Attempted synthesis of iodomethamphetamine with the use of protecting group chemistry

Abstract

Methamphetamine was first introduced for therapeutic purposes but eventually became a recreational drug. Due to extensive use and over prescription in World War II, side effects were noticed that lead to regulation and eventual criminalisation of methamphetamine use. This led to the establishment of clandestine laboratories with the purpose of illicitly producing methamphetamine. Since then, discovery and dismantlement of clandestine laboratories has become commonplace in Aotearoa and around the world. It was reported in 2019, that the social harm caused by the abuse of methamphetamine equated $1 billion a year. Iodomethamphetamine is an impurity that may be formed during the most common methods for clandestine synthesis of methamphetamine reported in New Zealand. Due to its thermal instability, iodomethamphetamine is likely to only be found at sites of clandestine laboratories and not at sites of methamphetamine use (as methamphetamine is commonly smoked). This presents the opportunity for the use of iodomethamphetamine as analytical marker for clandestine synthesis of methamphetamine. Attempted synthesis of iodomethamphetamine was done using protecting group chemistry with the t-Boc, triazene, trityl, mesyl and tosyl protecting groups. Use of the t-Boc protecting group lead to an SN2 intramolecular cyclisation reaction which resulted in formation of oxazolidinones. Tosyl and mesyl protections as well as attempts at direct dehydroxylation and iodination also led to oxazolidines being formed as the major product with some aziridines being identified in the tosylation reaction. The triazene and trityl protecting groups were later selected as an N-protecting groups in an attempt to avoid these by-products. Direct dehydroxylation and iodination of (4-bromophenyl)triazene protected ephedrine with diiodoethane was attempted as a way to directly synthesise the (4-bromophenyl)triazene protected iodomethamphetamine product. However, this method led to the deprotection of the triazene protecting group due to the formation of protons in the reaction. When the hindered base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added to the reaction, deprotection was still observed. Addition of the hindered base 2,6-lutidine to the reaction resulted in the starting material ((4-bromophenyl)triazene protected ephedrine) being observed. Analysis of the samples in this study was done using GC-MS, 1H NMR spectrometry, 13C NMR spectrometry and Positive-mode High Resolution Mass Spectrometry ((+)-HRESIMS). Due to ii the suspected thermal instability of both the triazene protected ephedrine and iodomethamphetamine, analysis of these products was limited to NMR analysis and HRESIMS.