added and the reaction mixture was stirred at RT for 18 hours. Another portion of 1-amino-2-methyl-propan-2-ol, EDCI, HOBT, DIPEA and THF (1.5 mL) was added and the reaction mixture was warmed at 45° C. for 3 hours. Aqueous saturated sodium bicarbonate solution was added and the mixture was extracted with DCM (×2). The combined organic extracts were dried (MgSO4), concentrated in vacuo and the residue purified by flash chromatography (SiO2, 0-10% MeOH in DCM) to give 472 as a white solid (92 mg, 44%). LCMS: RT=3.14 min, [M+H]+=497. 1H NMR δ (ppm) (DMSO-d6): 8.26 (1H, d, J=8.18 Hz), 8.06 (1H, s), 7.44 (1H, t, J=6.04 Hz), 7.19 (1H, dd, J=8.24, 1.80 Hz), 7.01 (1H, d, J=1.75 Hz), 5.82-5.74 (1H, m), 4.51 (1H, s), 4.32 (2H, t, J=5.03 Hz), 3.73-3.60 (3H, m), 3.39 (2H, t, J=5.06 Hz), 3.26-3.16 (2H, m), 3.10 (2H, s), 3.02 (2H, d, J=6.03 Hz), 1.50 (6H, d, J=6.59 Hz), 1.01 (6H, s)

1. temperaturethe reaction mixture was warmed at 45° C. for 3 hours
2. extractionthe mixture was extracted with DCM (×2)
3. dry with materialThe combined organic extracts were dried (MgSO4)
4. concentrationconcentrated in vacuo
5. customthe residue purified by flash chromatography (SiO2, 0-10% MeOH in DCM)