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

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).

1. stirringthe mixture was agitated overnight
2. addition(568 mg, 0.5 mmol) was added
3. stirringthe mixture was agitated for 30 minutes
4. filtrationThe solids were filtered
5. customthe filtrate was evaporated

ORD record

ord-0582583104c64bbaa4c0039022905d6d

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08093266B2