Profiling ephedrine prepared from N-methylalanine via the Akabori-Momotani reaction.

Novel methods for synthesising methylamphetamine precursors are appearing in clandestine laboratories within Australia. One such laboratory involved the synthesis of ephedrine from N-methylalanine and benzaldehyde via the Akabori-Momotani reaction. This article presents chiral and stable isotope ratios of ephedrine synthesised via this method, along with a chemical profile of methylamphetamine produced from this ephedrine. Based on the chiral results and the δ13 C, δ15 N, and δ2 H values, it is possible to distinguish ephedrine made via the Akabori-Momotani reaction from ephedrine of a "natural", "semi-synthetic", or "fully-synthetic" origin. Methylamphetamine and ephedrine samples synthesised from benzaldehyde having an enriched δ2 H value (ie, > 0‰), via the Akabori-Momotani reaction, had an isotopic profile which set them apart from all other methylamphetamine samples. It was noted, however, that using stable isotope ratios alone to determine the precursor of methylamphetamine is limited; they could not with confidence differentiate between methylamphetamine and ephedrine synthesised from benzaldehyde having a depleted δ2 H value (ie, <0‰) from other ephedrine sources and phenyl-2-propanone based methylamphetamine samples profiled.

Chiral analysis of chloro intermediates of methylamphetamine by one-dimensional and multidimentional NMR and GC/MS.

Impurity profiling and classification of abused drugs using chiral analytical techniques is of particular interest and importance because of the additional information obtained from this approach. When these methods are applied to the synthesis of illicitly used substances, they can supply valuable information about the conditions/chemicals used in the synthesis. We have applied GC and NMR methods to the study of intermediates found in methylamphetamine manufacture with the aim of linking the intermediates to the ephedrine/pseudoephedrine starting materials. Therefore, determination of the stereochemical makeup within samples of forensic interest is important giving further specific information to the analyst. This study investigates the stereochemical course of the Emde synthesis of methylamphetamine with particular focus on intermediate formation via the chlorination of ephedrine and pseudoephedrine enantiomers. The configurations of these chloro-phenethylamines were determined by 1D and 2D NMR analysis, and thereafter, the GC/MS analysis was carried out. We have shown here that chlorination of the ephedrine/pseudoephedrine compounds occurs via inversion (S(N)2) and retention (S(N)i) of configuration around the α carbon and mixture of diastereoisomers (chloroephedrine and chloropseudoephedrine) were formed, with the ratio of the resulting compounds dependent on the precursors used. The preparation and analytical properties of these intermediate standards provide data for laboratories interested in the stereochemical analysis of methylamphetamine intermediates such as forensic/law enforcement, and illustrate the value of using a combination of analytical methodology.

Investigation of the reaction impurities associated with methylamphetamine synthesized using the Nagai method.

The synthesis of methylamphetamine hydrochloride from l-ephedrine or d-pseudoephedrine hydrochloride via reduction with hydriodic acid and red phosphorus was investigated. Eighteen batches of methylamphetamine hydrochloride were synthesized in six replicate batches using three different reaction times. This allowed the investigation of the variation of impurities in the final product with reaction time. The results obtained have resolved previously conflicting impurity profile data reported in the literature for this synthesis route. The impurity profile was shown to change with reaction time, and all previously reported impurity components were identified but not in all batches. Additionally, 20 batches of methylamphetamine hydrochloride were synthesized from either from l-ephedrine or d-pseudoephedrine hydrochloride in reactions which were allowed to proceed for 24 h. The impurities present in the resulting batches were investigated, and route-specific impurities present in all batches were identified. Batch-to-batch fluctuations in the resultant chromatographic impurity profile, despite careful synthetic monitoring and control, were also noted.

Methylamphetamine synthesis: does an alteration in synthesis conditions affect the δ(13) C, δ(15) N and δ(2) H stable isotope ratio values of the product?

Conventional chemical profiling of methylamphetamine has long been employed by national forensic laboratories to determine the synthetic route and where possible the precursor chemicals used in its manufacture. This laboratory has been studying the use of stable isotope ratio mass spectrometry (IRMS) analysis as a complementary technique to conventional chemical profiling of fully synthetic illicit drugs such as methylamphetamine. As part of these investigations the stable carbon (δ(13) C), nitrogen (δ(15) N), and hydrogen (δ(2) H) isotope values in the precursor chemicals of ephedrine and pseudoephedrine and the resulting methylamphetamine end-products have been measured to determine the synthetic origins of methylamphetamine. In this study, results are presented for δ(13) C, δ(15) N, and δ(2) H values in methylamphetamine synthesized from ephedrine and pseudoephedrine by two synthetic routes with varying experimental parameters. It was demonstrated that varying parameters, such as stoichiometry, reaction temperature, reaction time, and reaction pressure, had no effect on the δ(13) C, δ(15) N, and δ(2) H isotope values of the final methylamphetamine product, within measurement uncertainty. Therefore the value of the IRMS technique in identifying the synthetic origin of precursors, such as ephedrine and pseudoephedrine, is not compromised by the potential variation in synthetic method that is expected from one batch to the next, especially in clandestine laboratories where manufacture can occur without stringent quality control of reactions.

Solvent-free microwave-assisted multi-component reaction for preparation of 2-amino-1-aryl-2-(cyclohex-1-enyl)ethanones as precursors of pseudoephedrine analogues.

Microwave irradiation of chloroacetylarenes and enamines induced an aza-Darzens reaction followed by rearrangement of the aziridinium intermediate to give (2-amino-3-alkenoyl)arenes that were reduced selectively to syn-beta-aminoalcohols as pseudo-ephedrine analogues.

Molecular imaging of cardiac sympathetic innervation by 11C-mHED and PET: from man to mouse?

UNLABELLED: Dysfunction of the sympathetic nervous system underlies many cardiac diseases and can be assessed by molecular imaging using PET in humans. Small-animal PET should enable noninvasive quantitation of the sympathetic nervous system in mouse models of human disease. For mice, however, the radioactivity needed to give acceptable image quality may be associated with a mass of unlabeled compound sufficient to block the binding of radioligand to its target. The present study assesses the feasibility of using [N-methyl-(11)C]meta-hydroxyephedrine ((11)C-mHED) to measure norepinephrine reuptake in humans, to determine cardiac innervation in mice. METHODS: Anesthetized mice were placed in a small-animal PET scanner. (11)C-mHED (containing 18% precursor metaraminol) was injected via a tail vein into each animal simultaneously. Fifteen minutes later, animals were injected with saline or metaraminol which competes with mHED for norepinephrine reuptake. (18)F-FDG was injected at 60 min to identify heart regions. After reconstruction of the list-mode data, radioactivity in myocardial regions was computed using in-house software, and time-activity curves were plotted. RESULTS: Hearts were clearly visualized after injection of (11)C-mHED. Injection of metaraminol at doses less than 50 nmol x kg(-1) had no effect, whereas doses greater than 100 nmol x kg(-1) caused a dose-dependent loss of specifically bound radioactivity. CONCLUSION: (11)C-mHED was successfully used to visualize and assess myocardial innervation in mice. Uptake of (11)C-mHED is displaceable by the false transmitter metaraminol. The total molar dose of metaraminol and (11)C-mHED must be considered in the analysis of PET data.

Delta(13)C, delta(15)N and delta(2)H isotope ratio mass spectrometry of ephedrine and pseudoephedrine: application to methylamphetamine profiling.

Conventional chemical profiling of methylamphetamine has been used for many years to determine the synthetic route employed and where possible to identify the precursor chemicals used. In this study stable isotope ratio analysis was investigated as a means of determining the origin of the methylamphetamine precursors, ephedrine and pseudoephedrine. Ephedrine and pseudoephedrine may be prepared industrially by several routes. Results are presented for the stable isotope ratios of carbon (delta(13)C), nitrogen (delta(15)N) and hydrogen (delta(2)H) measured in methylamphetamine samples synthesized from ephedrine and pseudoephedrine of known provenance. It is clear from the results that measurement of the delta(13)C, delta(15)N and delta(2)H stable isotope ratios by elemental analyzer/thermal conversion isotope ratio mass spectrometry (EA/TC-IRMS) in high-purity methylamphetamine samples will allow determination of the synthetic source of the ephedrine or pseudoephedrine precursor as being either of a natural, semi-synthetic, or fully synthetic origin.

Asymmetric catalysis route to anti,anti stereotriads, illustrated by applications.

A short sequence based on asymmetric catalysis, chirality transfer, and an optimized carbometallation protocol gave an anti,anti stereotriad building block in six steps. Both enantiomers of the chirality source, N-methyl ephedrine, are inexpensive, and the auxiliary is recoverable. In one chiral series, the building block was converted to the "B-2" intermediate in Miyashita's synthesis of scytophycin C; in the enantiomeric series, it was converted to a key intermediate for aplyronine A and to the polyketide "cap" for the callipeltins.

N-propargylamides via the asymmetric michael addition of B-alkynyl-10-TMS-9- borabicyclo[3.3.2]decanes to N-acylimines.

[Structure: see text] The asymmetric synthesis of N-propargylamides through Michael addition of the alkynylborane 1 to N-acylimines is reported. The N-acetylimines provide the best substrates for the process exhibiting high selectivity (56-95% ee) with predictable stereochemistry. In several cases, 5 crystallizes in essentially pure form (97-99% ee) and a single-crystal X-ray structure was also obtained for 5g (R1=R2=Me, R3=o-Cl-C6C4). The process regenerates 4 for its direct conversion back to 1 and facilitates the efficient recovery of the pseudoephedrine.

Highly diastereoselective catalytic Meerwein-Ponndorf-Verley reductions.

[reaction: see text] Very practical synthesis of ephedrine analogues in high yields and enantiopurity was realized by a highly diastereoselective Meerwein-Ponndorf-Verley (MPV) reduction of protected alpha-amino aromatic ketones using catalytic aluminum isopropoxide. The high anti selectivity resulted from the chelation of the nitrogen anion to the aluminum. In contrast, high syn selectivity was obtained with alpha-alkoxy ketones and other compounds via Felkin-Ahn control.

Nonracemic homopropargylic alcohols via asymmetric allenylboration with the robust and versatile 10-TMS-9-borabicyclo[3.3.2]decanes.

The asymmetric allenylboration of representative aldehydes with the stable, storable 1 is reported. Easily and efficiently prepared in either enantiomeric form from the air-stable crystalline 4 through simple Grignard procedures, 1 gives 6 cleanly. The latter is easily isolated in high yield and ee with predictable stereochemistry. The procedure also regenerates 4 for its direct conversion back to 1 and facilitates the efficient recovery of the pseudoephedrine. The net process is the synthetic equivalent of the asymmetric addition of allenylmagnesium bromide to aldehydes. [reaction: see text]

Investigation of the origin of ephedrine and methamphetamine by stable isotope ratio mass spectrometry: a Japanese experience.

Illicit drug abuse is a serious global problem that can only be solved through international cooperation. In Asian countries, the abuse of methamphetamine is one of the most pressing problems. To assist in the control of methamphetamine, the authors investigated in detail the character of ephedrine, which is a key precursor for the illicit manufacture of methamphetamine. Commercial ephedrine is produced by one of three methods: (a) extraction from Ephedra plants, (b) full chemical synthesis or (c) via a semi-synthetic process involving the fermentation of sugar, followed by amination. Although chemically there is no difference between ephedrine samples from different origins (natural, synthetic or semi-synthetic), scientific and analytical tools such as drug-characterization and impurity-profiling programmes may provide valuable information for law enforcement and regulatory activities as part of precursor control strategies. During the research under discussion in the present article, in addition to classical impurity profiling of manufacturing by-products, the use of stable isotope ratio mass spectrometry was investigated for determining the origin of the ephedrine that had been used as a precursor in seized methamphetamine samples. The results of carbon and nitrogen stable isotope ratio (delta13C and delta15N) analysis of samples of crystalline methamphetamine seized in Japan suggested that the drug had been synthesized from either natural or semi-synthetic ephedrine and not from synthetic ephedrine. Stable isotope ratio analysis is expected to be a useful tool for tracing the origins of seized methamphetamine. It has attracted much interest from precursor control authorities in Japan and the East Asian region and may prove useful in the international control of precursors.

N-methyl-N-trimethylsilyltrifluoroacetamide-promoted synthesis and mass spectrometric characterization of deuterated ephedrines.

Synthesis and mass spectrometric characterization of drugs or metabolites labeled by stable isotopes has been of great interest in fields of clinical, forensic and doping control analysis. Deuterated ephedrine and p-hydroxypseudoephedrine were prepared from corresponding amines by a novel procedure utilizing N- methyl-N-trimethylsilyltrifluoroacetamide and deuterated iodomethane. The mechanism of methylation was studied by mass spectrometry using phenylethylamine as a model compound, and a rearrangement based on an intermediate six-membered ring structure with a trimethylsilyl-enol-ether is proposed giving rise to a leaving group of trimethyliodosilane and the desired monomethylated product. Deuterated analogues to frequently quantitated ephedrines were readily synthesized with purities >90%, and mass spectra recorded under different ionization and dissociation conditions presented distinct fragmentation processes including eliminations of water and methylamine as well as the generation of a benzyl cation.

Determination of origin of ephedrine used as precursor for illicit methamphetamine by carbon and nitrogen stable isotope ratio analysis.

The sale of ephedrine, one of the precursors of methamphetamine, is strictly controlled and monitored in various countries to prevent the production of illicit methamphetamine. There are three kinds of production scheme for ephedrine manufacture, and it is very useful for precursor control to investigate the origin of ephedrine used for the synthesis of illicit methamphetamine. By means of stable isotope ratio mass spectrometry (IR-MS), we investigated the origin of ephedrine based on the delta(13)C and delta(15)N values. The various origins of ephedrine (biosynthetic, semisynthetic, or synthetic) could be discriminated clearly by using these values. The delta(15)N values of synthetic ephedrine were more negative than those of ephedrine from other sources. By the repeated distillation of methylamine in our laboratory, we confirmed that this could be due to isotope separation during distillation for the purification of methylamine used for ephedrine synthesis. The values for ephedrine used as the precursor were well-correlated with those for methamphetamine synthesized from it. This drug characterization analysis should be useful to illuminate the origin of the precursors used for clandestine methamphetamine and to trace the diversion of medicinal ephedrine for illicit manufacture of methamphetamine.

Stereoselective synthesis of delta-lactones from 5-oxoalkanals via one-pot sequential acetalization, Tishchenko reaction, and lactonization by cooperative catalysis of samarium Ion and mercaptan.

By the synergistic catalysis of samarium ion and mercaptan, a series of 5-oxoalkanals was converted to (substituted) delta-lactones in efficient and stereoselective manners. This one-pot procedure comprises a sequence of acetalization, Tishchenko reaction and lactonization. The deliberative use of mercaptan, by comparison with alcohol, is advantageous to facilitate the catalytic cycle. The reaction mechanism and stereochemistry are proposed and supported by some experimental evidence. Such samarium ion/mercaptan cocatalyzed reactions show the feature of remote control, which is applicable to the asymmetric synthesis of optically active delta-lactones. This study also demonstrates the synthesis of two insect pheromones, (2S,5R)-2-methylhexanolide and (R)-hexadecanolide, as examples of a new protocol for asymmetric reduction of long-chain aliphatic ketones.

Chloroephedrine: contaminant of methamphetamine synthesis with cardiovascular activity.

Chloroephedrine is an intermediate and possible contaminant formed when methamphetamine is manufactured using ephedrine or pseudoephedrine as precursors. The purpose of this study was to determine whether this contaminant has biological activity and might contribute to methamphetamine-induced cardiovascular toxicity. In conscious rats, the (-) and (+) isomers of chloroephedrine (0.1 and 1.0 mg/kg, i.v.) dose-dependently increased mean arterial pressure (MAP) and heart rate (HR). The potency of the pressor effects of (-) and (+)-chloroephedrine was between that of ephedrine and pseudoephedrine. The increases in HR elicited by the four stimulants were similar except that the tachycardia elicited by all doses of ephedrine and pseudoephedrine were preceded by a brief decrease in HR. The i.v. administration of 10 mg/kg of (+) or (-)-chloroephedrine produced biphasic (decrease followed by increase) the MAP and HR responses. Ephedrine and pseudoephedrine did not decrease MAP at any dose tested. The initial decrease in HR elicited by (-)-chloroephedrine was significantly reduced and the hypotensive response abolished by atropine, indicating that these components of the MAP and HR responses resulted from vagal activation. The secondary pressor response elicited by (-)-chloroephedrine was significantly reduced and the tachycardia significantly increased by pretreatment with phentolamine (3 mg/kg, i.v.). The increase in HR was reversed by propranolol. These results indicate that (-) and (+)-chloroephedrine have sympathomimetic properties similar to other known sympathomimetic stimulants. In addition, larger doses of chloroephedrine can activate the vagus nerve. The combination of (+)-methamphetamine and (-)-chloroephedrine did not markedly alter the magnitude of the MAP and HR responses of (+)-methamphetamine alone except at high doses of (-)-chloroephedrine (10 mg/kg). Contamination of illicit methamphetamine with chloroephedrine may have toxic consequences.

Factors affecting the production of L-phenylacetylcarbinol by yeast: a case study.

L-Phenylacetylcarbinol (L-PAC) is the precursor for L-ephedrine and D-pseudoephedrine, alkaloids possessing alpha- and beta-adrenergic activity. The most commonly used method for production of L-PAC is a biological method whereby the enzyme pyruvate decarboxylase (PDC) decarboxylates pyruvate and then condenses the product with added benzaldehyde. The process may be undertaken by either whole cells or purified PDC. If whole cells are used, the biomass may be grown and allowed to synthesize endogenous pyruvate, or the cells may be used as a catalyst only, with both pyruvate and benzaldehyde being added. Several yeast species have been investigated with regard to L-PAC-producing potential; the most commonly used organisms are strains of Saccharomyces cerevisiae and Candida utilis. It was found that initial high production rates did not necessarily result in the highest final yields. Researchers then examined ways of improving the productivity of the process. The substrate, benzaldehyde, and the product, L-PAC, as well as the by-products, were found to be toxic to the biomass. Methods examined to reduce toxicity include modification of benzaldehyde dosing regimes, immobilization of biomass or purified enzymes, modification of benzaldehyde solubility and the use of two-phase reaction systems. Various means of modifying metabolism to enhance enzyme activity, relevant metabolic pathways and yield have been examined. Methods investigated include the use of respiratory quotient to influence pyruvate production and induce fermentative activity, reduced aeration to increase PDC activity, and carbohydrate feeding to modify glycolytic enzyme activity. The effect of temperature on L-PAC yield has been examined to identify conditions which provide the optimal balance between L-PAC and benzyl alcohol production, and L-PAC inactivation. However, relatively little work has been undertaken on the effect of medium composition on L-PAC yield.

Improved synthesis of some commonly used PET radioligands by the use of [11C]methyl triflate.

[11C]Methyl triflate was compared with [11C]methyl iodide as a labelled precursor in the synthesis of some commonly used PET radioligands, L-[11C]deprenyl, [11C]m-hydroxyephedrine (MHED), [11C] beta-CIT, [11C] beta-CFT and [11C]SCH 39166 which have been prepared previously in comparatively low yields from [11C]methyl iodide. A new dopamine reuptake radioligand, [11C] alpha-CIT, was also prepared. The results demonstrate that higher yields are obtained with shorter reaction times, lower reaction temperatures and smaller amounts of precursors with [11C]methyl triflate.

Synthesis and preliminary evaluation of carbon-11-meta-hydroxyephedrine: a false transmitter agent for heart neuronal imaging.

Carbon-11-meta-hydroxyephedrine is a new radiotracer developed for mapping the sympathetic nerves of the heart. Carbon-11-meta-hydroxyephedrine is synthesized by direct N-methylation of metaraminol with [11C]methyl iodide in dimethyl formamide/dimethyl sulfoxide and purified by semi-preparative reversed-phase HPLC. Total synthesis time is 45 min from end-of-bombardment. Carbon-11-meta-hydroxyephedrine is produced in 40%-50% corrected radiochemical yield with a specific activity of 900 Ci/mmol. Routine radiochemical and chemical purity are 95% and 98%, respectively. Biodistribution studies in rats show high myocardial uptake. Pretreatment with desipramine, a drug known to selectively block neuronal uptake, results in a 92% decrease in tracer accumulation in the myocardium. Metabolic studies in guinea pigs show less than 5% metabolites in heart tissue 30 min after intravenous injection suggesting that [11C]meta-hydroxyephedrine is suitable for kinetic modeling. These preliminary results support this new tracer as a clinical agent for neuronal imaging of the heart.