Hydrochloric Acid → [5-(5-{3-Cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydro-1-isoquinolinyl]acetic acid hydrochloride

Participants

Reaction Steps

A solution of 5-[3-(3,4-dihydro-5-isoquinolinyl)-1,2,4-oxadiazol-5-yl]-2-[(1-methylethyl)oxy]benzonitrile (Preparation 8, 96.2 mg, 0.268 mmol) and mono ethyl malonate (95 μl, 0.805 mmol) in THF (2 mL) was irradiated in the microwave to 120° C. for 10 min. Concentration gave a yellow oil that was purified by MDAP to two fractions containing both the desired carboxylic acid plus the corresponding ethyl ester. The fractions were combined and redissolved in MeOH-THF-water (1:1:1, 1.5 mL). LiOH (9.7 mg, 0.403 mmol) was added and the solution irradiated to 100° C. for 18 min. More LiOH (4.2 mg, 0.175 mmol) and water (300 μl) were added and the solution irradiated to 100° C. for 3 min. The reaction mixture was acidified to pH2 with 2M aqueous HCl and the resulting precipitate filtered to give a white solid. This was dissolved in DMSO-MeOH, added to an SCX cartridge, eluting with methanolic ammonia. Concentration gave a white solid, that was suspended in 1M aqueous HCl and irradiated at 100° C. for 5.5 h. The white precipitate was filtered and dried in vacuo overnight to give the title compound as a white solid (25.5 mg). 1H NMR (400 MHz, CDCl3) δ 9.56 (2H, br. S), 8.52 (1H, d), 8.41 (1H, dd), 8.00 (1H, d), 7.61 (1H, d), 7.57 (1H, d), 7.52 (1H, t), 5.01-4.94 (2H, m), 1.39 (6H, d), remaining aliphatic signals obscured by solvent peaks; m/z (ES) 419 [M+H]+.

Provenance & Evidence