Reaction #1365700

Reaction equation

NaOH

LiAlH4

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

toluene

→

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

Solvents

toluene THF

THF

H2O

Water

Conditions

Workup

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

Procedure

To a cooled solution of LiAlH4 (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, the reaction was allowed to warm to room temperature. After 30 minutes at room temperature reaction was heated to >40° C. for 2 hr. 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 was 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 higher yield (but similar impurity profile) as with NaAlH4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvent.

Source