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-[β-(4-methylthiophenyl)isopropyl]amine, N,N-di-[β-(4-methylthiophenyl)isopropyl]methylamine, N,N-di-[β-(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, (1)H and (13)C NMR, and IR methods. The stereochemistry of (RR/SS) diasteromer of N,N-di-[β-(4-methylthiophenyl)isopropyl]amine was confirmed by a crystallographic method.     

A neolignan-type impurity arising from the peracid oxidation reaction of anethole in the surreptitious synthesis of 4-methoxyamphetamine (PMA)

The neolignan-type substance 2,4-dimethyl-3,5-bis(4'-methoxyphenyl) tetrahydrofuran is presented as a new forensic marker compound for the peracid oxidation of anethole. It is hypothesized that the formation of a stable intermediary carbocation in the hydrolysis reaction of anethole epoxide is not only responsible for the presence of 1,2-diols (and its esters) and 4-methoxyphenyl-2-propanone (PMP2P) but can also be the cause for the creation of this neolignan impurity due to interaction with anethole itself. Moreover, the applicability of this new forensic marker is demonstrated by its retrieval in clandestinely manufactured 4-methoxyamphetamine (PMA) preparations.     

Identification and synthesis of some contaminants present in 4-methoxyamphetamine (PMA) prepared by the Leuckart method

The clandestine synthesis of ring and side chain modified phenylisopropylamines continues to be a major source of these drugs of abuse. One method used for the synthesis of the amphetamine and related compounds involves the treatment of the appropriate ketone with formamide or ammonium formate followed by acid hydrolysis of intermediate N-formyl derivative. In this paper the synthesis of 4-methoxyamphetamine (PMA, 1) by the Leuckart method is investigated. The identification by means of gas chromatography-mass spectrometry (GC-MS) of methoxy derivative of N-(beta-phenylisopropyl)benzaldimine 9, methoxy derivative of N-(beta-phenylisopropyl)benzyl methyl ketimine 5, 1-(4-methoxyphenyl)-N-(4-methoxybenzyl)-2-propanamine 10, (RR/SS) and (RS) 1-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 6a-6c, (RR/SS) and (RS)-1-(4-methoxyphenyl)-N-methyl-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 7a-7c, (RR/SS) and (RS)-1-(4-methoxyphenyl)-N-formyl-N-[2-(4-methoxyphenyl)-1-methylethyl]-2-propanamine 8a-8c in crude PMA, are reported. The identity of these compounds was confirmed by independent synthesis of reference compounds. The NMR, MS, IR data, stereochemistry and some chromatographic properties of synthesized compounds are discussed. Finally, the results of the GC-MS analysis of illicitly prepared tablets, containing PMA 1 and 4-methoxymethamphetamine (PMMA, 2), are outlined. The presence of 4-methoxydimethylamphetamine 11, 4-methoxyethylamphetamine 12, and 4-hydroxymethamphetamine 13 are reported in these tablets. The identity of 2, 11, and 12 was confirmed by their independent synthesis.     

Anise oil as para-methoxyamphetamine (PMA) precursor

These days, MDMA is one of the most popular drugs of abuse. Due to its illegality, MDMA and its chemical precursors are watched by governmental organizations in many countries. To avoid conflicts with legal instances, underground chemists have tried to market several new unregulated amphetamine analogues, such as 4-MTA. Para-methoxyamphetamine (PMA), on the other hand, is regulated by law but its precursors are easily obtained since they are cheap and unwatched. This article presents such a case, namely the large scale synthesis of PMA using anethole, a main constituent of anise oil, as precursor. Anethole has been converted to its phenyl acetone analogue via peracid oxidation, while PMA itself has been synthesized using this ketone as precursor in the Leuckart synthesis. The synthesis of PMA using anethole as starting product has been investigated applying GC/MS and GC-HSPME/MS techniques, hereby discovering new specific (4-methoxyphenol) and already identified synthesis impurities (4-methyl-5-(4-methoxyphenyl)pyrimidine, N-(beta-4-methoxyphenylisopropyl)-4-methoxybenzyl methyl ketimine, 1-(4-methoxyphenyl)-N-(2-(4-methoxyphenyl)-1-methylethyl-2-propanamine, 1-(4-methoxyphenyl)-N-methyl-N-(2-(4-methoxyphenyl)-1-methylethyl-2-propanamine, N-(beta-4-methoxyphenylisopropyl)-4-methoxybenzaldimine). The new impurity 4-methoxyphenol is specific for the application of a peracid oxidation method where anethole is used as precursor.     

Application of solid-phase microextraction to the profiling of an illicit drug: manufacturing impurities in illicit 4-methoxyamphetamine

This article describes the application of solid-phase microextraction (SPME) to the recovery of manufacturing by-products and impurities from an illicit drug seizure. The preparation chosen for examination using this technique contained 4-methoxyamphetamine, an hallucinogenic amphetamine that has been encountered frequently in South Australia. Compounds found in the PMA preparation included 4-methoxyphenol, 4-methoxybenzaldehyde, 4-methoxyphenyl-2-propanone, 4-methoxyphenyl-2-propanol, 4-methoxyphenyl-propene, and (tentatively) 4-methyl-5-(4'-methoxyphenyl) pyrimidine. The presence of these compounds suggests that the active drug was prepared from 4-methoxybenzaldehyde via 4-methoxyphenyl-2-propanone using a Leuckardt reductive amination. In this instance, SPME was found to be a simple, rapid, and non-destructive recovery technique that gave results complementary to those provided by conventional liquid-liquid extraction. There is an indication that SPME might find application in profiling of illicit drugs.     

Basic and neutral route specific impurities in MDMA prepared by different synthesis methods. Comparison of impurity profiles

In this work, the neutral and basic impurities found in the precipitate of MDMA(*)HCl are presented. MDMA.HCl was prepared by the most popular synthesis methods used in clandestine manufacture, i.e. safrole bromination, Leuckart method and reductive amination with various reducing agents: Al/Hg, NaBH(4), NaBH(3)CN. 3,4-Methylenedioxyphenyl-2-propanone (MDP-2-P), the starting material in Leuckart reaction and reductive amination, was prepared by two different synthesis methods, i.e. by isosafrole oxidation and MDP-2-nitropropene reduction. The extraction of impurities was performed under alkaline and neutral conditions. Impurity profiles were obtained using GC/MS. Each synthesis method is characterised by its own route specific impurities. The influence of pH on the extraction of synthesis markers from 3,4-methylenedioxymethamphetamine (MDMA) samples is discussed and comparison of the profiles of basic and neutral impurities is presented.     

Synthesis of standards of the most important markers of Leuckart p-methoxymethamphetamine (PMMA). Examination of the influence of experimental conditions and a drug diluent on SPE/TLC profiling

The synthesis of characteristic markers of PMMA obtained by Leuckart method was described. The effectiveness of a procedure of SPE/TLC screening profiling of impurities was studied on the basis of selected impurities. The influence of glucose (a drug diluent) on the profile quality was investigated. The intermediate product (characteristic for the Leuckart synthesis) N-formyl-p-methoxymethamphetamine (1) and by-products: N-formyl-p-methoxyamphetamine (2), p-methoxyamphetamine (3), N,N-dimethyl-p-methoxyamphetamine (4), (RS) and (RR/SS) diastereoisomers of bis(1-methyl-2-(4-methoxyphenyl)ethyl)amine (meso-5 and rac-5), (RS) and (RR/SS) diastereoisomers of N-methyl-bis(1-methyl-2-(4-methoxyphenyl)ethyl)amine (meso-6 and rac-6), N-methyl-1,3-bis(4-methoxyphenyl)propane-2-amine (7) were synthesized. The substrate p-methoxyphenylacetone and the impurities 1 and 4 were used in the study of influence of experimental conditions and glucose on the profiling process and results. The experiments were carried out according to a 2(4) factorial design. The proposed criterions of the profile quality are based on matrix presentation of TLC patterns. They take into account the number of spots revealed, differences between R(f) values and intensity of fluorescence, simultaneously.     

Determination of synthesis method of ecstasy based on the basic impurities

MDMA was prepared by five different synthesis routes, i.e. by dissolving metal reduction (Al/Hg), cyanoborohydride reduction (NaBH(3)CN), borohydride reduction in low temperature (NaBH(4)), Leuckart reaction and safrole bromination. MDP-2-P was prepared by two different synthesis methods, i.e. by isosafrole oxidation and MDP-2-nitropropene reduction. Each of the synthesis routes was repeated three times in order to establish variation in qualitative composition of route specific impurities between different batches. The analysis of impurities in MDP-2-nitropropene, MDP-2-P, bromosafrole and MDMA was performed with GC-MS. GC/MS was used also in the analysis of impurities in starting materials: safrole, isosafrole and piperonal. As a result of our study the way of determination of MDMA synthesis route determination based on qualitative composition of impurities is proposed.     

Luminescent visualization of latent fingerprints by direct reaction with a lanthanide shift reagent.

The utilization of the lanthanide shift reagent tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium (III) [Eu(fod)3] as a simple one-step reagent for the luminescent visualization of latent fingerprints has been investigated. UV excitation of Eu(fod)3-treated prints, achieved by using a hand-held UV lamp or a Polilight, results in an orange emission at 614 nm. Time-resolved imaging is not required for visualization. Visualization of latent fingerprints on paper under the conditions used, although good, was found to be inferior to that obtained by standard DFO (1,8-diazafluoren-9-one) treatment, whereas visualization of prints obtained on aluminum drink cans and galvanized iron proved superior to that obtained by Superglue/panacryl treatment. Eu(fod)3 treatment can also be used first without compromising subsequent ninhydrin or DFO treatment, making it a 'nothing-to-lose" reagent.     

Chemical markers from the peracid oxidation of isosafrole

In this work, isomers of 2,4-dimethyl-3,5-bis(3,4-methylenedioxyphenyl)tetrahydrofuran (11) are presented as chemical markers formed during the peracid oxidation of isosafrole. The stereochemical configurations of the major and next most abundant diastereoisomer are presented. Also described is the detection of isomers of (11) in samples from a clandestine laboratory uncovered in South Australia in February 2004.     

1-Phenylethylamines: a new series of illicit drugs?

Since 1993 many seizures of 1-phenylethylamine have been made in several European countries. It was originally thought that 1-phenylethylamine had been made in error, but later information suggested that it had been prepared deliberately. The related compounds, 1-amino-1-(4-methylphenyl)ethane and 1-methylamino-1-phenylethane and the 1-propanamine isomer of 3,4-methylenedioxyamphetamine, have also occurred in isolated cases. Analytical data are presented on these amines as well as a number of Leuckart impurities in 1-phenylethylamine. The pharmacological effects of these substances are largely unknown.     

Reidentification of a major impurity in illicit amphetamine

An impurity previously reported in illicit amphetamine has been found as a by-product om the synthesis of N-formylamphetamine, a reaction precursor to amphetamine by the Leukart synthesis. Its reidentification as di-(1-phenylisopropyl) formamide has been supported by combined spectroscopic analysis of isolated fractions.     

Profiling of impurities in p-methoxymethamphetamine (PMMA) by means of SPE/TLC method. Examination of the influence of experimental conditions according to 2(4) factorial

In the present paper profiling of impurities in p-methoxymethamphetamine (PMMA) by means of SPE/TLC is reported. PMMA was synthesised by Leuckart procedure. The influence of experimental conditions on the profile quality was investigated. The experiments were carried out according to a 2(4) factorial. The proposed characteristics of the profile quality (optimisation criterions) are based on a matrix presentation of TLC patterns. They take into account, simultaneously, the number of spots revealed, differences between R(f) values and intensity of fluorescence.     

Using spectral information in forensic imaging

Improved detection of forensic evidence by combining narrow band photographic images taken at a range of wavelengths is dependent on the substance of interest having a significantly different spectrum from the underlying substrate. While some natural substances such as blood have distinctive spectral features which are readily distinguished from common colorants, this is not true for visualization agents commonly used in forensic science. We now show that it is possible to select reagents with narrow spectral features that lead to increased visibility using digital cameras and computer image enhancement programs even if their coloration is much less intense to the unaided eye than traditional reagents. The concept is illustrated by visualising latent fingermarks on paper with the zinc complex of Ruhemann's Purple, cyanoacrylate-fumed fingerprints with Eu(tta)(3)(phen), and soil prints with 2,6-bis(benzimidazol-2-yl)-4-[4'-(dimethylamino)phenyl]pyridine [BBIDMAPP]. In each case background correction is performed at one or two wavelengths bracketing the narrow absorption or emission band of these compounds. However, compounds with sharp spectral features would also lead to improved detection using more advanced algorithms such as principal component analysis.     

Identification of common impurities present in the synthetic routes leading to 4-methylthioamphetamine (4-MTA). Part II: Reductive amination and nitropropene route

In this paper the by-products arising during the synthesis of 4-methylthioamphetamine (4-MTA) by LiAlH(4) reduction of 1-(4-methylthiophenyl)-2-nitropropene (nitropropene route) and reductive amination of 4-methylthiophenyl-2-propanone in the presence of NaCNBH(4) are investigated. The identification of 4-methylthio derivatives of N-(β-phenylisopropyl)benzaldimine, 4-methylthio derivative of N-(β-phenylisopropyl)benzyl methyl ketimine, 1-(4-methylthiophenyl)-N-(4-methylthiobenzyl)-2-propanamine, (RS) and (SS/RR)-N,N-di-[β-(4-methylthiophenyl)isopropyl]amine, 4-methylthiobenzyl ether and methylthiobenzoic acid methyl ester as most prominent impurities in crude 4-MTA synthesised by reductive amination of 4-methylthiophenyl-2-propanone, is reported. Methylthio derivatives of 2-methyl-3-phenylaziridine, 2-benzylaziridine, and 4-methylthio derivative of BMK oxime as route-specific markers of nitropropene route leading to 4-MTA, were also characterized. The identity of these compounds was confirmed by their independent synthesis.     

A review of impurity profiling and synthetic route of manufacture of methylamphetamine, 3,4-methylenedioxymethylamphetamine,amphetamine, dimethylamphetamine and p-methoxyamphetamine

Amphetamine-type substances (ATS), like other synthetically derived compounds, can be produced by a multitude of synthetic pathways using a variety of precursors and reagents, resulting in a large number of possible contaminants (by-products, intermediates and impurities). This review article describes the common contaminants found in preparations of methylamphetamine (MA), 3,4-methylenedioxymethylamphetamine (MDMA), amphetamine (AP), N,N-dimethylamphetamine (DMA) and p-methoxyamphetamine (PMA) synthesised via common synthetic pathways including reductive amination, Leuckart method, Nagai method, Emde method, Birch reduction, “Moscow” method, Wacker process, “Nitrostyrene” method and the Peracid oxidation method.Contaminants can facilitate identification of the synthetic route, origin of precursors and may suggest information as to the location of manufacture of these illicit drugs. Contaminant profiling can provide vital intelligence for investigations in which linking seizures or identifying the synthetic pathway is essential. This review article presents an accessible resource; a compilation of contaminants resulting from a variety of manufacturing methods used to synthesise the most common ATS. It is important for research in this field to continue as valuable information can be extracted from illicit drug samples, increasing discrimination amongst ATS, and in turn, leading to an increase in evidential value and forensic drug intelligence from forensic drug samples.     

The significance of the legal term "corpse" in forensic medicine

The definition of the term "corpse" is relevant for medicine in general and most particularly so for forensic medicine, as it has direct consequences on practical work: legally, postmortems and autopsies may only be performed on corpses. With this in mind, the legal term "corpse" was examined on the basis of German State Law regulations and provisions. Approximately half the burial acts include a definition of "corpse", but even here there are certain variations. The definitions for "corpse" can be divided into four categories: 1) according to the lack of vital signs or sure signs of death 2) according to the degree of decomposition and/or cohesion of body parts 3) on the basis of severed body parts, and 4) terminological differentiation of stillbirths and neonatal fatalities from miscarriages. Laws vary greatly in their definition of the term "corpse". Therefore, the decision whether or not human remains or parts thereof qualify as a "corpse" should be left to medical discretion.     

The potential of urinary androstdiene markers to identify 4-androstenediol (4-ADIOL) administration in athletes

Doping control laboratories accredited by the World Anti-Doping Agency (WADA) require criteria that allow endogenous steroids to be distinguished from their synthetic analogues in urine. Methodology based on "looking outside the metabolic box" was used in this study to identify diagnostic urinary markers of 4-androstenediol (4-ADIOL) administration. Androst-2,4-diene-17-one and androst-3,5-diene-17-one are proposed to be formed in urine from acid-catalyzed hydrolysis of 4-ADIOL sulfoconjugate, a major phase II metabolic product of 4-ADIOL. The presence of these markers in the routine gas chromatography-mass spectrometry (GC-MS) steroid screen was suitable to identify samples requiring confirmation by gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) - to measure the carbon isotope ratio (δ(13)C) of the androstdiene markers and confirm their likely synthetic origin based on depleted (13)C content.     

Towards the Semantics of "Constitutive" in Judicial Reasoning

The aim of the paper is to supply a contribution to the semantics of "constitutive," as confined to the scope of judicial reasoning. More precisely, the aim of the paper is to inquire what links the use of "constitutive" in three distinct (seemingly unrelated) issues on adjudication, namely: (a) the procedural classification of different sorts of judicial decisions, (b) the epistemological debate on the very nature of judicial decisions, and (c) a logical query on the import constitutive rules might be taken to have in affecting the sort and/or the nature of judicial decisions in which they might occur as the legal premiss, grounding the solution of the case. The attempt to fix some markers towards the semantics of "constitutive" in judicial reasoning will have Alchourrón and Bulygin's analyses as a main point of reference.     

“推定”和“视为”之语词解读?——以我国现行民事法律规范为样本

立法层面观察,"推定"和"视为"语词频繁适用于我国法律规范中。学界和实务界普遍认为两语词表达的分别是法律推定和法律拟制制度。然而,以我国现行民事法律规范为样本进行分析,却发现"推定"和"视为"语词并非与法律推定和法律拟制相对应:"推定"大多表达法律推定,但也表达法律拟制和注意规定;"视为"大多表达法律拟制,但也表达推定制度和注意规定。立法层面法律推定、法律拟制和注意规定语词适用的混乱状态必将导致司法层面对于"推定"和"视为"语词的解读困境。因此,应当在厘清法律推定、法律拟制和注意规定本质的基础上,用统一、明确的语词进行相应的制度表达。