Reaction Steps
The mixture of 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (100 mg, 0.31 mmol), 4-(4-aminophenyl)-1-cyclopentylpiperidine-4-carbonitrile hydrochloride (350) (114 mg, 0.37 mmol), fine-powder cesium carbonate (400 mg, 1.24 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), BINAP (62 mg, 0.1 mmol) in 20 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 2.5 hours. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 10% MeOH in chloroform to isolate 3-((2R,3R)-1-(5-cyano-6-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (351). It was dissolved in 10 mL MeOH and 1 mL DMSO. To it were added one NaOH solid bead (about 100 mg), DIEA (60 μL), and then 1 mL 30% H2O2. The mixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was acidified with TFA (0.5 mL) and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(4-cyano-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide (352) as HCl salt (22 mg). LC-MS (ESI): adz (M+1) 574.6. UV: λ=270, 281, 309, 336, 371 nm. Proton NMR (CD3OD): δ 7.78 (2H, d, J=9.0 Hz), 7.67 (1H, s), 7.49 (2H, d, J=8.5 Hz), 5.09 (1H, m), 4.28 (1H, m), 3.88 (3H, m), 3.69 (1H, m), 3.36 (2H, m), 3.09 (1H, m), 2.97 (6H, s), 2.51 (2H, m), 2.40 (2H, m), 2.26 (2H, m), 1.89 (4H, m), 1.86-1.66 (6H, m), 1.17 (3H, d, J=6.5 Hz) ppm. Compound 353, 3-(4-(4-carbamoyl-1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide, was also found and isolated as a major by-product in the final step.
