1-Octanol → 4-Octyloxy-3-trifluoromethylbenzoic acid

Participants

Reaction Conditions

Reaction Steps

A 12 L round bottom flask was inerted and charged with 1-octanol (103 g, 0.793 mol, 1 equiv), THF (2 L), 1 M potassium tert-butoxide (2 L, 2.5 equiv) and heated to 65° C. and held for 45 minutes. The reaction was charged over 1 hour with 4-fluoro-3-trifluoromethyl benzoic acid (165 g, 0.793 mol) while maintaining the temperature at 64 to 67° C. After 2 hours, the reaction mixture was sampled. The sample was concentrated, quenched into 1 N HCl, extracted with ethyl acetate, removed the ethyl acetate, diluted with acetonitrile and injected in to the HPLC. The reaction was complete. The reaction mixture was stirred overnight at 18 to 23° C. The mixture was cooled to 5 to 10° C. and cautiously quenched with water (1.6 L). The quench was exothermic and the temperature was maintained at T<10° C. The resulting mixture was concentrated under vacuum until no noticeable THF was coming off. The resulting aqueous mixture was acidified to pH 1 to 2 using 6 N HCl (400 mL). The mixture was extracted with MTBE (2×2.5 L). The MTBE phases were combined, washed with brine (2 L), dried with magnesium sulfate, filtered over Celite, concentrated to afford the title product (279 g, 111% yield, 95.6% AUC by HPLC) as a tan solid.

Provenance & Evidence