Pyrrolidine → N-Boc-7-Fluorospiro[chromene-2,4'-piperidin]-4(3H)-one

HRID 1908053Notes

Reaction equation

HRID 1908053 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:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23](O)[CH:22]=1>CO>[F:20][C:21]1[CH:26]=[C:25]2[C:24]([C:27](=[O:29])[CH2:28][C:2]3([O:1]2)[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[CH:23][CH:22]=1

Participants

5

Reactant 3

HCID 31268PyrrolidineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 27373264'-Fluoro-2'-hydroxyacetophenone

Product 1

HCID 11013090N-Boc-7-Fluorospiro[chromene-2,4'-piperidin]-4(3H)-oneYield 21.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (7.5 g, 37.8 mmol) in pyrrolidine (4.5 mL, 54.1 mmol) and anhydrous methanol (10.2 mL) was added 1-(4-fluoro-2-hydroxy-phenyl)ethanone (5.8 g, 37.6 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, rinsing with hexanes to remove tert-butyl 4-oxo-7-pyrrolidin-1-yl-spiro[chromane-2,4′-piperidine]-1′-carboxylate (8.6 g), which was collected as light yellow solid; ESI-MS m/z calc. 386.2. found 387.2 (M+1)+; Retention time: 2.59 minutes (3 min run). The filtrate was concentrated and the residue was subjected to column chromatography (0-100% ethyl acetate/hexanes) to give tert-butyl 7-fluoro-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (2.7 g, 21%) as a light yellow solid; ESI-MS m/z calc. 335.2. found 336.2 (M+1)+; Retention time: 2.49 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J=8.6, 6.7 Hz, 1H), 6.80-6.62 (m, 2H), 3.88 (d, J=12.1 Hz, 2H), 3.21 (t, J=12.0 Hz, 2H), 2.71 (s, 2H), 2.02 (d, J=12.8 Hz, 2H), 1.62 (td, J=14.1, 4.8 Hz, 2H), 1.46 (s, 9H).

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. washrinsing with hexanes
  13. customto remove tert-butyl 4-oxo-7-pyrrolidin-1-yl-spiro[chromane-2,4′-piperidine]-1′-carboxylate (8.6 g), which
  14. customwas collected as light yellow solid
  15. customRetention time: 2.59 minutes (3 min run)
  16. concentrationThe filtrate was concentrated

Sources & evidence

ORD record
ord-df1ce629c86a444188068cb21eb6d249
Source dataset
uspto-grants-2013_12
Patent number
US08598164B2

Reaction notes

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