Hydrochloric Acid → HCID 18793463, compound

HRID 406480Notes

Reaction equation

HRID 406480 reaction equation
C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH:23]([CH3:28])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[NH4+].[OH-]>CCCCCC.CCOCC>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)([OH:27])[CH:23]([CH3:28])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 99931-Bromo-4-fluorobenzeneHCID 14923Ammonium HydroxideHCID 5609651-Benzyl-3-methyl-4-piperidoneHCID 178418339Butyllithium

Product 1

HCID 18793463HCID 18793463, compoundYield 84.2%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent4×HCID 8058HexaneSolvent

Conditions

Temperature
-50 °C

Procedure

To a solution of n-butyllithium (1-2 equivalents, preferably 1.1 equivalents) (1.6 M in hexane, 8.6 ml, 13.76 mmol) in Et2O (10.32 mL) was added a solution of 1-bromo-4-fluorobenzene (2.21 g, 12.63 mmol) in Et2O (5 ml) at about −50° C. After the reaction mixture was stirred at about −50° C. for about 40 min, a solution of 1-benzyl-3-methylpiperidin-4-one (2.00 g, 9.84 mmol) in Et2O (7 mL) was added dropwise. The mixture was allowed to warm up to about −20° C. to 0° C. (preferably −10° C.). 1M hydrochloric acid (20 mL) was added and the organic phase was discarded. Et2O (20 mL) was added to the aqueous solution and aqueous NH4OH was added to the solution until pH>9. The organic layer was separated and the aqueous layer was extracted with DCM (20 mL), The combined organic portions were washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 1-benzyl-4-(4-fluorophenyl)-3-methylpiperidin-4-ol (2.48 g, 84%) as an oil which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method a) Rt 1.63 min; m/z: (M+H)+ 300.

Workup

  1. temperatureto warm up to about −20° C. to 0° C. (preferably −10° C.)
  2. additionwas added to the solution until pH>9
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with DCM (20 mL)
  5. washThe combined organic portions were washed with brine (2×10 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-95345ab315f14d0281bad4e14488c3e8
Source dataset
uspto-grants-2014_06
Patent number
US08754107B2

Reaction notes

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