Hydrochloric Acid → 4-(4-Fluorophenyl)-3-methylpiperidine

HRID 406481Notes

Reaction equation

HRID 406481 reaction equation
C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(O)[CH:10]([CH3:22])[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH3:22])=[CH:16][CH:17]=1

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 18793463HCID 18793463, compound

Product 1

HCID 597646024-(4-Fluorophenyl)-3-methylpiperidineYield 66.5%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of 1-benzyl-4-(4-fluorophenyl)-3-methylpiperidin-4-ol (1.02 g, 3.41 mmol) in ethanol (18 mL) at 80° C. was added concentrated HCl (18 mL, 592 mmol). The reaction mixture was refluxed for 2 hour and then cooled to ambient temperature. The organic solvent was removed in vacuo. The aqueous solution was basified with concentrated NaOH to pH>9 then extracted with DCM (50 mL). The organic layer was washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in EtOH (2 mL) and acetic acid (0.2 mL). The reaction mixture was hydrogenated with Pd/C (10%) in an H-cube™ apparatus at 60° C. for 3 minutes. The solvent was removed in vacuo and the residue was purified by preparative RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate buffered to pH 4.5 for 2.5 min then 10% to 15% acetonitrile/0.05M aqueous ammonium acetate buffered to pH 4.5 over 4.0 min then 15% to 45% acetonitrile/0.05M aqueous ammonium acetate buffered to pH 4.5 over 4.0 min at 25 mL/min; APCI positive mode detection; Xterra prep. MS C18 19×50 mm column) to afford 4-(4-fluorophenyl)-3-methylpiperidine (0.438 g, 66%). RP-HPLC (Table 1, Method a) Rt 1.43 min; m/z: (M+H)+ 194.

Workup

  1. temperatureThe reaction mixture was refluxed for 2 hour
  2. customThe organic solvent was removed in vacuo
  3. extractionthen extracted with DCM (50 mL)
  4. washThe organic layer was washed with brine (2×10 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThe residue was dissolved in EtOH (2 mL)
  9. customThe solvent was removed in vacuo
  10. customthe residue was purified by preparative RP-HPLC (10% acetonitrile/0.05M aqueous ammonium acetate
  11. waitbuffered to pH 4.5 for 2.5 min
  12. wait10% to 15% acetonitrile/0.05M aqueous ammonium acetate buffered to pH 4.5 over 4.0 min
  13. wait15% to 45% acetonitrile/0.05M aqueous ammonium acetate buffered to pH 4.5 over 4.0 min at 25 mL/min

Sources & evidence

ORD record
ord-c75d3fdf3514454e97969d65377ea1ef
Source dataset
uspto-grants-2014_06
Patent number
US08754107B2

Reaction notes

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