Synthesis and Effects of PCP Analogs

A review by John Q. Beagle

Disclaimer: The compounds described in this article are powerful drugs. As with any drug, they should not be ingested without full understanding of their potential effects. More so than other recreational drugs, these compounds have the potential to produce dangerously disoriented states of consciousness. The synthetic procedures presented here are given for informational purposes only. Some of the steps presented are potentially dangerous for novice or under equipped chemists, and some of the compounds described are scheduled drugs, and therefore illegal to manufacture without proper licensing.

Contents:

Section I. Background information:

1. Structure of PCP and its analogs.
2. Structures of other compounds with PCP-like effects.
3. Historical background of PCP.
4. Clinical use and pharmacology.
5. Illicit use and subjective effects.

Section II. Known methods for synthesis of PCP analogs:

1. General overview of methods:
2. Methods I-III. Commonly used routes:
   1. Method I: Use of nitrile intermediates such as PCC:
      1. Overview of the two steps in the reaction scheme.
      2. Step 1. Synthesis of PCC- two possible methods.
      3. Step 2. Reaction of PCC with a Grignard reagent.
   2. Method II: Use of enamine intermediates:
      1. General description and reaction scheme.
      2. Details of the synthesis of PCP via an enamine.
   3. Method III: Use of imine intermediates:
      1. Overview of reaction.
      2. Example: Synthesis of PCE, the N-ethyl analog of PCP.
3. Methods IV-VI. Use of PCA (1-phenyl-cyclohexylamine) intermediate:
   1. Method IV: Use of an azide intermediate:
      PCA via PCOH (1-phenyl-1-cyclohexanol).
   2. Method V: The Ritter reaction:
      PCA from PCOH or 1-phenylcyclohexene.
   3. Method VI: Use of phenylacetonitrile:
      Formation of the cyclohexane ring by alkylation and hydrolysis/rearrangement to PCA.
4. Method VII: Use of N-benzoyl piperidine:
   Reaction with organometallic derivative of 1,5-dibromopentane to produce PCP.

Section III. Synthesis of PCP precursors:

1. Cyclohexanone:
   by the oxidation of cyclohexanol.
2. Piperidine:
   by reduction of pyridine.

Section IV. Synthesis of ketamine:

1. Overview of synthesis:
2. Detailed procedure:

Section V. Structure-Activity Relationships (SAR) of PCP analogs:

1. Background.
   biological evaluation of analogs.
2. Structural modifications of PCP:
   1. Alterations to the piperidine ring
      1. Non cyclic alkyl substituents.
      2. Cyclic alkylamines.
   2. Alterations to the aromatic (phenyl) ring:
      1. Addition of substituents to the phenyl ring.
      2. Replacements of phenyl by other aromatic rings.
   3. Alterations to the cyclohexane ring:
      1. Changes in ring size.
      2. Addition of substituents.

Section VI. Recent Research on PCP analogs:

1. Overview
2. Dopamine receptors:
   analogs that bind to a novel site on the dopamine transporter.
3. Sigma receptors:
   relationship to PCP pharmacology.
4. Opiate receptors:
   analogs with analgesic potential.
5. References