Dichloromethane → HCID 71208483, compound

Participants

Reaction Steps

While purging with argon, a 25 mL round-bottom flask was charged with 3-amino-methyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one (intermediate G) (50 mg, 0.157 mmol), 6-morpholinonicotinic acid (39.1 mg, 0.188 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphonate (HBTU) (71.3 mg, 0.188 mmol). Methylene chloride (5 mL) and N,N-diisopropylethylamine (202 mg, 274 μL, 1.57 mmol) were added, then the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over MgSO4, filtered, and concentrated. The crude product was purified using flash chromatography (12 g silica gel column, eluted with 100% methylene chloride ramped to 4% methanol in methylene chloride). Due to poor separation, a second purification was performed using a 23 g spherical silica column (100% methylene chloride ramped to 4% methanol in methylene chloride). N-[7-chloro-1-(2-chloro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-4-morpholin-4-yl-benzamide (46.8 mg, 57%) was obtained as a white solid at 97% purity according to reverse-phase HPLC. By analytical SFC, two peaks were present, suggesting possible atropisomers. The product was submitted to preparative SFC (WHELK-O1 R,R 3×25; modifier: ethanol; flow rate: 70 mL/min); however, the two products were only partially resolved. 1H NMR (DMSO-d6) δ ppm 8.45-8.69 (m, 2H) 8.26 (d, J=8.7 Hz, 1H) 7.56-8.07 (m, 6H) 7.45 (dd, J=8.7, 1.8 Hz, 1H) 6.81 (d, J=9.1 Hz, 1H) 6.67 (d, J=1.6 Hz, 1H) 4.34 (qd, J=15.0, 5.6 Hz, 2H) 3.58-3.78 (m, 4H) 3.38-3.58 (m, 4H). MS calcd. for C26H22Cl2N4O3 [(M+H)+] 510.0, obsd. 508.9.

Provenance & Evidence