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Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.75 h; Stage #2: at -78℃; for 19 h;
tert-Butyl 5-fluoro-2-oxo-1, 2-dihvdro-1'H spiro [indole-3, 4'-piperidinel-1'- carboxylate To a stirred solution of 5-fluoro-1, 3-dihydro-2H-indol-2-one (1.80 g, 11.9 mmol) in tetrahydrofuran (30 mL) was added dropwise a 1 M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (35.7 mL, 35.7 mmol) at-78 °C for 15 min and the mixture was stirred for 1.5 h at the same temperature. To the mixture was added dropwise a solution of tert-butyl bis (2-chloroethyl) carbamate (2.88 g, 11.9 mmol) in tetrahydrofuran (10 mL) at-78 °C, then this resulting mixture was slowly warmed up to room temperature and stirred for 19 h at the same temperature. The reaction mixture was quenched by the addition of ammonium chloride aqueous solution, and concentrated to give a brown residue. The crude material was partitioned between ethyl acetate and water, and then the organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/acetone (3/1) to afford 356 mg (15percent) of the title compound as a slight brown syrup: 'H-NMR (CDC13) 8 8.56 (1H, br. s), 7.03-6. 83 (3H, m), 3.89-3. 69 (4H, m), 1.92-1. 72 (4H, m), 1.50 (9H, s); MS (ESI) 319 (M-H)-.
7%
Stage #1: at -78℃; for 1 h; Stage #2: at -50℃; Reflux
5-fluoroindolin-2-one 5a (35 g, 231.576 mmol, 1 eq.) was added to a solution of LiHMDS (700 ml, 700 mmol, 3 eq) at -78°C. The mixture was stirred 1 hour at -78°C, then tert-butyl bis(2-chloroethyl)carbamate 5b (5 6.075 g, 231.576 mmol, 1 eq) wasadded, maintaining the internal temperature <-5 0°C. The reaction was then warmed to ambient temperature during 2 hours, and the reaction was refluxed overnight. The mixture was quenched with H20 and the mixture was partitioned between EtOAc and H20.The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuum. Theresulting residue was purified by high performance liquid chromatography (HPLC condition: Column: Synergi-10im, 250x50mm1.D, Flow rate: 80 ml/min, Mobile Phase A: Purified water (containing 0. 1percentTFA), Mobile Phase B: Acetonitrile, Gradient: 35- 65 percent( percentB)) to give 5.003 g (7percent yield) of tert-butyl 5-fluoro-2-oxospiro[indoline-3,4’- piperidine]- 1 ‘-carboxylate 5c.
tert-Butyl 5-fluoro-2-oxo-1, 2-dihvdro-1'H spiro [indole-3, 4'-piperidinel-1'- carboxylate To a stirred solution of 5-fluoro-1, 3-dihydro-2H-indol-2-one (1.80 g, 11.9 mmol) in tetrahydrofuran (30 mL) was added dropwise a 1 M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (35.7 mL, 35.7 mmol) at-78 C for 15 min and the mixture was stirred for 1.5 h at the same temperature. To the mixture was added dropwise a solution of tert-butyl bis (2-chloroethyl) carbamate (2.88 g, 11.9 mmol) in tetrahydrofuran (10 mL) at-78 C, then this resulting mixture was slowly warmed up to room temperature and stirred for 19 h at the same temperature. The reaction mixture was quenched by the addition of ammonium chloride aqueous solution, and concentrated to give a brown residue. The crude material was partitioned between ethyl acetate and water, and then the organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/acetone (3/1) to afford 356 mg (15%) of the title compound as a slight brown syrup: 'H-NMR (CDC13) 8 8.56 (1H, br. s), 7.03-6. 83 (3H, m), 3.89-3. 69 (4H, m), 1.92-1. 72 (4H, m), 1.50 (9H, s); MS (ESI) 319 (M-H)-.
7%
5-fluoroindolin-2-one 5a (35 g, 231.576 mmol, 1 eq.) was added to a solution of LiHMDS (700 ml, 700 mmol, 3 eq) at -78C. The mixture was stirred 1 hour at -78C, then tert-butyl bis(2-chloroethyl)carbamate 5b (5 6.075 g, 231.576 mmol, 1 eq) wasadded, maintaining the internal temperature <-5 0C. The reaction was then warmed to ambient temperature during 2 hours, and the reaction was refluxed overnight. The mixture was quenched with H20 and the mixture was partitioned between EtOAc and H20.The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuum. Theresulting residue was purified by high performance liquid chromatography (HPLC condition: Column: Synergi-10im, 250x50mm1.D, Flow rate: 80 ml/min, Mobile Phase A: Purified water (containing 0. 1%TFA), Mobile Phase B: Acetonitrile, Gradient: 35- 65 %( %B)) to give 5.003 g (7% yield) of tert-butyl 5-fluoro-2-oxospiro[indoline-3,4?- piperidine]- 1 ?-carboxylate 5c.
tert-butyl 5-fluoro-1-methyl-2-oxo-1,2-dihydro-1'H-spiro[indole-3,4'-piperidin]-1'-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
To a stirred solution of tert-butyl 5-fluoro-2-oxo-1, 2-dihydro-1'H-spiro [indole- 3, 4'-piperidine]-l'-carboxylate (step 1,166 mg, 0.518 mmol) in N, N dimethylformamide (4 mL) was added 70% sodium hydride in mineral oil (27 mg, 0.777 mmol) at 0 C and the mixture was stirred for 10 min at the same temperature. To the mixture was added methyl iodide (147 mg, 1.04 mmol) at 0 C, then this resulting mixture was slowly warmed up to room temperature and stirred for 18 h at the same temperature. The reaction mixture was diluted with toluene/ethyl acetate (1/3), then washed with water for two times, and then the organic layer was washed with brine, dried over sodium sulfate, and evaporated to afford 130 mg (75%) of the title compound as a slight yellow solid: 'H-NMR (CDC13) 6 7.05-6. 96 (2H, m), 6.79-6. 75 (1H, m), 3. 90-3. 73 (4H, m), 3.19 (3H, s), 1.87-1. 68 (4H, m), 1.50 (9H, s).
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