| 60% |
With pyridine In acetonitrile at 70℃; for 3h; Inert atmosphere; |
B17-166 No. B 17-166: 1 -(3-Chlorophenyl)-N-[4,4-dimethyl-1 -(2-methylcyclopropyl)-2-oxo-1 ,2,3,4-tetrahydro-quinolin-6-yl]methanesulfonamide
N-(2-Methylcyclopropyl)aniline (4.50 g, 30.57 mmol) and abs. pyridine (3.21 mE, 39.74 mmol) were dissolved under argon in abs. dichioromethane (60 mE) and cooled down to a temperature of 00 C., and then a solution of 3,3-dimethylacryloyl chloride (3.74 mE, 33.62 mmol) in abs. dichloromethane (15 mE) was added dropwise. The resulting reaction mixture was stirred at room temperature for 4 h, then washed with 10% HC1, and the organic phases were dried over magnesium sulfate and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), N-(3,3-dimethylacryloyl)-N-(2-methylcyclopropyl) aniline (6.41 g, 82% of theory) was isolated as a colorless oil of high viscosity, ‘H-NMR (400 MHz, CDC13 ö, ppm) 7.37 (m, 2H), 7.25 (m, 1H), 7.09 (m, 2H), 5.72 (m, 1H), 2.77 (m, 1H), 2.18 (s, 3H), 1.75 (s, 3H), 1.10 (d, 3H), 0.95-0.87 (m, 2H), 0.64-58 (m, 2H). Aluminum trichloride (13.05, 97.83 mmol) was admixed with abs. dichloromethane (100 mE) in a baked-out round-bottom flask under argon and cooled down to 00 C. Thereafier, N-(3,3-dimethylacryloyl)-N-(2- methylcyclopropyl)aniline (6.41 g, 27.95 mmol) was dissolved in abs. dichloromethane (50 ml) and slowly added dropwise to the initial charge of aluminum chloride. The resulting reaction mixture was stirred at 00 C. for 2 h and at room temperature for 4 h. On completion of conversion, the reaction solution was admixed with 10% HC1 and thoroughly extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), it was possible to isolate 4,4-dimethyl- 1 -(2-methylcyclopropyl)-6-nitro-3,4-dihydro- quinolin-2(1H)-one (2.05 g, 29% of theory) as a colorless solid, ‘H-NMR (400 MHz, CDC13 ö, ppm) 7.24 (m, 3H), 7.09-7.04 (m, 2H), 2.46 (s, 2H), 2.45 (m, 1H), 1.27 (d, 3H),1.23 (s, 6H), 1.16-1.10 (m, 1H), 1.03-0.79 (m, 2H). 4,4- Dimethyl- 1 -(2-methylcyclopropyl)-6-nitro-3,4-dihydroqui- nolin-2(1H)-one (2.05 g, 8.94 mmol) was dissolved in acetic anhydride (50 mE) and cooled down to 00 C., and copper(II) nitrate trihydrate (6.05 g, 25.03 mmol) was added in portions. The resulting reaction mixture was stirred at 00 C. for 1.5 h, and then ice-water was added cautiously, followed by dichloromethane afier stirring for 5 mm. The aqueous phase was then extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 4,4-dimethyl-1 -(2-methylcyclopropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (1950 mg, 72%) was isolated as a colorless solid, ‘H-NMR (400 MHz, CDC13 ö, ppm) 8.19 (m, 1H), 8.16 (m, 1H), 7.36 (d, 1H), 2.53 (s, 2H), 2.50-2.47 (m, 1H), 1.30 (d, 3H), 1.27 (s, 6H), 1.09-0.98 (m, 2H), 0.92-0.87 (m, 1H). In the next step, 4,4-dimethyl-1 -(2-methylcyclopropyl)-6-ni- tro-3,4-dihydroquinolin-2(1 H)-one (1950 mg, 7.11 mmol) was added together with tin(II) chloride dihydrate (6416 mg, 28.43 mmol) to abs. ethanol (50 mmol) and the mixture was stirred under argon at a temperature of 60° C. for 5 h. After cooling to room temperature, the reaction mixture was poured into ice-water and then adjusted to pH 12 using aqueous NaOH. The aqueous phase was then extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate heptane gradient), 6-amino-4,4-dimethyl-1 -(2-methylcyclo- propyl)-3,4-dihydroquinolin-2(1H)-one (1630 mg, 94% of theory) was isolated as a highly viscous foam, ‘H-NMR (400 MHz, CDC13 ö, ppm) 7.04 (d, 1H), 6.60 (m, 1H), 6.58 (m, 1H), 3.57 (br. s, 2H, NH), 2.44-2.38 (m, 3H), 1.27 (d, 3H), 1.19 (s, 6H), 1.03-0.89 (m, 2H), 0.83-0.78 (m, 1H).6-Amino-4,4-dimethyl-1 -(2-methylcyclopropyl)-3,4-dihyd- roquinolin-2(1H)-one (135 mg, 0.55 mmol) was dissolved together with (3-chlorophenyl)methanesulfonyl chloride (124 mg, 0.55 mmol) in abs. acetonitrile (10 mE) in a baked-out round-bottom flask under argon, then pyridine (0.13 mE, 3.47 mmol) was added and the mixture was stirred at 70° C. for 3 h. The reaction mixture was then concentrated under reduced pressure, the remaining residue was admixed with dil. HC1 and dichloromethane, and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By colunm chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1 -(3-chlorophenyl)-N-[4,4- dimethyl-1 -(2-methylcyclopropyl)-2-oxo- 1 ,2,3,4-tetrahyd- roquinolin-6-yl]methanesulfonamide (147 mg, 60% of theory) was isolated as a colorless solid. ‘H-NMR (400 MHz, CDC13 ö, ppm) 7.38-7.24 (m, 4H), 7.21 (m, 1H), 7.12 (m, 1H), 6.95 (d, 1H), 6.12 (s, 1H, NH), 4.31 (s, 2H), 2.46 (s, 2H), 2.43 (m, 1H), 1.28 (d, 3H), 1.22 (s, 3H), 1.21 (s, 3H), 1.03-0.92 (m, 2H), 0.83-0.78 (m, 1H). |
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