Synthesis of benzo-condensed cyclic cathinone derivatives

Recently, the number of new psychoactive substances (NPS), which are sold as legal alternatives to conventional or misused drugs, has been growing on the market. Via small chemical modifications in the basic structure of the already banned substances, new derivatives are made. Although they pose a real threat to human health, they do circumvent regulation system. This fact led us to formulate the aim of this work, which is the synthesis of cyclic derivatives of cathinones, substances that are derived from natural substance S-cathinone. All commercial reagents and solvents were used without additional purification. 1H NMR and 13 C NMR spectra measured for structure conformation were acquired on an Agilent 400-MR DDR2 spectrometer with CDCl3 or CH3OD as the solvent. Cyclic derivatives of cathinone with different size of benzo-condensed ring were prepared using different synthetic approaches optimised to maximum possible yields. The first intermediate with a six membered condensed ring was synthesised using a nucleophilic addition of an aryllithium on cyclobutanone to form corresponding cyclobutanol derivative. This alcohol was transferred to an α-tetralone system using a radical cyclization reaction with potassium peroxodisulfate and silver nitrate. A cycliclization reaction of differently substituted 4-arylbutanoic acids employing polyphosphoric acid was used as a second approach. Also, five and four membered condensed ring derivatives were synthesised using two different approaches. The first approach was based on Friedel-Crafts acylation, where phenylpropanoic and phenylethanoic acid were converted to chlorides using oxalyl chloride, then using aluminium (III) chloride as a catalyst the intramolecular ring-closing reaction was completed. The second approach was cyclization of acids by means of thionyl chloride and trifluoromethanesulfonic acid. The benzocycloheptane ring was prepared using all cyclization reactions mentioned above. All the above-described intermediates were subsequently subjected to the sequence of reactions to prepare the final derivatives. A reaction of cyclic ketones with isoamyl nitrite provided oximes which were reduced with zinc dust in acetic acid to form acetamides. These acetamides were hydrolysed using hydrochloric acid yielding corresponding amines. These amines were transformed to trifluoroacetamides, which were methylated using iodomethane and the final step, acid hydrolysis gave rise to the target N-methylated cyclic derivatives. Different approaches towards the synthesis of benzocondensed bicyclic ketones with various sizes of the aliphatic ring are presented. These compounds have been used as intermediates to prepare new cyclic cathinones and their formal metabolites (N-demethylated derivatives). All the novel substances are fully characterized and, moreover, the possibility of their chiral separation using HPLC is being studied to assign their absolute configuration and study the biological activity of enantiomers.