1,2-Dichloroethane → Hydrochloric Acid

Participants

Reaction Steps

(R)-5-(3-(3,3-Dimethylureido)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide (189) TFA salt (115 mg, 0.20 mmol) was dissolved in 10 mL dioxane and 10 mL 1,2-dichloroethane (DCE) with DIEA (175 μL, 1.0 mmol). To it was added cyclobutanone (450 μL, 6.0 mmol), and the mixture was stirred at RT for overnight. To it were added HOAc (112 μL, 2.0 mmol) and then NaBH(OAc)3 (212 mg, 1.0 mmol). The mixture was stirred at RT for 2 hours, diluted with 10 mL MeOH, concentrated in vacuo, acidified with 0.5 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-3-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide (217) as HCl salt (73 mg). MS found for C28H40N8O2 as (M+H)+ 521.7, (M−H)− 519.3. UV: λ=268, 277, 306, 336, 373 nm. Proton NMR (CD3OD): δ 7.65 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.29 (1H, m), 4.20 (1H, m), 3.78 (1H, m), 3.70 (1H, m), 3.60 (1H, s), 3.57 (1H, s), 3.30-3.20 (2H, m), 2.92 (2H, m), 2.87 (6H, s), 2.86 (1H, m), 2.37 (2H, m), 2.27 (2H, m), 2.14 (2H, m), 2.03 (1H, m), 1.90 (5H, m), 1.67 (2H, m) ppm.

Provenance & Evidence