9-Boc-2,2-difluoro-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecane synthesis

Yield:1179337-14-4 31%

Reaction Conditions:

with potassium tert-butylate in tetrahydrofuran at 70; for 0.583333 h;

Steps:

[00352] Step 2:[00353] To a stirring solution of potassium tert-butoxide (7.23 mL of 1 M, 7.23 mmol) in tetrahydrofuran (20 mL) at 70 °C was added a solution of tert-butyl 4-[[(2- bromo-2,2-difluoro-acetyl)amino]methyl]-4-hydroxy-piperidine-l-carboxylate (1.4 g, 3.62 mmol) in tetrahydrofuran (20 mL) over 15 min. After 20 min the reaction mixture was diluted with 1 : 1 brine/saturated NH₄CI and ethyl acetate. The organic layer was separated, washed with brine, dried over Na₂S0₄, filtered and concentrated in vacuo. Silica gel chromatography (40 g silica, 30-100%) ethyl acetate/hexane, product visualized by TLC with ninhydrin staining + heat ) provided tert-butyl 4,4-difluoro-3- oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (340 mg, 1.1 1 mmol, 31%) as a white solid. ESI-MS m/z calc. 306.1, found 307.5 (M+l)⁺; Retention time: 1.32 minutes (3 min run). NMR (400 MHz, DMSO-i? δ 9.00 (s, 1H), 3.75 (d, J = 13.3 Hz, 2H), 3.45 (d, J = 3.2 Hz, 2H), 3.07 (br s, 2H), 1.79 (d, J = 13.6 Hz, 2H), 1.72 - 1.60 (m, 2H), 1.41 (s, 9H).

References:

WO2012/125613,2012,A1 Location in patent:Page/Page column 132