Cesium carbonate → US9656988, Example 281

Participants

Reaction Conditions

Reaction Steps

The mixture of 3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile (405) (60 mg, 0.17 mmol), 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (58 mg, 0.21 mmol), fine-powder cesium carbonate (230 mg, 0.68 mmol), Pd(OAc)2(11 mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol) in 15 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 1 hour. 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-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile (406). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added one NaOH solid bead (about 100 mg), Et3N (60 μL), and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 30 min, 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, concentrated in vacuo, acidified with 0.2 mL TFA, and directly 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-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide (407) as HCl salt (58 mg, 59%). LC-MS (ESI): m/z (M+1) 575.8. UV: λ=268, 277, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.64 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz), 4.93 (1H, m), 4.56-4.30 (3H, m), 3.71 (2H, m), 3.55 (1H, m), 3.38 (3H, m), 3.13 (2H, m), 3.06 (1H, m), 2.97 (3H, s), 2.84 (1H, m), 2.25-1.65 (18H, m), 1.20 (3H, d, J=6.5 Hz) ppm.

Provenance & Evidence