Reaction Steps
To a solution of 3,5-dimethylhydroxy-benzoic acid (3.0 g, 18.05 mmol) in pyridine (7 mL), acetic anhydride (2.05 mL, 21.66 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Water was added and the compound was extracted with ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid (3.52 g, 94%). To a solution of 4-acetoxy-3,5-dimethyl-benzoic acid (6.02 g, 28.91 mmol) in CH2Cl2 (80 mL), oxalyl chloride (5.04 mL, 57.83 mmol) was added slowly, followed by a drop of dimethylformamide. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed and the solid acid chloride was dried under vacuum (6.37 g, 97%). To a solution of N,N,N,N-tetramethyl guanidine (2.77 mL, 22.078 mmol) in CH3CN (50 mL), a solution of 6,8-dimethoxy-isochroman-1,3-dione (4.46 g, 20.1 mmol) in CH3CN (100 mL) was added slowly at <0° C. (bath temperature −20° C.) over 30 min. Et3N (1 eq.) was added in one portion, followed by a solution of acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (6.37 g, 28.1 mmol) in CH3CN (50 mL) and stirred for 30 min. at <0° C. The reaction mixture was stirred at room temperature for 16 hour before being refluxed for 3 hour. After cooling to room temperature, the reaction mixture was quenched with 1 N HCl. The precipitated solid was filtered off to give a mixture of acetic acid 4-(6,8-dimethoxy-1,3-dioxo-isochroman-4-carbonyl-2,6-dimethyl-phenyl ester and acetic acid 4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester (combined 6.0 g). The above mixture of compounds (6.0 g) was dissolved in 30% H2SO4 (30 mL) and heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and the precipitated solid was filtered off to obtain a mixture of acetic acid 4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl-2,6-dimethyl-phenyl ester and 3-(4-hydroxy-3,5-dimethyl-phenyl)-6,8-dimethoxy-isochromen-1-one (5.5 g). The above mixture (5.5 g) was dissolved in methanol (30 mL) and K2CO3 (3.09 g, 22.4 mmol) and water (10 mL) were added. The reaction mixture was stirred at room temperature for 6 hours. The solvent was removed and the mixture was acidified with diluted HCl. The compound was extracted with ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to leave a residue which was purified by chromatography (Silica Gel, 230-250 mesh; 2% methanol in dichloromethane) to obtain 3-(4-hydroxy-3,5-dimethyl-phenyl)-6,8-dimethoxy-isochromen-1-one (1.46 g). To a solution of compound 3-(4-hydroxy-3,5-dimethyl-phenyl)-6,8-dimethoxy-isochromen-1-one (0.875 g, 2.68 mmol) in DMF (5 mL), NaH (0.129 g, 3.22 mmol) was added and the mixture was stirred for 1 hour. To the reaction mixture was added 1-chloro-2-iodo-ethane (1.23 mL, 13.4 mmol) and the mixture was stirred at room temperature for 16 hour. The reaction mixture was heated at 80° C. before being quenched with 1 N HCl at room temperature. The crude was purified by column chromatography (Silica Gel, 230-250 mesh; 2% methanol in dichloromethane) to give 3-[4-(2-chloro-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-isochromen-1-one (0.36 g, 35%). The compound 3-[4-(2-chloro-ethoxy)-3,5-dimethyl-phenyl]-6,8-dimethoxy-isochromen-1-one (0.36 g, 0.93 mmol) was dissolved in DMSO (5 mL) and morpholine (0.4 mL, 4.63 mmol) and Et3N (0.64 mL, 4.63 mmol) were added. The reaction mixture was heated at 110 C for 16 h before being cooled to room temperature. Water was added and the compound was extracted with ethyl acetate. The solvent was evaporated in vacuo to leave a residue which was purified by chromatography (Silica Gel, 230-250 mesh) to give 3-[3,5-dimethyl-4-(2-morpholin-4-yl-ethoxy)-phenyl]-6,8-dimethoxy-isochromen-1-one (0.13 g, 31%). The compound 3-[3,5-dimethyl-4-(2-morpholinyl-ethoxy)-phenyl]-6,8-dimethoxy-isochromen-1-one (0.13 g, 0.29 mmol) and NH3 (2.0 M solution in ethanol, 30 mL), were mixed in a steel bomb and heated at 130° C. for 16 hours. The solvent was removed and the crude compound was purified by chromatography (Silica Gel, 230-250 mesh). The compound was then converted into a salt by treatment with HCl in ether to give 3-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (80 mg, 59%); MS (ES) m/z: 349 (M+1); MP 196-198° C.
