Hydrochloric Acid → 4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoic acid

Participants

Reaction Steps

To a mixture of 95% dry sodium hydride (12 mg, 0.50 mmol) in anhydrous N,N-dimethylformamide (4 mL) at room temperature was added a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (78 mg, 0.30 mmol) (PT-010 made as in Example 1B, above) in anhydrous N,N-dimethylformamide (1 mL). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl 4-(bromomethyl)benzoate (271 mg, 1.00 mmol) in N,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at room temperature until the majority of the starting material was converted (checked by LCMS), then it was quenched by addition of methanol (5 mL). The reaction mixture was concentrated under reduced pressure, anhydrous toluene (10 mL) was added, and the solvent removed under reduced pressure. To this crude product (tert-butyl 4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate) was added 4N hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol). The reaction mixture was stirred at room temperature for 4 hours, and the solvent removed under reduced pressure. A second portion of 4N hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol) was added with stirring at room temperature for another 13 hours, the solvent removed under reduced pressure. The crude reaction product was subjected to reverse phase HPLC with a gradient of MeCN/H2O (2% to 98%) to afford 4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoic acid (70 mg, 0.16 mmol, 53%) (PT-088). LCMS mz 488.0 (M+H), 510.0 (M+Na), anal HPLC >98% in purity. 1H NMR (400 MHz; DMSO-d6) δ 7.90 (d, J=8.2 Hz, 2H); 7.86 (d, J=8.2 Hz, 2H); 7.78 (d, J=8.2 Hz, 2H); 7.68 (d, J=2.1 Hz, 1H); 7.53 (dd, J=8.3 and 2.1 Hz, 1H); 7.38 (d, J=8.2 Hz, 2H); 7.00 (d, J=8.6 Hz, 1H); 5.27 (s, 2H); 3.08 (m, 2H), 2.79 (m, 2H).

Provenance & Evidence