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) (80 mg, 0.25 mmol), 4-(1-cyclopropylpiperidin-4-yl)aniline (322, HCl salt, 76 mg, 0.30 mmol), fine-powder cesium carbonate (326 mg, 1.00 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (50 mg, 0.08 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 3 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 5% MeOH in DCM to isolate 3-((2R,3R)-1-(5-cyano-6-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (327). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added 100 μL Et3N, 100 mg powder cesium carbonate, and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 1.5 hour, diluted with 10 mL MeCN, stirred for 5 mM, concentrated on rotavap. The residue was treated with 0.3 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-cyclopropylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide (328) as HCl salt (76 mg, 58% yield). LC-MS (ESI): m/z (M+1) 521.8. 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), 4.98 (1H, m), 4.34 (1H, m), 3.87 (1H, m), 3.77 (1H, s), 3.74 (1H, s), 3.34 (2H, m), 3.02 (1H, m), 2.95 (6H, s), 2.90 (1H, m), 2.85 (1H, m), 2.15 (2H, m), 1.95-1.65 (6H, m), 1.17 (3H, d, J=7.0 Hz), 1.02 (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