Synthesis
Preparation of Example G-1. The synthesis of isoquinoline-6-carboxylic acid was carried out with reference to the method described in J. Org. Chem. vol. 48, 3344-3346 (1983). First, (4-bromobenzyl)-(2,2-diethoxyethyl)amine (51.4 g, 0.189 mmol, synthesized from 4-bromobenzaldehyde) was added to ice-cold concentrated sulfuric acid (20 g), and the mixture was subsequently added to a solution prepared from phosphorus pentoxide (40 g) and ice-cold concentrated sulfuric acid (360 g). The reaction mixture was stirred at 160°C for 2 hours. After completion of the reaction, the solution was gradually cooled to 0°C, filtered through a diatomaceous earth pad and the filtrate was neutralized with sodium carbonate. The neutralized solution was again filtered through a diatomaceous earth pad, the filtrate was extracted with ethyl acetate and the organic layer was dried with anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give 6-bromoisoquinoline (482 mg, 1.2%) as an orange oil.
Next, zinc cyanide (431 mg, 3.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.0367 mmol) were added to a solution of N,N-dimethylformamide (3.8 mL) of 6-bromoisoquinoline (382 mg, 1.84 mmol) and the mixture was stirred for 1 hr at 100 °C under nitrogen protection. Tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.0367 mmol) was added again and stirring was continued at 100°C for 2.5 hours. The reaction mixture was cooled to room temperature and extracted by adding ethyl acetate and water, the organic layer was washed with water and dried with anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to give isoquinoline-6-carbonitrile (234 mg, 83%) as a yellow solid.
Finally, isoquinoline-6-carbonitrile (51 mg, 0.331 mmol) was dissolved in diethylene glycol (1.0 mL), potassium hydroxide (9 mg, 0.166 mmol) was added, and the mixture was stirred for 3 h at 160 °C. The reaction was completed by cooling to room temperature. After completion of the reaction, it was cooled to room temperature, neutralized with hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated. Water was added to the residue and the precipitated solid was collected, washed with water and dried under vacuum to give the target product isoquinoline-6-carboxylic acid (12 mg, 21%) as a yellow solid.
References
[1] Patent: EP1782811, 2007, A1. Location in patent: Page/Page column 58
[2] Patent: EP1669348, 2006, A1. Location in patent: Page/Page column 66
[3] Journal of the American Chemical Society, 1939, vol. 61, p. 183
[4] Patent: CN106831575, 2017, A. Location in patent: Paragraph 0020; 0024
