反应详情

温度

140 °C

A pressure tube was charged with 6-chloro-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide (310 mg, 1.00 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (429 mg, 2.00 mmol) and NMP (4 mL). The reaction mixture was stirred at 140° C. for 18 h, then the NMP was distilled using a Kugelrohr under high vacuum and at 120° C. to afford a brown viscous oil. The crude oil was dissolved in dichloromethane and methanol then adsorbed onto silica and purified by chromatography (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH, 40 min) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5,6-dimethoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate as a brown viscous oil (291.3 mg). This was dissolved in dichloromethane (2 mL) and TFA (740 mg, 500 μL, 6.49 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The TFA and the dichloromethane were removed in vacuo and the residue obtained was purified by chromatography (Spherical silica 20-45 μm, 50 g, Versaflash from Supelco, eluting with 0.1:1.9:98 NH4OH:methanol:dichloromethane to 0.6:11.4:88 NH4OH:methanol:dichloromethane, 40 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5,6-dimethoxypyridin-2-ylamino)pyridazine-3-carboxamide (81 mg, 21%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (br. s., 1H), 8.34 (br. s., 1H), 7.59 (br. s., 1H), 7.46 (s, 1H), 7.35 (d, J=8.08 Hz, 1H), 6.70 (d, J=7.83 Hz, 1H), 6.57 (d, J=8.34 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H), 3.10 (br. s., 1H), 2.03 (br. s., 2H), 1.18-1.78 (m, 8H), 0.98-1.12 (m, 1H); LC-MS 388 [M+H]+.

1. distillationthe NMP was distilled
2. customat 120° C. to afford a brown viscous oil
3. custompurified by chromatography (spherical silica 20-45 μm, 11 g, Versaflash from Supelco, eluting with 100% dichloromethane to 88:11.4:0.6 dichloromethane:methanol:NH4OH, 40 min)