Mannich reaction of acetylcyclohexane (V), paraformaldehyde and 1-norephedrine (I) in the presence of hydrochloric acid yields alifedrine hydrochloride. Mannich reaction of 1-acetylcyclohexene (VI) with paraformaldehyde and (I) followed by catalytic hydrogenation of the resulting beta-aminoketone (III) also gives alifedrine hydrochloride.
For [14C]-labelling of alifedrine, the following reaction sequence has been used: In the first step Friedel-Crafts'-like acylation of ethylene (A) with cyclohexanoyl chloride (VII) in the presence of aluminum chloride yields beta-chloroethylcyclohexyl ketone (VIII), which reacts with (I) to give alifedrine hydrochloride. Alifedrine has also been synthesized by catalytic hydrogenation of (V) with 1-norephedrine (I) in the presence of hydrochloric acid and paraformaldehyde.
Alifedrine hydrochloride can be synthesized by condensation of acetylcyclohexane with the bisoxazolidine (IV), which is obtained by reaction of (I) with paraformaldehyde in aqueous solution. Finally, alifedrine can be obtained by condensation of 3-oxo-3-cyclohexylpropanal (X) and norephedrine (I) under reducing conditions (VI).