反应详情

温度

60 °C

tert-Butyl 2-(2,6-difluorophenyl)-4-(5-(4-fluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate was suspended in MeOH (20 mL) in a pressure vessel and to this was added a solution of HCl in 1,4-dioxane (4 M, 20 mL, 80.0 mmol). The vessel was sealed and the mixture heated at 60° C. for 16 hr. The solvent was removed under reduced pressure and the residue was purified via silica gel column chromatography (0-10% 7 N ammonia in MeOH/DCM) to yield 5-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide as a pale brown solid (653 mg, 70% over two steps). The 4-amino and the 5-fluoro groups are cis. 1H NMR (400 M Hz, CDCl3) δ 8.63 (s, 1H), 7.84 (s, 1H), 7.37-7.29 (m, 1H), 7.03 (t, J=8.7 Hz, 2H), 6.13 (s, 2H), 4.48 (dtd, J=47.9, 8.6, 3.6 Hz, 1H), 3.72 (s, 3H), 3.37-3.15 (m, 5H), 2.23-1.92 (m, 3H), 1.75-1.67 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 466 (M+1). Chiral separation of the racemic mixture by SFC gave 147 as a single enantiomer. 1H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 7.59 (s, 1H), 7.56-7.43 (m, 3H), 7.26 (dd, J=14.5, 5.9 Hz, 2H), 4.82 (dd, J=47.0, 7.4 Hz, 1H), 3.63 (s, 3H), 3.29-3.15 (m, 4H), 3.08-2.91 (m, 2H), 2.24-2.06 (m, 1H), 1.91-1.76 (m, 2H), 1.74-1.59 (m, 1H). MS (ESI) m/z: 466.1 [M+H+].

1. customThe vessel was sealed
2. customThe solvent was removed under reduced pressure
3. customthe residue was purified via silica gel column chromatography (0-10% 7 N ammonia in MeOH/DCM)