反应详情

To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (303 mg, 0.55 mmol) in tetrahydrofuran (2.78 ml) and methanol (2.78 ml) at 25° C. was added hydrazine (0.17 ml, 5.55 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was then converted to the HCl salt by adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-[(1S)-2-amino-1-(cyclohexylmethyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (190 mg, 0.389 mmol, 70.0% yield) as a yellow solid: LCMS (ES) m/z=415, 417 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (br. s., 1H) 8.06 (s, 4H) 7.74 (s, 1H) 4.25 (dd, J=8.84, 4.29 Hz, 1H) 3.77 (s, 3H) 2.87-2.93 (m, 2H) 1.71-1.79 (m, 1H) 1.64 (d, J=9.85 Hz, 3H) 1.54 (br. s., 1H) 1.48 (br. s., 1H) 1.37 (dd, J=13.26, 4.93 Hz, 1H) 1.14 (br. s., 1H) 1.17 (d, J=7.33 Hz, 2H) 0.93 (d, J=10.86 Hz, 1H) 0.82-0.89 (m, 1H).

1. concentrationthe solution was concentrated
2. customdry loaded onto silica
3. custompurified by column chromatography (5% MeOH in DCM (1% NH4OH))
4. additionby adding excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml)