Water → (-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methylpiperidine

HRID 1278520Notes

Reaction equation

HRID 1278520 reaction equation
[Li+].[Cl-].C([O:5][C:6]([C@H:8]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][C:11](=O)[N:10]([CH3:22])[C:9]1=O)=O)C.O.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:13]2[CH2:12][CH2:11][N:10]([CH3:22])[CH2:9][C@H:8]2[CH2:6][OH:5])=[CH:15][CH:16]=1

Participants

7

Reactant 4

HCID 962Water2×HCID 14798Sodium HydroxideHCID 433294Lithium Chloride2×HCID 15405466trans-3-Ethoxycarbonyl-4-(4'-fluorophenyl)-1-methylpiperidine-2,6-dione2×

Product 1

HCID 2734218(-)-trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methylpiperidine

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 8028TetrahydrofuranSolvent2×

Procedure

To a cooled mixture of NaAlH4 (0.22 mol) in toluene is added LiCl (0.11 mol) in THF. Note: LiCl can be added to the reactor prior to the addition of NaAlH4 or after the addition of the substrate, (+/−)trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione. Next, (+/−)trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) is added in THF (65 ml) holding the temperature below 15° C. After addition is completed, reaction is allowed to warm to room temperature. After 30 minutes at room temperature, the reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene. The filtered solution is then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and similar impurity profile as with LiAlH4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.

Workup

  1. customthe temperature below 15° C
  2. additionAfter addition
  3. customreaction
  4. temperaturethe reaction is heated to >40° C. for 2 hr
  5. temperatureThe reaction is then cooled to <5° C.
  6. customthe temperature below 15° C
  7. customThe solid inorganic salts are removed by filtration
  8. washThese solids are washed with additional THF or toluene
  9. concentrationThe filtered solution is then concentrated

Sources & evidence

ORD record
ord-10b6824bcbc0490f9bb5c5e5887e5132
Source dataset
uspto-grants-2002_09
Patent number
US06444190B2

Reaction notes

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