Trifluoroacetic acid → 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide

Participants

Reaction Conditions

Reaction Steps

To a solution of 6-chloro-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (102 mg, 350 μmol) in N-methyl-2-pyrrolidinone (6 ml) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (150 mg, 699 μmol) and the mixture heated to 150° C. for 3 d. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (150 mg, 699 μmol) was added and the reaction heated to 150° C. for an additional 2 d, then cooled, concentrated, and purified by chromatography (silica, 50 μm, 40 g, Analogix, 96:3.8:0.2 to 84:15.2:0.8; dichloromethane:MeOH:NH4OH) to give a mixture of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate and 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (33 mg). This mixture was dissolved in dichloromethane (2 mL) then TFA (370 mg, 250 μL, 3.24 mmol) was added. After 18 h, the mixture was concentrated in vacuo and the residue obtained was purified by chromatography (spherical silica, 20-45 μm, 25 g, Versaflash Supelco, 96:3.8:0.2 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 25 min gradient to afford 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (12 mg, 9%) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.35 (br. s., 1H) 8.33 (s, 1H) 7.96 (br. s., 1H) 7.44 (t, J=7.83 Hz, 1H) 6.70 (d, J=7.58 Hz, 1H) 6.61 (d, J=8.08 Hz, 1H) 5.61 (br. s., 1H) 5.31 (br. s., 1H) 3.75 (br. s., 1H) 3.19 (d, J=3.28 Hz, 1H) 2.89-3.01 (m, 1H) 1.32-1.80 (m, 8H) 1.27 (d, J=6.82 Hz, 6H). LCMS (EI/CI) m/z: 370 [M+H].

Provenance & Evidence