A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (40 mg, 0.125 mmol), (R)-3-amino-4-phenyl-butyric acid HCl salt (270 mg, 1.25 mmol) (PepTech Corporation), and NaOMe (101 mg, 1.88 mmol) in 2-methoxyethanol (10 mL) was refluxed for 1.5 h. The resulting mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and water. Hydrochloric acid (1 M) was added with vigorous stirring until pH ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (5-40% EtOAc/hexanes+2% AcOH). The compound isolated was then dissolved in MeOH (2 mL) and treated with 2 M NaOH (2 mL) for 2 h. Hydrochloric acid (1 M) was added to acidify the mixture, and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (5-40% EtOAc/hexanes+2% AcOH) to give 33 mg of the title compound. MS: (+) m/z 468.06 (M+1).
