Reaction Steps
The mixture of (3aR,7aR)-tert-butyl 4-(6-chloro-5-cyanopyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (417) (400 mg, 1.10 mmol), 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (340 mg, 1.21 mmol), fine-powder cesium carbonate (1.08 g, 3.30 mmol), Pd(OAc)2 (74 mg, 0.33 mmol), BINAP (206 mg, 0.33 mmol) in 40 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 1.5 hour. The mixture was cooled to RT, diluted with 150 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 6% MeOH in DCM to isolate (3aR,7aR)-tert-butyl 4-(5-cyano-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (418) (480 mg, 76%). It was dissolved in 25 mL MeOH and 2 mL DMSO. To it were added fine-powder Cs2CO3 (100 mg) 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 diluted with 150 mL EtOAc, washed with water ×2, concentrated in vacuo to give crude (3aR,7aR)-tert-butyl 4-(5-carbamoyl-6-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazin-2-yl)octahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (419). It was treated with 1:1 TFA/DCM at RT for 5 min, concentrated in vacuo, and subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((3aR,7aR)-dihydro-1H-pyrrolo[3,2-b]pyridin-4(2H,5H,6H,7H,7aH)-yl)pyrazine-2-carboxamide (420) as HCl salt. LC-MS (ESI): m/z (M+1) 490.4. UV: λ=263, 272, 303, 334, 370 nm. Proton NMR (CD3OD): δ 7.68 (1H, s), 7.57 (2H, d, J=8.5 Hz), 7.30 (2H, d, J=9.0 Hz), 5.16 (1H, m), 4.21 (1H, m), 3.85 (1H, m), 3.72 (2H, d, J=13.0 Hz), 3.58 (2H, m), 3.42 (1H, m), 3.12 (3H, m), 2.89 (1H, m), 2.35 (1H, m), 2.20 (2H, m), 2.14-1.71 (15H, m) ppm.
