Triethylamine → 6-(2-Biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

A slurry of 2-biphenyl-4-yl-3-cyclopentylpropionic acid (prepared in Example 21, 1.25 g 4.25 mmol) in methylene chloride (10 mL) was treated with dry N,N-dimethylformamide (5 drops). The reaction mixture was cooled to 0° C. and then treated dropwise with oxalyl chloride (1.85 mL, 21.23 mmol). The reaction mixture was allowed to stir at 0° C. for 30 min and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was concentrated in vacuo to provide an orange semi-solid residue. This residue was treated with a small amount of methylene chloride and was slowly added to a cooled (0° C.) solution of 6-aminonicotinic acid methyl ester (776 mg, 5.10 mmol) and triethylamine (1.19 mL, 8.50 mmol) in methylene chloride (10 mL). The resulting reaction mixture was stirred at 0° C. and allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The resulting residue was partitioned between water and ethyl acetate, and the layers were separated. The aqueous layer was further extracted with ethyl acetate (1×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 6-(2-biphenyl-4-yl-3-cyclopentyl-propionylamino)-nicotinic acid methyl ester (325 mg, 18%) as a white solid: mp 63-65° C.; EI-HRMS m/e calcd for C27H28N2O3 (M+) 428.2099, found 428.2100.

Provenance & Evidence