反应详情

温度

150 °C

To a stirred solution of 6-chloro-4-(6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxamide (104 mg, 359 mmol) in N-methyl-2-pyrrolidinone (5 mL) was added DMAP (47 mg, 377 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (154 mg, 718 μmol). The mixture was heated to 150° C. for 1.5 days, then a stream of N2 was blown into the flask while heating at 140° C. to evaporate the volatile solvents. The residue obtained was then purified by chromatography (silica, 50 μm, 60 g, Analogix, 97:2.75:0.15 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 30 min) to afford tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-cyclopropylpyridin-2-ylamino)pyridazin-3 ylamino)cyclohexylcarbamate (126 mg, containing some residual NMP) as a brown viscous oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 11.43 (br. s., 1H) 8.17 (br. s., 1H) 8.03 (br. s., 1H) 7.44 (br. s., 1H) 7.03 (br. s., 1H) 6.80 (br. s., 1H) 6.60 (br. s., 1H) 5.76 (br. s., 1H) 5.49 (br. s., 1H) 3.82 (br. s., 1H) 3.24 (br. s., 1H) 2.03 (br. s., 1H) 1.32-1.91 (m, 8H) 1.45 (s., 9H) 1.05 (d, J=16.62 Hz, 4H). LCMS (EI/CI) m/z: 468 [M+H]. This was used directly in the next step without further purification.

1. temperaturewhile heating at 140° C.
2. customto evaporate the volatile solvents
3. customThe residue obtained
4. customwas then purified by chromatography (silica, 50 μm, 60 g, Analogix, 97:2.75:0.15 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 30 min)