Cesium carbonate → US9656988, Example 221

Participants

Reaction Conditions

Reaction Steps

The mixture of 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (222) (250 mg, 0.81 mmol), tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (400 mg, 1.22 mmol), fine-powder cesium carbonate (800 mg, 2.43 mmol), Pd(OAc)2 (55 mg, 0.24 mmol), BINAP (150 mg, 0.24 mmol) in 30 mL dioxane was degassed with nitrogen stream for 3 mM It was then stirred in 115° C. bath in nitrogen atmosphere for 2 hours. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered using ChemGlass OP-6602-12 disposable funnel. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 8% MeOH in DCM to isolate (R)-tert-butyl 4-(4-(3-cyano-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate (288). It was dissolved in 10 mL MeOH and 3 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for overnight, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 150 mL EtOAc, washed with water ×3, dried, and subjected to silica flash column using 0 to 10% MeOH in DCM to isolate (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate. It was treated with 20 mL commercial 4N HCl in dioxane at RT for 45 mM, and concentrated to dryness to give crude (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (289) as HCl salt. It was subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases for purification. MS found for C25H36N8O2 as (M+H)+ 481.3. UV: λ=268, 277, 306, 336, 373 nm.

Provenance & Evidence