Identification and synthesis of by-products found in 4-methylthioamphetamine (4-MTA) produced by the Leuckart method

The synthesis of the designer drug 4-methylthioamphetamine (4-MTA) has been carried out using the well-known Leuckart reaction in four versions. The treatment of 4-methylthiophenylacetone with formamide, mixture of formamide/formic acid, ammonium formate, and mixture of ammonium formate and formic acid followed by acid hydrolysis brought about the formation of 4-MTA contaminated with a number of impurities. The gas chromatography mass-spectrometry (GC-MS) analysis of the reaction mixtures allowed identification of the most prominent impurities, such as diasteromers of N,N-di-[beta-(4-methylthiophenyl)isopropyl]amine, N,N-di-[beta-(4-methylthiophenyl)isopropyl]methylamine, N,N-di-[beta-(4-methylthiophenyl)isopropyl]formamide, the Schiff bases derived from 4-MTA and 4-methylbenzaldehyde (benzaldimine) and 4-methylthiophenylacetone (ketimine) as well as some heterocycles: 4-methyl-5-(4'-methylthiophenyl)pyrimidine, 4-(4'-methylthiobenzyl)pyrimidine, 2,6-dimethyl-3,5-di-(4'-methylthiophenyl)pyridine, 2,4-dimethyl-3,5-di-(4'-methylthiophenyl)pyridine. The correctness of identification was confirmed by independent synthesis of these compounds. Each synthesized reference compound was characterized by means of MS, H-1 and C-13 NMR, and IR methods. The stereochemistry of (RR/SS) diasteromer of N,N-di-[beta-(4-methylthiophenyl)isopropyl]amine was confirmed by a crystallographic method. (C) 2011 Elsevier Ireland Ltd. All rights reserved.