1,1'-Carbonyldiimidazole → HCID 178517362, compound

Participants

Reaction Steps

(R)-tert-Butyl3-cyclohexyl-1-(3,5-dibromopyrazin-2-ylamino)-1-oxopropan-2-ylcarbamate. (R)-2-(tert-Butoxycarbonylamino)-3-cyclohexylpropanoic acid (1.00 g, 3.69 mmol), 1,1′-carbonyldiimidazole (896 mg, 5.53 mmol), dichloromethane (3 mL), and DMF (1 mL) were combined in a scintillation vial and stirred 3.75 h at room temperature under nitrogen. 3,5-Dibromopyrazin-2-amine (1.86 g, 7.37 mmol) was added and the resulting mixture sealed and heated 21 h at 40° C., then 22.5 h at 50° C. Diisopropylethylamine (1.3 mL, 7.37 mmol) was added and the resulting mixture sealed and heated at 45° C. with stirring overnight. The dichloromethane was removed on a rotary evaporator. The resulting mixture was diluted with ethyl acetate and water and shaken in a separatory funnel. The resulting suspension was filtered through Celite and the filter cake washed thoroughly with ethyl acetate. Brine was added to the filtrate and the resulting two layers separated in a separatory funnel. The organics were washed with water, then brine, and concentrated on a rotary evaporator. The residue was dissolved in methanol, filtered, and purified using reverse-phase preparatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Vials containing product were combined and neutralized with saturated aqueous sodium bicarbonate. Acetonitrile was removed on a rotary evaporator and the resulting aqueous mixture extracted with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator, and dried under vacuum to give the desired product (616 mg, 33%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.77 (s, 1H), 7.14 (d, J=8.20, 1H), 4.26 (q, J=7.81, 1H), 1.77 (d, J=12.49, 1H), 1.58-1.72 (m, 5H), 1.51-1.57 (m, 2H), 1.38 (s, 9H), 1.07-1.25 (m, 3H), 0.80-0.98 (m, 2H); MS (ESI) m/z 507 [M+1]+.

Provenance & Evidence