Methanol → tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-chloro-6-methylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate

Participants

Reaction Conditions

Reaction Steps

A pressure tube was charged with 6-chloro-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxamide (600 mg, 2.01 mmol), tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (863 mg, 4.03 mmol) and NMP (6 mL) to give a yellow suspension. The reaction mixture was stirred at 140° C. for 2.5 days. After cooling to room temperature, the NMP was distilled off using a Kugelrohr to afford a brown, viscous oil. This crude material was dissolved in dichloromethane and methanol and adsorbed onto silica gel. Purification by chromatography (spherical silica 20-45 m, 50 g, Versaflash column from Supelco, eluting from 100% dichloromethane to 84:15.2:0.8 dichloromethane/methanol/NH4OH), to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-chloro-6-methylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (242.3 mg) as a brown solid. The product was then dissolved in dichloromethane (3 mL) and TFA (2.96 g, 2 mL, 26.0 mmol) was added. The mixture was stirred at room temperature for 2 h. The excess 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 a gradient of 0.05:0.95:99 NH4OH:methanol:dichloromethane up to 0.6:11.4:88 NH4OH:methanol:dichloromethane over 40 min) to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(5-chloro-6-methylpyridin-2-ylamino)pyridazine-3-carboxamide (152 mg, 4%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.77 (br. s., 1H), 8.42 (br. s., 1H), 8.05 (br. s., 1H), 7.59-7.80 (m, 2H), 6.78-6.99 (m, 2H), 3.18 (br. s., 1H), 2.57 (br. s., 4H), 1.21-1.42 (m, 2H), 1.20-1.81 (m, 8H), LC-MS 376 [M+H]+.

Provenance & Evidence