Hydrochloric Acid → 4-(1-Methyl-4-phenyl-1H-imidazol-2-yl)-piperidin-4-ol dihydrochloride

HRID 419734Notes

Reaction equation

HRID 419734 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C([Li])CCC.C(OC([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)=O)(C)(C)C.[ClH:32]>O1CCCC1.C(Cl)Cl.[Cl-].[Na+].O.O1CCOCC1.CO>[ClH:32].[ClH:32].[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[C:28]1([OH:31])[CH2:29][CH2:30][NH:25][CH2:26][CH2:27]1

Participants

10

Reactant 4

HCID 313Hydrochloric Acid2×HCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 27487821-methyl-4-phenyl-1H-imidazoleHCID 178418339Butyllithium

Product 1

HCID 666499444-(1-Methyl-4-phenyl-1H-imidazol-2-yl)-piperidin-4-ol dihydrochloride

Reagents, catalysts & solvents 5

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×HCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
-78 °C

Procedure

Dissolve 1-methyl-4-phenyl-1H-imidazole (9.05 mmoles; 1.43 g) in anhydrous tetrahydrofuran (30.00 mL) and the mixture cooled to −78° C. Slowly add n-butyl lithium (1.30 equiv; 11.77 mmoles; 7.35 mL) (1.6M in hexanes) and the reaction stirs at −78° C. for 30 minutes then add a THF (20 mL) solution of N-T-butoxycarbonyl-4-piperidone (11.77 mmoles; 2.34 g) dropwise over 20 min. Allow to stir overnight with warming to room temperature. Dilute with DCM and saturated aq. sodium chloride/water (50/50), (2×DCM), then dry over MgSO4. Filter and concentrate to 3.8 g crude yellow oil. Purify the reaction by using ISCO chromatography over a Biotage 40M column eluting with 50:50 EtOAc:Hex at a flow rate of 40 mL/min. Concentrate product fractions to 2.00 g of 4-hydroxy-4-(1-methyl-4-phenyl-1H-imidazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white solid. ES-MS (M+H)=358.3. Dissolve it in 5 mL dichloromethane and add hydrogen chloride (20.00 mmoles; 5.00 mL)(4M in dioxane) slowly at room temperature. After approximately 5 min the solution becomes cloudy and add 3 mL of methanol to get the reaction back into solution. After 1 h the reaction is 95% complete. Add 1 mL of 4M HCl in dioxane and stir 15 min. Concentrate to 2.1 g of 4-(1-Methyl-4-phenyl-1H-imidazol-2-yl)-piperidin-4-ol dihydrochloride as a light yellow solid. MS(ES): (m/z)=258.3 [M+H].

Workup

  1. temperaturewith warming to room temperature
  2. dry with materialthen dry over MgSO4
  3. filtrationFilter
  4. concentrationconcentrate to 3.8 g crude yellow oil
  5. customPurify
  6. customthe reaction
  7. washeluting with 50:50 EtOAc
  8. dissolutionDissolve it in 5 mL dichloromethane
  9. waitAfter approximately 5 min the solution becomes
  10. customto get
  11. customthe reaction back into solution
  12. waitAfter 1 h the reaction is
  13. stirringstir 15 min
  14. concentrationConcentrate to 2.1 g of 4-(1-Methyl-4-phenyl-1H-imidazol-2-yl)-piperidin-4-ol dihydrochloride as a light yellow solid

Sources & evidence

ORD record
ord-e9c535f3383c4d678349c71adc4f8526
Source dataset
uspto-grants-2012_01
Patent number
US08093383B2

Reaction notes

Loading…