Triethylamine → Methyl (+)-3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate

Participants

Reaction Steps

Intermediate 5 (31.64 g, 94.61 mmol), β-alanine ethyl ester hydrochloride (45.9 g, 284 mmol), and 1-hydroxybenzotriazole hydrate (80%, 20 wt % water, 47.9 g, 284 mmol) were suspended in dichloromethane (946 mL). Triethylamine (119 mL, 852 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46.0 g, 237 mmol) were added, and the solution was stirred at room temperature for 10 h. The reaction mixture was washed with water (3×900 mL), then sat. aq NaCl (300 mL). The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) followed by chiral SFC (Chiralpak AD-H column, 30×250, 20% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier) gave methyl(+)-3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate (Intermediate 6, analytical chiral SFC 4.6 min retention) and methyl(−)-3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate (Intermediate 7, analytical chiral SFC 6.5 min retention)—note that ethyl ester was converted to methyl ester during the reaction and/or purification sequence. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.4 Hz, 2H), 7.64-7.58 (m, 2H), 7.55-7.48 (m, 3H), 7.44 (t, J=7.7 Hz, 1H), 7.16 (t, J=7.4 Hz, 1H), 6.76 (t, J=5.5 Hz, 1H), 5.48 (q, J=7.2 Hz, 1H), 4.78 (d, J=7.0 Hz, 1H), 3.76 (q, J=6.0 Hz, 2H), 3.70 (s, 3H), 2.64 (t, J=5.9 Hz, 2H), 2.29 (s, 3H), 2.04-1.82 (m, 2H), 1.52-1.29 (m, 2H), 0.98 (t, J=7.3 Hz, 3H).

Provenance & Evidence