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With water; sodium carbonate In methanolHeating / reflux
To a solution of methanol (20 mL) and saturated sodium carbonate solution (20 mL) are added a mixture of l-(6-Bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro- ethanone and l-(8-bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (3 g, 9.7 mmol). The reaction mixture is refluxed overnight, concentrated and the residue is extracted with dichloromethane. The combined organic layers are washed with water and brine, dried over sodium sulfate and the solvent is evaporated. The crude product is purified by column chromatography (silica gel, 230-400 mesh) using 0-2percent methanol in chloroform as eluent to obtain 8-bromo-l,2,3,4-tetrahydro-isoquinoline as colorless viscous oil (first fraction, 0.45 g, 22percent) and 6-Bromo-l,2,3,4-tetrahydro-isoquinoline as white solid (second fraction, 1.0 g, 48percent). MS m/z 211.9 (M+l)
With water; sodium carbonate In methanolHeating / reflux
To a solution of methanol (20 mL) and saturated sodium carbonate solution (20 mL) are added a mixture of l-(6-Bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro- ethanone and l-(8-bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (3 g, 9.7 mmol). The reaction mixture is refluxed overnight, concentrated and the residue is extracted with dichloromethane. The combined organic layers are washed with water and brine, dried over sodium sulfate and the solvent is evaporated. The crude product is purified by column chromatography (silica gel, 230-400 mesh) using 0-2percent methanol in chloroform as eluent to obtain 8-bromo-l,2,3,4-tetrahydro-isoquinoline as colorless viscous oil (first fraction, 0.45 g, 22percent) and 6-Bromo-l,2,3,4-tetrahydro-isoquinoline as white solid (second fraction, 1.0 g, 48percent). MS m/z 211.9 (M+l)
With water; sodium carbonate; In methanol;Heating / reflux;
To a solution of methanol (20 mL) and saturated sodium carbonate solution (20 mL) are added a mixture of l-(6-Bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro- ethanone and l-(8-bromo-3,4-dihydro-lH-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone (3 g, 9.7 mmol). The reaction mixture is refluxed overnight, concentrated and the residue is extracted with dichloromethane. The combined organic layers are washed with water and brine, dried over sodium sulfate and the solvent is evaporated. The crude product is purified by column chromatography (silica gel, 230-400 mesh) using 0-2percent methanol in chloroform as eluent to obtain 8-bromo-l,2,3,4-tetrahydro-isoquinoline as colorless viscous oil (first fraction, 0.45 g, 22percent) and 6-Bromo-l,2,3,4-tetrahydro-isoquinoline as white solid (second fraction, 1.0 g, 48percent). MS m/z 211.9 (M+l)
With water; potassium carbonate; In methanol; at 20℃;
Potassium carbonate (66.2 mmol) was added in one portion to a solution of 6-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline and 8-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (17.6 mmol) in MeOH (130 mL) and water (45 mL). The reaction mixture was allowed to stir at rt overnight and then diluted with EtOAc (150 mL). The mixture was washed with brined, dried over Na2SO4, filtered, and concentrated to give 6-bromo-1,2,3,4-tetrahydroisoquinoline and 8-bromo-1,2,3,4-tetrahydroisoquinoline (5.0 g, 100percent) as a white solid.
[00986]Part C. Preparation of 6-bromo-l,2,3,4-tetrahydroisoquinoline.; [00987] To a solution of the product from Part B (9.5g, 30.8mmol) in methanol (231ml) and water (77ml) at room temperature was added potassium carbonate (8.52g, 61.7mmol) and the reaction was stirred at room temperature for 30min. The reaction was diluted with water and 25percent isopropanol in chloroform and the pH was adjusted to 9 with IN HCl. The mixture was extracted twice with 25percent isopropanol in chloroform. The combined organic layers were dried overmgSO4, filtered and concentrated to give the title compound, contaminated with the 8-bromo isomer (6.55g, quantitative).
With ethanol; ammonia; water; at 20 - 60℃;
This mixture was stirred with absolute EtOH (100 mL) and 25percent ammonium hydroxide (10 mL) at 60 °C for 4 h. More 25percent ammonium hydroxide (15 mL) was added and stirring continued at RT overnight. The volatiles were evaporated to leave the crude amine as a white solid. LC-MS mlz 212/214 (M+l).
With ethanol; ammonia; water; at 20 - 60℃;
The above material was stirred with absolute EtOH (100 mL) and 25percent ammonium hydroxide (10 mL) at 60 0C for 4 h. More 25percent ammonium hydroxide (15 mL) was added io and stirring continued at RT overnight. The volatiles were evaporated to leave the crude amine as a white solid. LC-MS mlz 212, 214 (M+l).
With triethylamine; In dichloromethane; at 0 - 20℃; for 1h;
The compound (2.253 g) obtained in Example 17-1 was dissolved in anhydrous THF (11 ml) and added with a 1 mol/l borane-THF complex/THF solution (manufactured by Kanto Chemical Co., Inc.) (55.4ml). The whole was refluxed overnight under heating. After the whole was left for cooling, methanol was added thereto and the solvent was distilled off. The resultant was added with 1 mol/l hydrochloric acid and refluxed under heating for 3 hours. After completion of the reaction, the solution was cooled with ice and added with a 1 mol/l sodium hydroxide aqueous solution and 27% ammonium water, followed by extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was distilled off. The resultant was dissolved in anhydrous dichloromethane (40 ml), added with triethylamine (1.53 ml), and cooled with ice. Trifluoroacetic anhydride (1.55 ml) was added thereto and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the resultant was added with a saturated aqueous sodium hydrogen carbonate solution, subjected to extraction with chloroform, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, thereby obtaining the subject compound (2.23 g) as a white solid. MS(FAB,Pos.):m/z=308,310[M+H]+