(1S,2R)-Cyclohexane-1,2-diamine, N1-BOC protected → Ammonium Hydroxide

Participants

Reaction Conditions

Reaction Steps

6-Chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (841 mg, 3.03 mmol) was dissolved in NMP (2 mL) and to this solution was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (649 mg, 3.03 mmol) and the reaction mixture heated in an oil bath with stirring at 120° C. for 24 h. A second equivalent of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (649 mg, 3.03 mmol) was added and reaction continued for 72 h. The mixture was cooled, then the NMP solvent was distilled off under high vacuum. The residue was dissolved in dichloromethane containing few drops of methanol and passed through a silica plug eluting with 5% of a 9:1 MeOH:NH4OH solution in CH2Cl2 to yield tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5,6-dimethylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate mixed with 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide. The mixture was suspended in CH2Cl2 (3 mL) then TFA (1.48 g, 13.0 mmol) was added and mixture stirred at room temperature for 18 h. The mixture was concentrated in vacuo and the residue obtained was purified by chromatography (spherical silica 20-45 uM, 50 g, Versaflash Supelco, 0 to 10% of a 9:1 MeOH:NH4OH solution in CH2Cl2, 20 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (550 mg, 49% yield over two steps) as an off-white solid. 1H NMR (DMSO-d6) δ: 11.48 (s, 1H), 8.36 (br. s., 1H), 8.05 (s, 1H), 7.60 (br. s., 1H), 7.47 (d, J=8.1 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 3.87 (br. s., 1H), 3.15 (br. s., 1H), 2.45 (s, 3H), 2.20 (s, 3H), 1.44-1.79 (m, 8H), 1.32 (br. s., 2H); LC-MS 356.1 [M+H]+.

Provenance & Evidence