反应详情

温度

115 °C

The mixture of 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (75 mg, 0.23 mmol), 4-(1-cyclopropyl-4-methylpiperidin-4-yl)aniline (342) (65 mg, 0.28 mmol), fine-powder cesium carbonate (230 mg, 0.70 mmol), Pd(OAc)2 (16 mg, 0.07 mmol), BINAP (44 mg, 0.07 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 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 10% MeOH in DCM to isolate 3-((2R,3R)-1-(5-cyano-6-(4-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (343). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added fine-powder cesium carbonate (50 mg), DIEA (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 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-(1-cyclopropyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide (344) as HCl salt (68 mg, 55% overall yield for 2 steps). LC-MS (ESI): m/z (M+1) 535.9. UV: λ=268, 278, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.74-7.64 (3H, m), 7.38-7.33 (2H, m), 5.08 (1H, m), 4.33 (1H, m), 3.88 (1H, m), 3.62-3.47 (2H, m), 3.05 (2H, m), 2.96 (6H, s), 2.70-2.64 (2H, m), 2.20-2.12 (2H, m), 1.91-1.86 (4H, m), 1.75 (1H, m), 1.66 (1H, m), 1.45-1.26 (3H, s), 1.17 (3H, d, J=7.0 Hz), 1.02-0.89 (4H, m) ppm.

1. customwas degassed with nitrogen stream for 3 min
2. temperatureThe mixture was cooled to RT
3. additiondiluted with 100 mL EtOAc
4. filtrationfiltered
5. concentrationThe filtrate was concentrated in vacuo