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

HRID 2204129Notes

Reaction equation

HRID 2204129 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 1 N 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 1 N 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-ca724282dc6141dfaa4caf2530459c2b
Source dataset
uspto-grants-2016_06
Patent number
US09365588B2

Reaction notes

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