Indole cannabimimetics, commonly referred to as �Spice,� are psychoactive designer drugs created to mimic the effects of cannabis. Illegal use and abuse of these synthetic cannabinoids has created a need for certified reference standards to identify and quantitate these drugs in clinical and forensic samples. Additionally, due to their fast metabolism in vivo, the preparation of the major metabolites and their stable-isotope labeled internal standards is of high priority.  Herein, a regioselective, highly efficient synthesis of cannabimimetic indole metabolites is reported.  Reaction of 4-substituted naphthoic acids and 2-methoxyphenylacetic acid with thionyl chloride afforded naphthoyl chlorides and phenylacetyl chlorides, respectively, in quantitative yields. These acyl chlorides were then utilitized in a Friedel-Crafts type regioselective acylation of indole/indole-D7 to give exclusively 3-substituted acyl indoles in 45-80 % yields.  While there are alternative acylation methods reported in the literature, these methods tend to be problematic and low yielding. The current method provides both mild acylation conditions and comparatively high yields.  These resulting 3-acylindoles were N-alkylated under mild conditions with 1-bromo-4-pentanol to give JWH-250, JWH-122, JWH-210 cannabinoid metabolites.  

Regioselective Friedel Crafts type  acylation of indoles: An improvement on the synthesis of cannabimimetic indole metabolites

247th National Meeting (2014)

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