Sodium Chloride → Methyl 3-(6-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinamido)propanoate

Participants

Reaction Steps

To a solution of methyl 6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinate (400.0 mg, 0.46 mmol) in tetrahydrofuran (5 mL) was added a solution of LiOH monohydrate (378 mg, 9.02 mmol) in water (5 mL) dropwise at 0° C. After the addition, the mixture was stirred at room temperature for 48 hours. Tetrahydrofuran was removed under reduced pressure and the remaining aqueous residue was acidified to pH=3 by addition of 1N HCl. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was dissolved in N,N-dimethylformamide (5 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (637 mg, 1.68 mmol) was added. The mixture was stirred for 15 minutes at ambient temperature. Methyl 3-aminopropanoate hydrochloride (150 mg, 1.10 mmol) and diisopropylethylamine (540 mg, 4.2 mmol) were added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour. The mixture was poured into saturated NaCl (20 mL) and was extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated. Purification by preparative TLC gave methyl 3-(6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butoxy)nicotinamido)propanoate (400 mg) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.40 (m, 1H), 7.87-7.90 (m, 1H), 7.56-7.61 (m, 4H), 7.41-7.48 (m, 4H), 6.74 (d, 1H), 6.62-6.65 (m, 1H), 6.15-6.19 (m, 1H), 3.59-3.54 (m, 5H), 2.53-2.56 (m, 2H), 1.94-2.01 (m, 1H), 1.57-1.73 (m, 2H), 0.89-0.94 (m, 6H).

Provenance & Evidence