Reaction Scheme III. Synthesis via imines:

This is the best route for synthesis of compounds with mono N-alkyl substituents, such as PCE (ref. 10). An intermediate imine is formed by the reaction of cyclohexanone and the appropriate primary amine. The phenyl group can then be introduced with phenyllithium (ref 15, 16). This route gives an overall yield of ~60%, with a difficulty rating of 2 out of 10 and a hazard rating of 3 out of 10 (ref. 64).

The monoalkyl analogs produced by this method can be further transformed to dialkyl derivatives if desired, by formylation or acetylation and reduction. Another variation on this route by which N,N-dialkyl analogs can be formed is the reaction of the intermediate imine with an alkyl halide to give a quaternary salt. This salt, upon reaction with phenyllithium gives the mixed N,N-dialkyl derivative of PCP (ref 10, 11). Another variation utilizes a primary amine and cyclohexanone, and traps the imine as a nitrile intermediate as in Scheme I (ref. 57).

PCE, as well as its N-methyl and N-propyl analogs have been produced in clandestine labs by this method. These analogs were of some popularity in the illicit drug trade during the1970's, but are now encountered infrequently.



Example: Synthesis of PCE (N-ethyl-1-phenylcyclohexylamine):

A mixture of 100 g of anhydrous ethylamine and 220 g of cyclohexanone was kept 16 hours, then shaken with solid KOH. The lower oil layer, which comprises the imine ( N-cyclohexylidenethylamine), was then removed by decantation. This intermediate is best used crude, but it can be distilled under good vacuum (bp 68-75 C at 22 mm Hg). The imine has also been prepared in illicit labs by stirring the amine and cyclohexanone in ether or toluene containing anhydrous sodium sulfate, followed by filtration.

Next, a solution of phenyllithium was prepared by adding 11 g of lithium metal slowly to 76 ml bromobenzene in 500 ml of ether. This was added dropwise to a solution of 51 g of the N-cyclohexylidenethylamine in 500 ml of ether, with stirring and cooling to keep the temp at 0 deg C. The mixture was heated to reflux with stirring for one hour, and then decomposed by addition of water. The ether layer was separated, washed with water, and extracted into dilute HCl. The acid layers were basified with NaOH and extracted back into organic solvent. The solvent can now be evaporated to yield N-ethyl-1-phenylcyclohexylamine (PCE) freebase. This can be purified by vacuum distillation (bp 104-108 at 2.5 mm Hg).

The HCl salt of PCE can be prepared by dissolving the base in isopropanol, gassing with HCl, and adding ether slowly to precipitate the salt. The salt can be purified by recrystallization from a mixture of isopropanol and ether (mp 236-237 C).

 Next Section: PCP via phenylcyclohexylamine (PCA)

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