(1-Benzyl-4,4-difluoropiperidin-3-yl)methanol synthesis

Yield:1303973-25-2 58.1 g

Reaction Conditions:

with lithium aluminium tetrahydride in tetrahydrofuran at 5;

Steps:

Intermediate 27: [4,4-Difluoro-1-(phenylmethyl)-3-piperidinyl]methanol

Intermediate 27: [4,4-Difluoro-1-(phenylmethyl)-3-piperidinyl]methanol
Ethyl 4,4-difluoro-1-(phenylmethyl)-3-piperidinecarboxylate (65.0 g, 0.230 mol) was dissolved in THF (900 ml).
The solution was cooled to 5° C., and lithium aluminium hydride (8.7 g, 0.230 mol, 1.0 eq) (Alfa) added in portions over 1 h, with the temperature kept below 5° C.
The mixture was removed from the cooling, and stirred for a further 90 min.
Once ¹H NMR confirmed the absence of starting material, the reaction mixture was cooled to below 5° C., and ethyl acetate (325 ml) added (slightly exothermic), followed by saturated sodium potassium tartrate solution (solid NaK tartrate from Aldrich, 1 L) (exothermic, bubbles a lot).
The quenched mixture was allowed to reach room temperature and dichloromethane (1.5 L) added.
The mixture was stirred overnight then transferred to a separating funnel, and the layers separated.
The aqueous layer was extracted with dichloromethane (1.0 L), and the combined organic layers dried (MgSO₄), and the solvent evaporated to give the product as a pale yellow oil (58.1 g).
GC 8.46 min.

References:

US2014/5188,2014,A1 Location in patent:Paragraph 0639; 0640; 0641