Hydrochloric Acid → Bms-973013

Participants

Reaction Steps

1-(1-(2-((6R,9S)-6-(2,3-Difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1-(1-(2-((6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one. In a 100 mL round-bottomed flask was 2-((6,9-trans)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetic acid (46.0 mg, 0.145 mmol) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (95 mg, 0.435 mmol) (bis-HCl salt) in CH2Cl2 (4 ml) to give a colorless suspension. Hunig's Base (0.127 ml, 0.725 mmol) and 3-(DIETHOXYPHOSPHORYLOXY)-1,2,3-BENZO-TRIAZIN-4(3H)-ONE (87 mg, 0.290 mmol) were added. The reaction mixture was diluted with DMF (1 ml). Most solids were dissolved. It was stirred at rt overnight. 44 h: LCMS indicated complete conversion. It was diluted with EtOAc and washed with water. The layers were separated. The organic layer was washed with brine, dried with Na2SO4, and concentrated to a tan oil/gel. Purification by FCC (ISCO) up to 8% MeOH in CH2Cl2 afforded the desired product as a tan foam (68 mg, 86% for 2 steps). MS (ESI)[M+H+]=518.27; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.44 (br. s., 1H) 8.25-8.42 (m, 1H) 8.05 (d, J=5.29 Hz, 1H) 7.38 (t, J=8.44 Hz, 1H) 7.20-7.31 (m, 1H) 6.83-7.10 (m, 5H) 4.87 (d, J=12.34 Hz, 1H) 4.53-4.73 (m, 1H) 4.43 (t, J=15.36 Hz, 1H) 3.81-4.00 (m, 1H) 3.36-3.60 (m, 2H) 3.24 (t, J=12.97 Hz, 1H) 2.94 (t, J=11.21 Hz, 1H) 2.33-2.80 (m, 4H) 2.05-2.31 (m, 3H) 1.80-2.05 (m, 3H) 1.38-1.63 (m, 1H). The racemic product was resolved by chiral HPLC (Chiralpak AD-H analytical column, 4.6×250 mm, 5 μm; Mobile Phase: 40% MeOH in CO2; Temp: 35° C.; Flow rate: 2.0 mL/min. for 26 min; Injection: 5 uL of ˜2 mg/mL in MeOH). Compound (6R,9S) was the first peak with tR=13.88 min while compound (6S,9R) was the second peak with tR=19.19 min).

Provenance & Evidence