Reaction Steps
(+/−)-4-(3-methyl-1-((3-methylquinolin-2-yl)amino)butyl)benzoic acid trifluoroacetic acid salt (461 mg, 1.00 mmol), β-alanine ethyl ester hydrochloride (645 mg, 3.99 mmol), and 1-hydroxybenzotriazole hydrate (80%, 20 wt % water, 674 mg, 3.99 mmol) were suspended in dichloromethane (10.0 mL). Triethylamine (1.40 mL, 9.97 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (776 mg, 3.99 mmol) were added, and the solution was stirred at room temperature for 66 hours. The reaction mixture was diluted with dichloromethane (40 mL), washed with water (3×30 mL) and sat. aq NaCl (20 mL), 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, 10 mm×250 cm, 25% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier) gave ethyl 3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate, isomer 1 (analytical chiral SFC 6.1 min retention) and 3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido) propanoate as a mixture of methyl and ethyl esters, isomer 2 (analytical chiral SFC 6.7 min retention). Ethyl ester: 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.2 Hz, 2 H), 7.66-7.57 (m, 2 H), 7.56-7.48 (m, 3 H), 7.44 (t, J=7.4 Hz, 1 H), 7.16 (t, J=7.4 Hz, 1 H), 6.81-6.73 (m, 1 H), 5.60-5.52 (m, 1 H), 4.73 (d, J=6.8 Hz, 1 H), 4.16 (q, J=7.0 Hz, 2 H), 3.71 (q, J=6.0 Hz, 2 H), 2.62 (t, J=5.9 Hz, 2 H), 2.28 (s, 3 H), 1.93-1.82 (m, 1 H), 1.81-1.70 (m, 1 H), 1.69-1.60 (m, 1 H), 1.26 (t, J=7.1 Hz, 3 H), 1.04 (d, J=6.4 Hz, 3 H), 0.97 (d, J=6.2 Hz, 3 H). Methyl ester: 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.2 Hz, 2 H), 7.66-7.57 (m, 2 H), 7.56-7.48 (m, 3 H), 7.44 (t, J=7.4 Hz, 1 H), 7.16 (t, J=7.3 Hz, 1 H), 6.81-6.71 (m, 1 H), 5.60-5.52 (m, 1 H), 4.77-4.69 (m, 1 H), 3.76-3.66 (m, 5 H), 2.66-2.59 (m, 2 H), 2.28 (s, 3 H), 1.93-1.82 (m, 1 H), 1.81-1.70 (m, 1 H), 1.69-1.60 (m, 1 H), 1.04 (d, J=6.4 Hz, 3 H), 0.97 (d, J=6.4 Hz, 3 H).
