1,2-Dichloroethane → 3-(1,4'-bipiperidin-1'-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide

Participants

Reaction Conditions

Reaction Steps

A mixture of 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.174 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.046 g, 0.261 mmol), EDC (133 mg, 0.695 mmol), HOBT (26.6 mg, 0.174 mmol), and N,N-diisopropylethylamine (0.303 mL, 1.737 mmol) in N,N-dimethylformamide (2 mL) and tetrahydrofuran (2 mL) was stirred at 50° C. overnight. The solvent was removed in vacuo. The residue was dissolved in DMSO and purified via HPLC (Waters, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 3-(1,4′-bipiperidin-1′-ylmethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.040 g, 30% yield). 1H NMR (400 MHz, CDCl3) δ 10.22 (br. s., 1H), 8.75 (s, 1H), 8.31 (d, J=9.03 Hz, 1H), 8.23 (dd, J=2.01, 8.78 Hz, 1H), 7.77-7.84 (m, 2H), 7.65-7.72 (m, 2H), 7.54-7.60 (m, 2H), 7.46 (dd, J=1.76, 5.02 Hz, 3H), 6.26 (br. s., 1H), 3.60-3.78 (m, 2H), 3.15 (s, 3H), 2.66 (br. s., 1H), 2.38 (br. s., 4H), 2.18 (br. s., 1H), 2.12 (br. s., 1H), 1.53-1.64 (m, 10H), 1.37-1.46 (m, 2H); MS (m/z) 733.3 (M+H+). Human TRPV4 FLIPR pIC50=8.5

Provenance & Evidence