1,2-Dichloroethane → 6-(3-{[(3,4-dimethoxy-benzoyl)-methyl-amino]-methyl}-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

Participants

Reaction Steps

3-[(3,4-Dimethoxy-benzoylamino)-methyl]-benzoic acid methyl ester (100 mg, 0.32 mmol), was dissolved in 5 mL DMF. Iodomethane (20 mL, 0.32 mmol) and NaH (15 mg, 0.62 mmol) were added. The mixture was stirred at room temperature for 2 hours, then diluted with 15 mL water and extracted with 3×10 mL ethyl acetate. The combined organic solvent was dried with Na2SO4 and evaporated to give 80 mg of crude product which was used without purification. The intermediate, 3-{[(3,4-dimethoxy-benzoyl)-methyl-amino]-methyl}-benzoic acid methyl ester, was dissolved in methanol (20 mL). NaOH (2 mL, 4M, 8 mmol) was added and the mixture was stirred at room temperature overnight, then diluted with 20 mL water. The resulting solution was neutralized with 1N HCl and extracted with dichloromethane (3×15 mL). Evaporation of the solvent afforded 80 mg of crude product as yellow oil which was used without further purification. The intermediate, 3-{[(3,4-dimethoxy-benzoyl)-methyl-amino]-methyl}-benzoic acid (80 mg, 0.24 mmol) was combined with 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (70 mg, 0.28 mmol), EDC (80 mg, 0.51 mmol) and HOBt (80 mg, 0.59 mmol) in a reaction vial. DMF (2 mL) was added followed by Hunig's base (0.1 mL, 0.57 mmol). The mixture was stirred at room temperature for 16 h. The product was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the intermediate, 6-(3-{[(3,4-dimethoxy-benzoyl)-methyl-amino]-methyl}-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester, as a yellow oil. This intermediate was dissolved in dichloromethane (4 mL), and trifluoroacetic (1 mL) was added thereafter. The mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title product as a TFA salt (119 mg, 65% yield, 4 steps); MS, electrospray, 460 (M+H).

Provenance & Evidence