Water → 1-[(4-{[3-Methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)carbonyl]-4-piperidinecarboxylic acid

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Reaction Steps

To a suspension of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoic acid (16) (0.149 g, 0.388 mmol) in toluene (3 mL) was added oxalyl chloride (0.06 mL, 0.087 g, 0.687 mmol, 1.8 eq) followed by DMF (1 drop). The reaction mixture was stirred at RT under N2 for 45 min. The reaction mixture was concentrated to give crude 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoyl chloride as a yellow oil. Isonipecotic acid (0.051 g, 0.39 mmol), triethylamine (0.12 mL, 0.087 g, 0.86 mmol) and H2O (2 mL) were combined and the solution was cooled in an ice-water bath under N2. To the cold isonipecotic acid solution was slowly added dropwise a solution of 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}benzoyl chloride in THF (2 mL) with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir for 5 d. The pH of the reaction mixture was adjusted to ˜1 (litmus paper) with 1 N HCl and the acidic reaction mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with H2O (2×), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude title compound. The crude product was purified by flash chromatography over SiO2 with CH2Cl2:MeOH (94:6) to give 0.133 g (69%) of compound 17 as an amorphous solid. 1H NMR (400 MHz; DMSO-d6): δ 1.42 (m, 2H), 1.80 (m, 2H), 2.17 (s, 3H), 2.93 (br s, 2H), 3.87 (s, 3H), 6.59 (d, J=8.6 Hz, 2H), 7.09 (dd, J=2.5 Hz, 9.2 Hz, 1H), 7.15 (m, 4H), 7.25 (m, 3H), 7.35 (d, J=2.4 Hz, 1H), 7.61 (d, J=9.1 Hz, 1H), 7.70 (s, 1H), 12.25 (br s, 1H). AP LRMS m/z 494 (M−H)−.

Provenance & Evidence