Cesium carbonate → HCID 118114703, compound

Participants

Reaction Conditions

Reaction Steps

The mixture of (R)-1-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,3,3-trimethylurea (294, 390 mg, 1.21 mmol), tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (670 mg, 2.42 mmol), fine-powder cesium carbonate (1600 mg, 4.84 mmol), Pd(OAc)2 (134 mg, 0.60 mmol), BINAP (374 mg, 0.60 mmol) in 60 mL dioxane was degassed with nitrogen stream for 5 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 120 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 20 to 100% EtOAc in DCM to isolate (R)-tert-butyl 4-(4-(3-cyano-6-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)piperidine-1-carboxylate (295) in >80% yield. It was dissolved in 40 mL MeOH and 10 mL DMSO. To it were added two NaOH solid bead (about 200 mg) and then 2 mL 30% H2O2. The mixture was stirred at RT for 3 hours, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 120 mL EtOAc, washed with water ×2, concentrated, and subjected to silica flash column using 0 to 7% MeOh in DCM to give crude (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)piperidine-1-carboxylate (296). It was treated with 30 mL commercial 4N HCl in dioxane for 90 min, and concentrated in vacuo to afford crude (R)-3-(4-(piperidin-4-yl)phenylamino)-5-(3-(1,3,3-trimethylureido)piperidin-1-yl)pyrazine-2-carboxamide (297) hydrochloride.

Provenance & Evidence