Impurity profiling and synthesis of a series of analogues and isomers of Bromo-DragonFLY

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Jones, Roisin Anne
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University College Cork
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BromoDragon-FLY (BDF) is a highly hallucinogenic amphetamine that fits into a category known as New Psychoactive Substances (NPS), a group of illicit drugs which has risen to prominence in the last two decades. The most common route to making amphetamine-type stimulants (ATS) in clandestine laboratories is the Leuckart reaction, which converts a precursor ketone to the desired amine. The Leuckart reaction produces characteristic route-specific impurities that can facilitate the identification of the synthetic pathway employed. The Leuckart impurities typically present in the highest yield are isomeric benzyl and phenyl pyrimidines. The aim of this thesis work was first to independently synthesise, isolate and characterise a series of pyrimidines related specifically to the Leuckart synthesis of BDF, and then to use those pyrimidines as analytical standards in HPLC analysis of the corresponding Leuckart reactions. In addition to the pyrimidines, an isomeric impurity in the synthesis of a BDF precursor was also targeted as a potential impurity in BDF (though not related to the Leuckart reaction specifically): the independent synthesis, isolation and characterisation of this isomeric impurity was also a key aim of this thesis work in order to contribute to the overall understanding of the potential impurity profile of BDF. There are three synthetic steps from a 2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b′]difuran (THBD) ketone precursor to BDF: bromination, aromatisation and the Leuckart reaction. Depending on the order that these steps are performed in, there are eight potential pyrimidine impurities arising from the formation of BDF. In this work, seven of these eight pyrimidines are independently synthesised and fully characterised (by 1H/13C nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy and mass spectrometry (MS)) as analytical standards, using palladium-catalysed coupling reactions. Several alternate synthetic pathways to the pyrimidines are also explored, and although none of these alternate routes were successful, a number of novel compounds were successfully isolated and characterised. As mentioned, there are three steps to BDF from THBD which can be carried out in any order: four Leuckart reactions were completed to simulate each of the possible synthetic routes from THBD to BDF. Impurity profiling was carried out by high-performance liquid chromatography (HPLC) analysis, using the previously synthesised analytical standards and the crude reaction mixtures generated during the Leuckart reactions. This work determined that the pyrimidine impurities generated during the Leuckart reaction are detectable and distinguishable by HPLC, making them useful route-specific markers for the Leuckart reaction. Previous work in our group discovered that during the bromination of the phenyl core en route to THBD, a small percentage of the 2,3-dibromo isomer was formed in conjunction with the desired 2,5-dibromo isomer. When carried through the Grignard ring-closing step, an isomer of THBD was formed in < 1 % overall yield: 1,2,7,8-tetrahydrobenzo[1,2-b:4,3-b′]difuran (iTHBD). This isomer of THBD is not known in the literature, and was immediately identified as a compound of interest due to its status as a potential pharmacophore of unknown properties, and also as a potential impurity in illicitly sold BDF. To this end, a synthetic pathway was designed to produce iTHBD specifically, which was sucessfully carried out in ~ 5 % overall yield over four steps from p-benzoquinone starting material. This yield was significantly impacted by the formation of inseparable regioisomers in the second step of the synthetic pathway, but nonetheless represents an improvement over the yield seen when iTHBD is produced as a side-product in the synthesis of THBD.
Chemistry , Synthesis , Organic chemistry , Impurity profiling
Jones, R. A. 2019. Impurity profiling and synthesis of a series of analogues and isomers of Bromo-DragonFLY. PhD Thesis, University College Cork.