Hydrochloric Acid → Hydrochloric Acid

Participants

Reaction Conditions

Reaction Steps

A 2-dram vial was charged with 7-(oxiran-2-yl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 13A, 0.085 g, 0.200 mmol), N-methyl-2-pyrrolidinone (1 mL), (S)-ethyl piperidine-3-carboxylate (0.062 mL, 0.401 mmol) and lithium per chlorate (4.26 mg, 0.040 mmol). The vial was sealed and the contents were heated at 100° C. for 6.5 h and then left stirring at room temperature for 65 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and brine (2×15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield a brown oil. To the brown oil was added acetonitrile (2 mL) and 6N hydrochloric acid (2 mL) and the contents were heated at 60° C. for 5 h. The reaction mixture was concentrated under reduced pressure. To the residue was added TFA (5 drops) followed by 2 mL of MeOH and the material was purified by reverse phase preparative HPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Product containing fractions were isolated and concentrated. Acetonitrile (2 mL) and 6N hydrochloric acid (2 mL) were added to the resulting oil and the contents were heated at 60° C. for 2 h. The reaction mixture was concentrated and freeze dried to yield (3S)-1-(2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethyl)piperidine-3-carboxylic acid, hydrochloric acid (0.046 g, 0.074 mmol, 37.0% yield) as a pale yellow solid.

Provenance & Evidence