1,1-Dichloroethane → Hydrochloric Acid

Participants

Reaction Conditions

Reaction Steps

To 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydro-2H-benzo[g] indazole-7-carbaldehyde (Preparation 22C, 0.15 g, 0.366 mmol) in methanol (2 mL) and dichloroethane (2 mL) was added azetidine-3-carboxylic acid (0.044 g, 0.440 mmol) at room temperature followed by 5 drops of acetic acid. The reaction mixture was heated at 60° C. for 1 h, cooled to room temperature, and sodium cyanoborohydride (0.028 g, 0.440 mmol) was added in one lot. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and the resulting brown oil was partitioned between dichloromethane (20 mL) and water (10 mL). The cloudy dichloromethane layer was separated, washed with brine (10 mL), dried over sodium sulfate, and concentrated. To the resulting semi-solid material was added methanol (5 mL) and the contents were triturated and filtered. The filtrate was concentrated under reduced pressure and purified using Prep. 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). Fractions corresponding to the product were collected and concentrated. LCMS indicated the fraction to be a mixture of the desired product and methyl ester. The pH of the residual solution was adjusted to ˜5 with 1N sodium hydroxide. The resulting solid out was filtered and washed with water (2×5 mL), ethyl acetate (2×5 mL) and dried. The solid was dissolved in acetonitrile (3 mL) and 6N hydrochloric acid (3 mL) and the contents were heated at 90° C. for 2.5 h. LCMS indicated the fraction to be a mixture of the desired product and the methyl ester. The contents were heated at 90° C. for an additional 4 h. The reaction mixture was concentrated and azeotroped twice with THF (5 mL). The pale yellow solid was triturated with acetonitrile (3 mL), filtered, washed with acetonitrile (2×3 mL) and dried to yield 1-((3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydro-2H-benzo[g]indazol-7-yl)methyl)azetidine-3-carboxylic acid, hydrochloric acid (0.04 g, 0.075 mmol, 21% yield). The compound had an HPLC retention time=2.88 min (condition A); LC/MS M+1=495.1.

Provenance & Evidence