5-Fluoro-1,2-dihydro-2-oxo-spiro[3H-indole-3,4'-piperidine]-1'-carboxylic acid 1,1-dimethylethyl ester

Synthesis

General procedure for the synthesis of 1'-BOC-5-fluoro-1,2-dihydro-2-oxo-spiro[3H-indole-3,4'-piperidine] from 5-fluoroindol-2-one and tert-butyl N,N-bis(2-chloroethyl)carbamate: to a stirred solution of 5-fluoroindol-2-one (1.80 g, 11.9 mmol) in tetrahydrofuran (30 mL) at -78 °C A tetrahydrofuran solution (35.7 mL, 35.7 mmol) of 1 M sodium bis(trimethylmethylsilyl)amide was slowly added dropwise for 15 min. The reaction mixture was continued to be stirred at the same temperature for 1.5 hours. Subsequently, tert-butyl N,N-bis(2-chloroethyl)carbamate (2.88 g, 11.9 mmol) solution of tetrahydrofuran (10 mL) was added dropwise to the reaction mixture at -78 °C. After dropwise addition, the reaction mixture was slowly warmed to room temperature and stirred at that temperature for 19 hours. Upon completion of the reaction, the reaction was quenched by the addition of an aqueous ammonium chloride solution and the reaction mixture was subsequently concentrated to give a brown residue. The crude product was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by column chromatography on silica gel (100 g) using hexane/acetone (3/1) as eluent, resulting in 356 mg (15% yield) of 1'-BOC-5-fluoro-1,2-dihydro-2-oxo-spiro[3H-indole-3,4'-piperidine] as a light brown slurry. The product was confirmed by 1H-NMR (CDCl3) and mass spectrometry (ESI): 1H-NMR (CDCl3) δ 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)- .

References

[1] Patent: WO2005/92858, 2005, A2. Location in patent: Page/Page column 60
[2] Patent: WO2014/60411, 2014, A1. Location in patent: Page/Page column 40