3,4-Dimethoxybenzoic acid (100 mg, 0.55 mmol) was dissolved in DMF (1 mL). EDC (124.6 mg, 0.65 mmol) and HOBt (81 mg, 0.6 mmol) were added, followed by N-methylmorpholine (0.71 mL, 0.65 mmol). The resulting solution was agitated for 1 h. 3-Aminomethylphenyl-carbamic acid tert-butyl ester (111 mg, 0.5 mmol) was then added and the resulting mixture was agitated overnight. The reaction mixture was diluted with 4 mL dichloromethane, and the resulting mixture was washed with 1 N HCl (2×5 mL), NaHCO3 (saturated aqueous, 2×5 mL), and brine (1×5 mL), dried, and the solvents were evaporated to provide 190 mg (quantitative yield) of {3-[(3,4-dimethoxy-benzoylamino)-methyl]-phenyl}-carbamic acid tert-butyl ester, which was dissolved in dichloromethane (2 mL). SCX (1.14 g, 1.0 mmol) was added and the resulting mixture was agitated for 48 h. The reaction mixture was filtered and the solids were washed with dichloromethane (2×2 mL) and methanol (2×2 mL). The product was eluted with NH3 in methanol (7 N, 2×2 mL). The solvents were evaporated to provide 112 mg (78% yield) of N-(3-amino-benzyl)-3,4-dimethoxy-benzamide as a white solid, which was used directly. 3,4-Dihydro-1H-isoquinoline-2,6-dicarboxylic acid 2-tert-butyl ester (19.1 mg, 0.069 mmol), EDC (19.2 mg, 0.1 mmol), and HOBt (12.2 mg, 0.09 mmol) were combined in a reaction tube, and DMF (1 mL) was added. To the resulting solution was added N-methylmorpholine (0.013 mL, 0.12 mmol), and the mixture was agitated for 1 h. The intermediate prepared above, N-(3-amino-benzyl)-3,4-dimethoxy-benzamide (17 mg, 0.059 mmol), was then added as a solution in DMF (0.3 mL), and the reaction mixture was agitated overnight. The reaction mixture was diluted with 6 mL dichloromethane, and the resulting mixture was washed with 1 N HCl (2×2 mL), NaHCO3 (saturated aqueous, 2×2 mL), and brine (1×2 mL), dried, and concentrated to 32 mg of 6-{3-[(3,4-dimethoxy-benzoylamino)-methyl]-phenylcarbamoyl}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester as an oil, which was redissolved in dichloromethane (1 mL) and treated with SCX (284 mg, 0.25 mmol). The resulting mixture was agitated overnight. The reaction mixture was filtered and the solids were washed with dichloromethane (2×2 mL) and methanol (2×2 mL). The product was eluted with NH3 in methanol (7 N, 2×2 mL), and the eluant was evaporated. The resulting residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound as a formate salt (20 mg, 77% yield-2 steps), MS analysis electrospray, 446 (M+H).
