Reaction Steps
In a 100 mL round-bottomed flask was dissolved 2-((5S,6S)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7-dihydro-5H-cyclohepta[b]pyrazin-9-yl)acetic acid (63.4 mg, 0.147 mmol) (crude 10, azeotroped twice with dry benzene and further dried under high vacuum) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (96 mg, 0.441 mmol) (bis-HCl salt) in methylene chloride (2 mL) to give a colorless suspension. Hunig's base (0.128 mL, 0.735 mmol) and 3-(diethoxyphosphoryloxy)-1,2,3-benzo-triazin-4(3H)-one (88 mg, 0.29 mmol) were added. The reaction mixture was diluted with dimethylformamide (0.5 mL) The mixture was stirred at rt overnight. LCMS indicated complete conversion. It was diluted with ethyl acetate and washed with water and 0.5N sodium hydroxide. The organic layer was washed with brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by flash column chromatography CISCO) up to 10% methanol in methylene chloride afforded the desired product (59.6 mg, 64%) as a greenish solid: 1H NMR (400 MHz, CDCl3) 11.29 (s, 1H), 8.53 (s, 1H), 8.47 (d, J=2.5 Hz, 1H), 8.08 (d, J=5.2 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.28-7.17 (m, 1H), 7.15-6.94 (m, 3H), 6.61 (dd, J=15.2, 9.3 Hz, 1H), 6.55-6.40 (m, 1H), 5.51 (q, J=8.6 Hz, 1H), 4.85 (d, J=12.2 Hz, 1H), 4.59 (s, 1H), 4.22 (s, 1H), 4.07-3.85 (m, 2H), 3.76 (d, J=16.2 Hz, 1H), 3.28 (t, J=12.0 Hz, 1H), 2.71 (t, J=12.3 Hz, 1H), 2.50-2.08 (m, 4H), 2.02-1.83 (m, 2H), 1.27 (s, J=2.3 Hz, 9H).
