Dimethylformamide → 3-[3-(4-Cyano-phenyl)-ureidomethyl]-N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide

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Reaction Steps

3-Methoxycarbonyl-benzyl-ammonium chloride (605 mg, 3.0 mmol) was dissolved in 6 mL DMF in a reaction vial. Si-dimethylamine (silica-bound dimethylamine; 3.3 g, 5 mmol) was added and the mixture was agitated for 1 hour. Subsequently, p-cyanophenylisocyanate (403.5 mg, 2.8 mmol) was added and the mixture was agitated overnight. SCX (strong cation exchanger; silica-bound benzenesulfonic acid; (568 mg, 0.5 mmol) was added and the mixture was agitated for 30 minutes. The solids were filtered, and the filtrate was evaporated to provide 843 mg (91% yield) of the desired urea, 3-[3-(4-cyano-phenyl)-ureidomethyl]-benzoic acid methyl ester, which was used directly. The intermediate urea was dissolved in 7 mL THF. A solution of lithium hydroxide (410 mg, 10 mmol) in 3 mL water was added. The resulting mixture was heated at 50° C. for 2 hours then cooled to room temperature. The organic phase was evaporated, and the remaining aqueous solution was neutralized. 3-[3-(4-Cyano-phenyl)-ureidomethyl]-benzoic acid (118 mg, 0.4 mmol) was isolated as a white solid by filtration (710 mg; 93% yield) and was used directly. The intermediate acid (118 mg, 0.4 mmol), EDC (115 mg, 0.6 mmol), and HOBt (67.6 mg, 0.5 mmol) were combined in a reaction vial and DMF (1 mL) then N-methylmorpholine (0.066 mL, 0.6 mmol) were added. The reaction mixture was agitated for 1 h, then 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (104.3 mg, 0.42 mmol) was added. Shaking was continued overnight. The reaction mixture was diluted to 6 mL with dichloromethane, washed with 1N HCl (3×2 mL), NaHCO3 (satd. aq., 3×2 mL), and brine (1×2 mL), dried, and the solvents were evaporated to give 220 mg of the intermediate 7-{3-[3-(4-cyano-phenyl)-ureidomethyl]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, which was treated directly with a solution of TFA (0.6 mL) in dichloromethane (2 mL). The reaction mixture was stirred for 2 h, and then the solvents were evaporated. The residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient. The title compound was collected as a solid (137 mg, 77%-2 steps) following evaporation of the solvent; MS analysis electrospray, 426 (M+H).

Provenance & Evidence