Water → 4-(2-Fluorophenyl)-1-methylpiperidin-4-OL

HRID 647526Notes

Reaction equation

HRID 647526 reaction equation
C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.O>O1CCCC1>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:18]1([OH:21])[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1

Participants

6

Reactant 4

HCID 962WaterHCID 612591-Bromo-2-fluorobenzeneHCID 740491-Methyl-4-piperidoneHCID 178418339Butyllithium

Product 1

HCID 126940234-(2-Fluorophenyl)-1-methylpiperidin-4-OL

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

46 ml of 2.4 M n-butyllithium are added over a 15 minute span to a mixture cooled to -70° C. of 17.5 g of 2-bromofluorobenzene and 50 ml of tetrahydrofuran. After total addition, the reaction mixture is stirred at between -60° to -70° C. for 15 minutes to enable complete lithiation, which results in a tan colored solution. A mixture of 11.3 g of 1-methyl-4-piperidone in 20 ml of tetrahydrofuran is added to the solution at a rate to maintain the reaction medium's temperature below -60° C. After total addition, the reaction mixture is stirred at the same low temperature for one hour before being permitted to warm to ambient temperature. Water is added and the biphasic mixture is permitted to separate into its organic and aqueous phases. The organic phase is collected and the aqueous phase is extracted thrice with ether and the ether extracts are combined with the organic phase. The combined organic solution is extracted with an excess of 2 N hydrochloric acid and then discarded. The acidic solution is basified with ammonium hydroxide, producing a heavy oil which is dissolved in a 1:1 ethyl acetate ether mixture. This solution is dried and then concentrated to dryness, leaving a viscous oil which crystallizes with cooling. The solid product is recrystallized from a benzene-hexane mixture to give prisms, mp 127°-129° C. of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine.

Workup

  1. additionAfter total addition
  2. customresults in a tan colored solution
  3. additionis added to the solution at a rate
  4. temperatureto maintain the reaction medium's temperature below -60° C
  5. additionAfter total addition
  6. stirringthe reaction mixture is stirred at the same low temperature for one hour
  7. customto separate into its organic
  8. customThe organic phase is collected
  9. extractionthe aqueous phase is extracted thrice with ether
  10. extractionThe combined organic solution is extracted with an excess of 2 N hydrochloric acid
  11. customproducing a heavy oil which
  12. customThis solution is dried
  13. concentrationconcentrated to dryness
  14. customleaving a viscous oil which
  15. customcrystallizes
  16. temperaturewith cooling
  17. customThe solid product is recrystallized from a benzene-hexane mixture

Sources & evidence

ORD record
ord-68ffb73277fe414889b8f801a5b75c35
Source dataset
uspto-grants-1983_10
Patent number
US04409229

Reaction notes

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