An approach to shortening the timeframe between the emergence of new compounds on the drugs market and the availability of reference standards: The microscale syntheses of nitrazolam and clonazolam for use as reference materials, utilizing polymer‐supported reagents

Abstract

Nitrazolam and clonazolam are 2 designer benzodiazepines available from Internet retailers. There is growing evidence suggesting that such compounds have the potential to cause severe adverse events. Information about tolerability in humans is scarce but typically, low doses can be difficult to administer for users when handling bulk material. Variability of the active ingredient in tablet formulations can also be of a concern. Customs, toxicology and forensic laboratories are increasingly encountering designer benzodiazepines, both in tablet and powdered form. The unavailability of reference standards can impact on the ability to identify these compounds. Therefore, the need arises for exploring in-house approaches to the preparation of new psychoactive substances (NPS) that can be carried out in a timely manner. The present study was triggered when samples of clonazolam were received in powdered and tablet form at a time when reference material for this drug was commercially unavailable. Therefore, microscale syntheses of clonazolam and its deschloro analog nitrazolam were developed utilizing polymer-supported reagents starting from 2-amino-2'-chloro-5-nitrobenzophenone (clonazolam) and 2-amino-5-nitrobenzophenone (nitrazolam). The final reaction step forming the 1,2,4-triazole ring moiety was performed within a gas chromatography-mass spectrometry (GC-MS) injector. A comparison with a preparative scale synthesis of both benzodiazepine derivatives showed that microscale synthesis might be an attractive option for a forensic laboratory in terms of time and cost savings when compared with traditional methods of synthesis and when qualitative identifications are needed to direct forensic casework. The reaction by-product profiles for both the micro and the preparative scale syntheses are also presented.

Identification of seven psychedelic 2,5‐dimethoxy‐phenylethyl‐amine‐based designer drugs via benchtop 1H nuclear magnetic resonance spectroscopy

“…2C-BÁHCl (1), 2C-CÁHCl (2), 2C-DÁHCl (3), 2C-EÁHCl (4), 2C-PÁHCl (5), 2C-T-2ÁHCl (6), and 2C-T-7ÁHCl (7) were provided as seized samples of high purity from the research chemicals library of the Forensic Science Institute of the State Criminal Police Office [23] of Lower Saxony, Germany. Deuterated dimethyl sulfoxide + 0.1% TMS (DMSO-d 6 ) was used as received from Deutero GmbH.…”

“…Most methods rely on known reference standards for identification, and slight modifications to structural motifs that render forensic and customs laboratories largely blind. [ 6 ] For unambiguous characterization of unknown substances, tandem methods, [ 7 ] or state of the art analytical techniques like nuclear magnetic resonance (NMR) spectroscopy are required. [ 8 ]…”

“…laboratories largely blind. [6] For unambiguous characterization of unknown substances, tandem methods, [7] or state of the art analytical techniques like nuclear magnetic resonance (NMR) spectroscopy are required. [8] Since its realization in the late 1940s, [9] NMR spectroscopy has been increasingly utilized for structural elucidation of more and more complex molecules.…”

Clonazolam Intoxication Case Report

“…1 As an unregulated central nervous system depressant, clonazolam dosage determination remains unpredictable as reference standards are scarce. 11…”

“…Clonazolam is an alprazolam derivative, which has been found to be 2.5 times stronger 1 . As an unregulated central nervous system depressant, clonazolam dosage determination remains unpredictable as reference standards are scarce 11 …”