Hydrochloric Acid → 1'-(4-Methoxy-3-(trifluoromethyl)benzoyl)spiro[chroman-2,4'-piperidin]-4-one

HRID 2204108Notes

Reaction equation

HRID 2204108 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].N1CCCC1.[CH3:16][O:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)=[O:23])=[CH:20][C:19]=1[C:33]([F:36])([F:35])[F:34].Cl>ClCCl.C(OCC)(=O)C.CO>[CH3:16][O:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([N:24]2[CH2:25][CH2:26][C:27]3([CH2:9][C:8](=[O:10])[C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=4)[O:1]3)[CH2:28][CH2:29]2)=[O:23])=[CH:20][C:19]=1[C:33]([F:36])([F:34])[F:35]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 83752'-HydroxyacetophenoneHCID 31268PyrrolidineHCID 58551177HCID 58551177, compound

Product 1

HCID 585510781'-(4-Methoxy-3-(trifluoromethyl)benzoyl)spiro[chroman-2,4'-piperidin]-4-oneYield 79%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

1-(2-Hydroxyphenyl)ethanone (1.80 g, 13.3 mmol) was added portion wise at 25° C. to pyrrolidine (2.20 mL, 26.6 mmol) followed by portion-wise addition of 1-(4-methoxy-3-(trifluoromethyl)benzoyl)piperidin-4-one (4.00 g, 13.3 mmol). Anhydrous methanol (868 μL) was then added and the red slurry was heated at 80° C. for 3 hours. The reaction was cooled to 25° C. and was stirred overnight. Ethyl acetate (5 mL) and 1M HCl (aq, 5 mL) were added. The aqueous layer was separated and discarded. 1M NaOH (aq, 5 mL) was added and the aqueous layer was separated and discarded. A brine solution was added (10 mL) and the aqueous layer was separated and discarded. The organic layer was dried over Na2SO4, filtered and the solvent was evaporated to provide an oil. The crude oil was dissolved in dichloromethane and was purified by column chromatography using 0-50% ethyl acetate/hexanes to provide 1′-(4-methoxy-3-(trifluoromethyl)benzoyl)spiro[chroman-2,4′-piperidin]-4-one (4.4 g, 79%) as a off-white solid. ESI-MS m/z calc. 419.4, found 420.2 (M+1)+. Retention time: 2.63 minutes (4 min run).

Workup

  1. temperatureThe reaction was cooled to 25° C.
  2. customThe aqueous layer was separated
  3. addition1M NaOH (aq, 5 mL) was added
  4. customthe aqueous layer was separated
  5. additionA brine solution was added (10 mL)
  6. customthe aqueous layer was separated
  7. dry with materialThe organic layer was dried over Na2SO4
  8. filtrationfiltered
  9. customthe solvent was evaporated
  10. customto provide an oil
  11. customwas purified by column chromatography

Sources & evidence

ORD record
ord-3da8b383e3644a60b8b38ba157ca5152
Source dataset
uspto-grants-2016_06
Patent number
US09365588B2

Reaction notes

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