A solution of (6-bromo-isoquinolin-4-yl)-acetic acid methyl ester (52 mg, 0.19 mmol), prepared as described as an intermediate for Intermediate 31, in DMF (3 ml) is added to zinc dicyanide (26 mg, 0.2 mmol) under a nitrogen atmosphere. To the resulting mixture is added 1,1′-bis(diphenylphosphino)ferrocene (15 mg) and tris(dibenzylideneacetone)dipalladium(0) (8 mg) and the resulting mixture stirred at 120° C. for 22 h. The solution is cooled and diluted with chloroform (30 ml) and washed with water (2×20 ml) followed by brine (20 ml). Further chloroform is added (40 ml) and the solution dried over MgSO4, filtered and concentrated. Repetitive flash silica column chromatography (eluants 40:1 CH2Cl2:methanol, then 50:1 CH2Cl2:methanol) gives (6-cyano-isoquinolin-4-yl)-acetic acid methyl ester [MH]+ 227. This intermediate is saponified by treatment with LiOH in 3:1 THF/water. The resulting mixture is partially evaporated to remove the THF, diluted to 10 ml with water then washed with ethyl acetate. The aqueous phase is then neutralised with 1M hydrochloric acid (to pH 4-5) and exhaustively extracted with ethylacetate. The organic phase is dried over MgSO4, filtered and concentrated to give (6-cyan-isoquinolin-4-yl)-acetic acid M+ 212. Intermediate 57: (5-Chloro-6-methoxy-isoquinolin-4-yl)-acetic acid is prepared as described in the procedure for intermediate 29. Intermediate 58: To a solution of (6-trimethylsilanylethynyl-isoquinolin-4-yl)-acetic acid methyl ester, as prepared for Intermediate 32 (0.19 g, 0.64 mmol), in anhydrous methanol (7 ml) is added K2CO3 (72 mg) and the resulting mixture stirred for, 1 h. Additional K2CO3 (11 mg) is then added and stirring continued for 30 min. The mixture is then neutralised with glacial acetic acid and concentrated. Purification by flash silica column chromatography (ethylacetate/hexane 1:1) gives (6-ethynyl-isoquinolin-4-yl)-acetic acid methyl ester M+ 225. This intermediate (79 mg, 0.35 mmol) is dissolved in methanol under an inert atmosphere and 10% Pd on carbon (79 mg) added. The resulting suspension is stirred vigorously under an atmosphere of gaseous hydrogen. After 90 mins, filtration, washing with methanol and concentration give (6-ethyl-isoquinolin-4-yl)-acetic acid methyl ester M+ 229. To a solution of this intermediate (68 mg, 0.30 mmol) in THF/methanol/water (3:1:1, 3.5 ml) is added LiOH (12.5 mg) and the mixture stirred for 20 h at room temperature. Concentration under reduced pressure gives lithium (6-ethyl-isoquinolin-4-yl)-acetate M+ 221. Intermediate 59: A solution of Intermediate 29 (0.5 g, 2.3 mmol) is suspended in aqueous 48% HBr (10 ml) and then heated at 100° C. for 48 h. Further aqueous 48% HBr (10 ml) is then added and heating continued at 100° C. for an additional 24 h. The reaction mixture is cooled to 5° C. for 4 h and the resulting solid separated by filtration. Washing with water and drying under high vacuum at 50° C. gives (6-hydroxy-isoquinolin-4-yl)-acetic acid hydrobromide [MH]+ 204.4. This intermediate (0.15 g, 0.53 mmol) is suspended in DMF (2 ml) and K2CO3 (0.22 g, 1.58 mmol) added followed by ethyliodide (0.085 ml, 1.06 mmol) and the resulting mixture stirred at room temperature for 2 h. Concentration and purification by flash silica column chromatography (eluant: CH2Cl2/methanol 10:1) gives (6-ethoxy-isoquinolin-4-yl)-acetic acid ethyl ester [MH]+ 260. This intermediate (25 mg, 0.11 mmol) is dissolved in water (1 ml) and LiOH added (5 mg, 0.11 mmol). The resulting mixture is stirred for 30 min at room temperature. Acidification with minimum 6N HCl and concentration gives crude (6-ethoxy-isoquinolin-4-yl)acetic acid.
