Pyrrolidine → tert-Butyl 6-fluoro-4-oxo-3,4-dihydro-1'H-spiro[1-benzopyran-2,4'-piperidine]-1'-carboxylate

HRID 1908044Notes

Reaction equation

HRID 1908044 reaction equation
[O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.N1CCCC1.[F:20][C:21]1[CH:22]=[CH:23][C:24](O)=[C:25]([C:27](=[O:29])[CH3:28])[CH:26]=1>CO>[F:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][CH:22]=1)[O:1][C:2]1([CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)[CH2:28][C:27]2=[O:29]

Participants

5

Reactant 3

HCID 31268PyrrolidineHCID 959922-Acetyl-4-fluorophenolHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylate

Product 1

HCID 11759463tert-Butyl 6-fluoro-4-oxo-3,4-dihydro-1'H-spiro[1-benzopyran-2,4'-piperidine]-1'-carboxylateYield 67%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.1 g, 60.9 mmol) in pyrrolidine (7.3 mL, 87.2 mmol) and anhydrous methanol (16.5 mL) was added 1-(5-fluoro-2-hydroxy-phenyl)ethanone (9.3 g, 60.7 mmol). The reaction mixture was stirred at 80° C. for 2.5 hours. The methanol was removed under reduced pressure and the resulting residue was dissolved in ethyl acetate (150 mL), washed with 1N HCl (1×150 mL) and brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow oil. The oil was diluted with hexanes (400 mL) and was heated at 60° C. until in solution. Once dissolved, the solution was allowed to cool to 25° C. The crystals were collected via vacuum filtration, rinsed with hexanes to obtain tert-butyl 6-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (13.6 g, 67%) as a light yellow solid. ESI-MS m/z calc. 335.2. found 336.7 (M+1)+. Retention time 1.85 minutes (3 min run).

Workup

  1. customThe methanol was removed under reduced pressure
  2. dissolutionthe resulting residue was dissolved in ethyl acetate (150 mL)
  3. washwashed with 1N HCl (1×150 mL) and brine (2×100 mL)
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto yield a yellow oil
  8. temperaturewas heated at 60° C. until in solution
  9. dissolutionOnce dissolved
  10. temperatureto cool to 25° C
  11. filtrationThe crystals were collected via vacuum filtration
  12. washrinsed with hexanes

Sources & evidence

ORD record
ord-3a455becc6904ec5a13c43105cd349fb
Source dataset
uspto-grants-2013_12
Patent number
US08598164B2

Reaction notes

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