Reaction #1365701

Reaction equation

toluene

H2O

NaOH

(+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione

Water

→

(+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine

Solvents

toluene THF

THF

Conditions

Workup

1. 1
   TemperatureTo a cooled 50
2. 2
   workup.ADDITIONAfter addition
3. 3
   OtherAfter 30 minutes at room temperature reaction
4. 4
   Temperatureis heated to >40° C. for 2 hr
5. 5
   OtherReaction
6. 6
   Temperatureis then cooled to <5° C.
7. 7
   Otherthe temperature below 15° C
8. 8
   OtherThe solid inorganic salts are removed by filtration
9. 9
   WashThese solids are washed with additional THF or toluene
10. 10
    ConcentrationThe filtered solution is then concentrated

Procedure

To a cooled 50:50 mole mixture of NaAlH4/LiAlH4 (0.22 mol) in toluene/THF under argon is 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 is complete, the reaction is allowed to warm to room temperature. After 30 minutes at room temperature reaction is heated to >40° C. for 2 hr. 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.

Source