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

HRID 1278517Notes

Reaction equation

HRID 1278517 reaction equation
C([O:3][C:4]([C@H:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C:9](=O)[N:8]([CH3:20])[C:7]1=O)=O)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:11]2[CH2:10][CH2:9][N:8]([CH3:20])[CH2:7][C@H:6]2[CH2:4][OH:3])=[CH:13][CH:14]=1

Participants

7

Reactant 4

HCID 962Water2×HCID 1140TolueneHCID 14798Sodium HydroxideHCID 15405466trans-3-Ethoxycarbonyl-4-(4'-fluorophenyl)-1-methylpiperidine-2,6-dione

Product 1

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

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 22635083Tetrahydrofuran tolueneSolvent

Procedure

To a cooled solution of NaAlH4 (0.22 mol) in toluene/THF under argon was added (+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15° C. After addition was complete, reaction was allowed to warm to room temperature. After 30 minutes at room temperature, the reaction was heated to >40° C. for 2 hr. The reaction was then cooled to <5° C. and toluene (50 ml) was added. Water (9 ml) was then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH were used as necessary. The solid inorganic salts were removed by filtration. These solids were washed with additional THF or toluene. The filtered solution was then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in lower yield (but 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. additionAfter addition
  2. customreaction
  3. temperaturethe reaction was heated to >40° C. for 2 hr
  4. temperatureThe reaction was then cooled to <5° C.
  5. customthe temperature below 15° C
  6. customThe solid inorganic salts were removed by filtration
  7. washThese solids were washed with additional THF or toluene
  8. concentrationThe filtered solution was then concentrated

Sources & evidence

ORD record
ord-575733b9661e402ab01bcd528da08b40
Source dataset
uspto-grants-2002_09
Patent number
US06444190B2

Reaction notes

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