Potassium tert-butoxide → Tert-butyl 4,4-difluoro-3-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate

HRID 712993Notes

Reaction equation

HRID 712993 reaction equation
[CH3:1]C(C)([O-])C.[K+].Br[C:8]([F:28])([F:27])[C:9]([NH:11][CH2:12][C:13]1(O)[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:10]>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[F:27][C:8]1([F:28])[CH2:1][C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:12][NH:11][C:9]1=[O:10]

Participants

6

Reactant 2

HCID 23665647Potassium tert-butoxideHCID 57988980tert-Butyl 4-((2-bromo-2,2-difluoroacetamido)methyl)-4-hydroxypiperidine-1-carboxylate

Product 1

HCID 68291888Tert-butyl 4,4-difluoro-3-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylateYield 31%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

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-1-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 NH4Cl and ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, 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, 1.11 mmol, 31%) as a white solid. ESI-MS m/z calc. 306.1. found 307.5 (M+1)+; Retention time: 1.32 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) 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).

Workup

  1. customThe organic layer was separated
  2. washwashed with brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. temperatureSilica gel chromatography (40 g silica, 30-100% ethyl acetate/hexane, product visualized by TLC with ninhydrin staining+heat)

Sources & evidence

ORD record
ord-4cf4859811b94776b473d762f3b0508f
Source dataset
uspto-grants-2015_11
Patent number
US09181273B2

Reaction notes

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