Ephedrine Precursor

It has been proposed that aziridines may be more widespread in biological systems than is generally realized [190]. Many drugs such as ephedrine (124 Scheme 11.18) and pronethalol (125) and endogenous metabolites such as adrenaline (126) contain a P-aminoalcohol moiety, which may act as a precursor to an aziridine metabolite that may explain the known carcinogenicity of some of these compounds such as pronethalol. 

Major manufacturing and trading countries now routinely supply pre-export notifications for all shipments of precursors of amphetamine-type stimulants in international trade. The Board has noted that, because of the effective controls and monitoring mechanisms that now exist for the licit trade in the raw materials, traffickers in certain regions are increasingly turning to pharmaceutical preparations as a source of the required precursors, particularly ephedrine and pseudoephedrine. 

In a new development following the emergence of methcathinone abuse in Southern Africa, an attempt to divert 100 kg of ephedrine, an immediate precursor of methcathinone, was uncovered in South Africa when the substance was ordered for delivery to Zimbabwe. The shipment was stopped prior to the identification of the suspects or the laboratory involved. It is therefore unclear whether the illicit drug laboratory was located in Zimbabwe or whether the substance was to have been smuggled back into South Africa to laboratories already existing in that country. 

Operational activities have continued under Project Prism, the international initiative designed to address diversion of the five main precursors used in the illicit manufacture of amphetamine-type stimulants, namely, ephedrine, 3,4-methylene-dioxyphenyl-2-propanone (3,4-MDP-2-P), l-phenyl-2-propanone (P-2-P), pseudo-ephedrine and safrole, as well as the equipment used in such illicit manufacture. Activities during 2004 have focused on launching operations to address weaknesses in control and monitoring mechanisms identified during 2003, such as monitoring... 

These alkaloids can also be derived from non-aminoacid precursors. The N atom is inserted into the molecule at a relatively late stage, for example, in the case of steroidal or terpenoid skeletons. Certainly, the N atom can also be donated by an amino acid source across a transamination reaction, if there is a suitable aldehyde or ketone. Pseudoalkaloids can be acetate and phenylalanine-derived or terpenoid, as well as steroidal alkaloids. Examples of pseudoalkaloids include such compounds as coniine, capsaicin, ephedrine, solanidine, caffeine, theobromine and pinidine (Figure 6). More examples appear in Table 1. 

Ephedrine has not been extensively studied in humans despite its long history of use. Its ability to activate 3 receptors probably accounted for its earlier use in asthma. Because it gains access to the central nervous system, it is a mild stimulant. Ingestion of ephedrine alkaloids contained in ma huang has raised important safety concerns. Pseudoephedrine, one of four ephedrine enantiomers, has been available over the counter as a component of many decongestant mixtures. However, the use of pseudoephedrine as a precursor in the illicit manufacture of methamphetamine has led to restrictions on its sale. 

Global seizures of ATS continue to be dominated by seizures of methamphetamine. Over the 2000-2005 period, 49 per cent of ATS seizures were in the form of methamphetamine, 15 per cent in the form of amphetamine, and 14 per cent in the form of ecstasy. The trend in recent years, however, has been towards rising proportions of amphetamine and falling proportions of methamphetamine, reflecting improved control over the two main methamphetamine precursors, ephedrine and pseudo-ephedrine. 

Board (INCB), was informed of some 1,900 shipments involving ephedrine and pseudo-ephedrine between November 2004 and October 20055. Between November 2005 and October 2006, over 2,200 shipments of ATS precursors were monitored. This resulted in 99 detailed investigations, including 40 cases involving 165 mt of ephedrine and pseudo-ephedrine that were interdicted or suspended. 6... 

This is reflected in the declining number of seized methamphetamine labs, from 17,199 in 2004 to 12,144 in 2005. Precursor control has also had a positive impact. Pseudo-ephedrine seizures in North America fell dramatically from a record 174.4 mt in 2004 to 0.6 mt in 2005. Ephedrine seizures also declined from 2.1 to 1.4 mt 9. Expressed in ATS equivalents, the precursors seized in 2004 would have been sufficient to produce 118 mt of methamphetamine those seized in 2005 would have been sufficient to produce only 1.3 mt.10... 

The USA also reduced the availability of over-the-counter (OTC) pharmaceutical preparations containing ATS precursors, notably pseudo-ephedrine. Similar controls in Canada (since 2003) reduced the flow of OTC preparations containing pseudo-ephedrine across the border. These efforts squeezed out large numbers of kitchen labs, and thus led to less US laboratory seizures in 2005 - a trend which appears to have continued in... 

Role of Project PRISM in countering synthetic drugs and their precursors , INCB presentation to the Conference Europe-Asia Cooperation on Synthetic Drugs and their Precursors , Paris, 6-7 March 2007. These are substantial amounts. By comparison, total licit trade in ephedrine and pseudo-ephedrine is estimated at around 30 mt and 1,200 mt respectively. [Source INCB, 2005 Precursors]. The 16 mt of interdicted/suspended shipments could have been used to produce 110 mt of methamphetamine. Were this to have ended up on the illicit market, it would have increased global methamphetamine production by some 40 per cent. 

Amphetamine/methamphetamine precursor (P2P seized in USA) ] Amphetamine precursors (P2P, phenylacetic acid, norephedrine) I Methamphetamine precursors (pseudo-ephedrine, ephedrine) Trend... 

Europe as a whole accounted for about 6 per cent of global ephedrine seizures over the 2004-2005 period. Listed in order of importance, the following European countries reported seizures of methamphetamine precursors over the same period the Czech Republic, Greece, the Russian Federation, the UK, Bulgaria, Germany, Iceland, Romania, Hungary, Slovakia, the Ukraine, France, Norway and Latvia. In 2006, EUROPOL noted increased export, transshipment and diversion of ephedrine and pseudo-ephedrine to the European Union.24... 

The Russian Federation has only reported the seizure of amphetamine labs many of these labs may, however, have produced methamphetamine. The main ATS precursors seized in Russia is ephedrine. This would point towards the production of methamphetamine (or methcathinone, locally known as ephedrone). In contrast, no seizures of P-2-P or of phenyl acetic acid, which could confirm the production of amphetamine in the country, were reported in recent years. 

In the Russian Federation, seizures of ephedrine suggested that methamphetamine was the main ATS being produced. According to EUROPOL, however, the precursor BMK (or P-2-P, normally used to produce amphetamine) originating in Russia was identified in the European Union in 2004. These precursors were marked with 4-Tert-Butyl (the so-called -Factor) and their origin could thus be identified. They were traf-... 

Pyruvate decarboxylase Production of (R)-phenylacetylcarbinol, a precursor of ephedrine in MES-KOH buffer /1 -pentanol [28]... 

The Chemical Diversion and Trafficking Act of 1988 defines precursor chemicals that can be used in the process of producing illicit drugs. Companies producing or supplying such chemicals must keep certain records and report orders that are suspicious or above a specified size prior to delivery. The Domestic Chemical Diversion Control Act of 1993 further e.xpanded these controls, dealing particularly with the diversion of ephedrine (found in over-the-counter antihistamines) to the production of methamphetamines ( speed ). 

Although initially available as an injectable solution for the treatment of obesity, D-metham-phetamine hydrochloride is currently available as conventional and prolonged release tablets. Illicit methamphetamine is synthesized from the precursors phenylacetone and iV -methylformamide (dl mixture) or alternatively from ephedrine or pseudoephedrine by red phosphorus/acid reduction. 

With benzaldehyde 144 or halogenated derivatives (Cl, F) as acceptors the yeast-PDC-catalyzed addition proceeds with almost complete stereoselectivity to furnish the corresponding (R)-configurated 1-hydroxy-1-phenylpropanones 145 [447]. For practical reasons, whole yeast cells are most often used as the catalyst, with only small loss of enantioselectivity [423,424]. The conversion of benzaldehyde in particular has gained industrial importance because the acyloin is an important precursor for the synthesis of L-(-)-ephedrine [448]. Otherwise, the substrate tolerance is remarkably broad for aromatic aldehydes on the laboratory scale, however, yields of acyloins are usually low because of the prior or consequent reductive metabolism of aldehyde substrate and product, giving rise to considerable quantities of alcohol 146 and vicinol diols 147, respectively [423,424,449], The range of structural variability covers both higher a-oxo-acids (e.g. -butyrate, -valerate) as the donor component, as well as a,/J-un-saturated aldehydes (e.g. cinnamaldehyde 148) as the acceptor [450]. 

Enzymatic processes also advance in the area of large-scale pharma intermediates /flactam antibiotics can now be produced in a fully biotechnological process, including the semi-synthesis from the /flactam core to the penicillin or cephalosporin. A precursor to ephedrine, long produced by a whole-cell process in yeast, can be obtained from benzaldehyde and acetaldehyde with the help of pyruvate dehydrogenase acting as a carboligase. 

The a-keto acid decarboxylases such as pyruvate (E.C. 4.1.1.1) and benzoyl formate (E.C. 4.1.1.7) decarboxylases are a thiamine pyrophosphate (TPP)-dependent group of enzymes, which in addition to nonoxidatively decarboxylating their substrates, catalyze a carboligation reaction forming a C-C bond leading to the formation of a-hydroxy ketones.269-270 The hydroxy ketone (R)-phenylacetylcarbinol (55), a precursor to L-ephedrine (56), has been synthesized with pyruvate decarboxylase (Scheme 19.35). BASF scientists have made mutations in the pyruvate decarboxylase from Zymomonas mobilis to make the enzyme more resistant than the wild-type enzyme to inactivation by acetaldehyde for the preparation of chiral phenylacetylcarbinols.271... 

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