Water → tert-Butyl (3-(2-dimethylamino-ethoxy)-4-methyl-phenyl)-carbamate

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Reaction Steps

tert-Butyl(3-hydroxy-4-methyl-phenyl)-carbamate (7). A solution of 5-amino-2-methylphenol (6, 1.0 g, 8.12 mmol) and di-tert-butyl dicarbonate (1.95 g, 8.93 mmol) in THF (25 mL) was heated under reflux overnight. After cooling to room temperature, the solution was diluted with EtOAc (75 mL) and the resulting mixture was washed with water (70 mL), 1N HCl (2×70 mL) and brine (70 mL). The organic layer was then dried over MgSO4, the solids were filtered, and the filtrate was concentrated under reduced pressure. The desired product 7 was obtained as an oil (2.16 g) and was carried on to the next step without further purification. Step 2. tert-Butyl(3-(2-dimethylamino-ethoxy)-4-methyl-phenyl)-carbamate (8). A mixture of 7 (2.16 g, 9.68 mmol), 2-(dimethylamino)-ethyl chloride hydrochloride (1.53 g, 10.6 mmol) and K2CO3 (5.35 g, 3.87 mmol) in DME (28 mL)/H2O (7 mL) was heated under reflux overnight. After cooling to room temperature, the solution was diluted with EtOAc (100 mL) and the resulting solution was washed with H2O (2×100 mL) and brine (100 mL). The organic layer was dried over MgSO4, the solids were filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel to give 8 as an oil (1.15 g) which upon standing became a solid. Step 3. 3-(2-Dimethylamino-ethoxy)-4-methylaniline (9). A solution of 8 (1.15 g) in 6N HCl (10 mL) was heated at 60° C. for 4 hours. After cooling to room temperature, the solution was neutralized with 6N NaOH solution. The aqueous mixture was extracted with EtOAc (2×30 mL), the combined organic layers were washed with brine (1×50 mL) and dried over MgSO4. The solids were filtered, and the filtrate was concentrated under reduced pressure to give the desired product as an oil (0.68 g). Step 4. (3-(2-Dimethylamino-ethoxy)4-methyl-phenyl)-(2-methyl-quinolin-4-yl)-amine. To a solution of 9 (0.25 g, 1.29 mmol) and 5 (0.29 ml, 1.44 mmol) in EtOH (8 mL) were added 2 drops of conc. HCl. The mixture was heated under reflux overnight. After cooling to room temperature, EtOH was removed under reduced pressure. The residue was partitioned between sat. NaHCO3 (aq.) and EtOAc (100 mL each) and the aquous layer was extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, the solids were filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on Florisil® (50% EtOAc/Hexanes to 15% MeOH/EtOAc) to yield the title compound as a light yellow solid (0.25 g). The compounds of Examples 4-11 were synthesized in the same manner as Example 3.

Provenance & Evidence