John D. Power

The identification of tert‐butyl‐4‐anilinopiperidine‐1‐carboxylate (4‐anilinopiperdine‐t‐BOC or 4‐AP‐t‐BOC) in many seized falsified ‘Xanax’ tablets has been reported after being encountered in forensic casework in late 2019 and early 2020 in Ireland. This substance was also detected in a pink powder submitted for analysis in March 2020. The pink powder was part of a larger seizure comprising brown powders which contained morphine or diamorphine (heroin) or a type of counterfeit heroin or heroin adulterant (known as ‘bash’). Novel benzodiazepines and other substances are being detected as ingredients in falsified benzodiazepine tablets more frequently on the illicit market. The detection of 4‐AP‐t‐BOC in benzodiazepine tablets is noteworthy and 4‐AP‐t‐BOC is added to the list of adulterants found in benzodiazepine tablets emerging in Europe. The presence of 4‐AP‐t‐BOC in both falsified ‘Xanax’ and powdered seizures is unusual, and analytical data are presented to assist with the identification of this compound in suspected illicit substances. The presence of 4‐AP‐t‐BOC in the tablets was confirmed using gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses, and spectral fragmentation pathways were suggested. To the authors' best knowledge, information about the biological activity of 4‐AP‐t‐BOC is not available. The removal of the t‐BOC protecting group yields 4‐anilinopiperidine which has been reported to be involved in the synthesis of fentanyl.

The availability of new psychoactive substances on the recreational drug market continues to create challenges for scientists in the forensic, clinical and toxicology fields. Phenmetrazine (3‐methyl‐2‐phenylmorpholine) and an array of its analogs form a class of psychostimulants that are well documented in the patent and scientific literature. The present study reports on two phenmetrazine analogs that have been encountered on the NPS drug market following the introduction of 3‐fluorophenmetrazine (3‐FPM), namely 4‐methylphenmetrazine (4‐MPM) and 3‐methylphenmetrazine (3‐MPM). This study describes the syntheses, analytical characterization and pharmacological evaluation of the positional isomers of MPM. Analytical characterizations employed various chromatographic, spectroscopic and mass spectrometric platforms. Pharmacological studies were conducted in order to assess whether MPM isomers might display stimulant‐like effects similar to the parent compound phenmetrazine. The isomers were tested for their ability to inhibit uptake or stimulate release of tritiated substrates at dopamine, norepinephrine and serotonin transporters using in vitro transporter assays in rat brain synaptosomes. The analytical characterization of three vendor samples revealed the presence of 4‐MPM in two of the samples and 3‐MPM in the third sample, which agreed with the product label. The pharmacological findings suggest that 2‐MPM and 3‐MPM will exhibit stimulant properties similar to the parent compound phenmetrazine, whereas 4‐MPM may display entactogen properties more similar to MDMA. The combination of test purchases, analytical characterization, targeted organic synthesis and pharmacological evaluation of NPS and their isomers is an effective approach for the provision of data on these substances as they emerge in the marketplace.

This perspective examines amphetamine importations into Ireland. Some novel by-products were detected and linked to a change in the method of production of P2P from APAAN. These by-products remained present during subsequent Leuckart reaction conditions. Novel by-products from substituted cathinone synthesis reactions were also isolated and characterized.

1‐Phenyl‐2‐propanone (P2P) is an internationally monitored precursor that has become increasingly difficult for illicit amphetamine producers to source, which means that alternative routes to its preparation have become increasingly important. One such approach includes the hydrolysis of alpha‐phenylacetoacetonitrile (APAAN) with sulfuric acid. Previously, we reported the identification of 4,6‐dimethyl‐3,5‐diphenylpryid‐2‐one following implementation of hydrolysis conditions and it was proposed that this compound might serve as one route specific by‐product in the APAAN to P2P conversion. This study continued to explore the presence of impurities formed during this conversion and expanded also into a second route of P2P synthesis starting from alpha‐methylstyrene (AMS). All P2P products underwent the Leuckart procedure to probe the presence of P2P‐related impurities that might have carried through to the final product. Two by‐products associated with the APAAN hydrolysis route to P2P were identified as 2,3‐diacetyl‐2,3‐diphenylsuccinonitrile (1) and 2‐methyl‐1‐phenyl‐1,3‐dicarbonitrile‐1H‐indene (2), respectively. Two by‐products associated with the AMS route to P2P and subsequent Leuckart reaction were 1,1,3‐trimethyl‐3‐phenyl‐2,3‐dihydro‐1H‐indene (3) and 1‐phenyl‐N‐(phenylethyl)propan‐2‐amine (4), respectively. The two indenes (2 and 3) identified in synthesized amphetamine originating from P2P suggested that it might be possible to differentiate between the two synthetic routes regarding the use of APAAN and AMS. Furthermore, the association of these compounds with amphetamine production appears to have been reported for the first time. The presence of compounds 1 – 4 in seized amphetamine samples and waste products could facilitate the suggestion whether APAAN or AMS were employed in the synthesis route to the P2P. Copyright © 2016 John Wiley & Sons, Ltd.

2‐Amino‐1‐(4‐bromo‐2,5‐dimethoxyphenyl)ethan‐1‐one (bk‐2C‐B) has been recently offered for purchase by a variety of Internet retailers. This substance may be considered a cathinone analogue of the phenethylamine 2‐(4‐bromo‐2,5‐dimethoxyphenyl)ethan‐1‐amine (2C‐B) which suggests that it may have psychoactive effects in humans. A test purchase of bk‐2C‐B was carried out and its identity was confirmed by a range of analytical techniques including nuclear magnetic resonance spectroscopy, gas and liquid chromatography, and high‐resolution mass spectrometry. Confirmation was also obtained from the synthesis of bk‐2C‐B based on the implementation of the Delépine reaction in which the α‐brominated intermediate was reacted with hexamethylenetetramine to afford the primary amine. Analysis of underivatized bk‐2C‐B by gas chromatography–mass spectrometry (GC‐MS) showed that there was potential for artificial formation of 1‐(4‐bromo‐2,5‐dimethoxyphenyl)ethanone and a pyrazine dimer, these substances were not detected when employing liquid chromatographic analysis. Ion chromatography and X‐ray crystallography analysis confirmed that the purchased bk‐2C‐B consisted of a hydrochloride and hydrobromide salt mixture, which indicated that it might have been prepared by the hexamethylenetetramine route followed by hydrochloric acid hydrolysis of the quaternary ammonium salt. X‐ray crystallography also revealed that the purchased (mixed HCl/HBr salt) and synthesized bk‐2C‐B (HCl salt) exists as polymorphs. Copyright © 2014 John Wiley & Sons, Ltd.