Ephedrine and pseudoephedrine

V.Sandford. Enzymatic Process Development for R-PAC An Intermediate for Ephedrine and Pseudoephedrine Production. PhD Thesis UNSW (2002). 

Many Governments reported on their licit requirements for ephedrine and pseudoephedrine for 2003 72 Governments reported on ephedrine and 59 reported on pseudoephedrine. The Board welcomes that development and encourages all Governments concerned to continue to collect and analyse such data. 

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 order to gain a better understanding of the international trade in such preparations, the Board requested all Governments to provide information on the manufacture of and trade and trafficking in pharmaceutical preparations containing ephedrine and pseudoephedrine. By 1 November 2004, 80 Governments had responded to the Board s request. 

While the seizures of ephedrine and pseudoephedrine are mainly restricted to countries where the illicit manufacture of methamphetamine takes place, the identification of suspicious orders in international trade provides valuable information on the methods and routes used by traffickers to divert the substances they require. Some of the routes uncovered during 2004 are shown in figure III below. 

Routes used for trafficking in and attempted diversions of ephedrine and pseudoephedrine, identified through successful action by competent national authorities, 2003-2004... 

In its report for 2003 on the implementation of article 12, 4 the Board urged Governments of countries in South and South-East Asia to be vigilant concerning phenylacetic acid. With more effective controls over ephedrine and pseudoephedrine, traffickers were attempting to divert other chemicals for use in illicit manufacture, P-2-P and phenylacetic acid being the chemicals of choice. 

Chlorpheniramine reduces the allergic response of the organism caused by histamine. It is nsed for allergy symptoms, rhinitis, and also as an ingredient in numerons compositions with ephedrine and pseudoephedrine, which are recommended for colds, npper respiratory... 

Cunningham, J.K. and Liu, L.M., Impacts of federal ephedrine and pseudoephedrine regulations on methamphetamine-related hospital admissions, Addiction, 98, 1229, 2003. 

The concentration of cyclodextrins is also very important for optimizing the chiral resolution. Some reports have been published on this issue [7-14,45], Mularz et al. [45] studied the effect of the concentration of /i-cyclodextrin on the chiral resolution of ephedrine and pseudoephedrine. The authors reported... 

The six optically active alkaloids ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, and the N-methylated N-methylephedrine and N-methylpseudoephedrine are described in detail in Reti s review (2). Two new alkaloids of related structure have since been identified in Ephedra species, namely, (9-benzoylpseudoephedrine (271) and the oxazolidine derivative ephe-droxane (272). The 4-quinolone derivative ephedralone, recently isolated from Ephedra alata (273), may be of similar biogenetic origin as the ephedrines. Ephedra species also contain macrocyclic alkaloids of more complex structure (275). The two major Ephedra alkaloids (—)-ephedrine and (+)-pseudoephedrine are diastereomers. (—)-Ephedrine has the erythro and (+)-pseudoephedrine has the threo configuration. 

The tricarbonylchromium entity promotes ipso-Smiles rearrangement of the O-phenyl derivatives of ephedrine and pseudoephedrine to the N-phenyl derivatives [32]. Indeed, treatment of the sodium alkoxide derived from (1 R,2S)-ephedrine with fluorobenzene complex... 

All the compounds that we have talked about so far have been cyclic, because the diastereoisomers are easy to visualize two diastereoisomers can be identified because die substituents are either on the same side or on opposite sides of the ring (cis or irans). But acyclic compounds can exist as diastereoisomers too. Take these two, for example. Both ephedrine and pseudoephedrine are members of the amphetamine class of stimulants, which act by imitating the action of the hormone adrenaline. 

Ephedrine and pseudoephedrine are stereoisomers that are clearly not mirror images of each other—only one of the two stereogenic centres in ephedrine is inverted in pseudoephedrine—so they must be diastereoisomers. Thinking in terms of stereogenic centres is useful, because, just as this compound has two stereogenic centres and can exist as two diastereoisomers, any compound with more than one stereogenic centre can exist in more than one diastereoisomeric form. 

The natural enantiomers of the two diastereomers are (-)-ephedrine and (+)-pseudoephedrine, which does not tell you which is which, or (lR,2S)-(-)-ephedrine and (lS,2S)-(+)-pseudoephedrine, which does. From that you should be able to deduce the corresponding structures. 

For most substances, just their presence in a urine sample means a positive result. Other substances must be present in an amount higher than a certain threshold. According to Dr. Ayotte, a male athlete would have to consume "10 very strong French coffees within 15 min" to go over the 12 mg/L limit for caffeine. Ephedrines and pseudoephedrines, two decongestants that are found in cough remedies and that act as stimulants, have a cut-off level. This allows athletes to take them up to one or two days before a competition. 

In response to the increase noted in 2006 of suspicious shipments of ephedrine and pseudoephedrine to countries in Africa, Central and South America and West Asia, the Project Prism Task Force launched on 1 January 2007 a targeted six-month operation, entitled Crystal Flow. 

Having examined the results achieved during Operation Crystal Flow, the Board notes that increased monitoring of ephedrine and pseudoephedrine caused traffickers to obtain non-scheduled substances. Some of the non-scheduled substances were traded specifically to circumvent controls. The Board therefore urges competent authorities to establish adequate mechanisms for identifying suspicious transactions involving non-scheduled chemical substances. 

Between 1 November 2006 and 31 October 2007, 2,773 individual shipments involving international trade in ephedrine and pseudoephedrine were monitored under Project Prism. Of those shipments, 553 involved ephedrine (totalling 311 tons) and 2,220 involved pseudoephedrine (totalling 1,380 tons). The shipments were exported by 31 countries and territories and were destined to 140 importing countries and territories. The Board launched enquiries into 352 shipments with the Governments of 71 countries and territories. 

The Board is seriously concerned about evidence that Africa has become a major area used for the diversion of precursors of amphetamine-type stimulants. During the period 2006-2007, participants in Project Prism and Operation Crystal Flow identified numerous suspicious shipments to Africa, where the consignments were to be diverted, or to North America or Oceania. In total, over 75 tons of ephedrine and pseudoephedrine were prevented from being diverted to or through Africa. The Democratic Republic of the Congo alone was the destination of seven stopped shipments involving a total of 23 tons of pseudoephedrine in 2007. 

One of the most commonly used methods of diversion in 2007 was the falsification of import permits. The Islamic Republic of Iran, for instance, suspended a consignment of 6 tons of pseudoephedrine that was being sent to Somalia in 2007. The import permit accompanying the order purportedly authorized the importation of 15 tons each of ephedrine and pseudoephedrine. According to data from exporting countries, however, the legitimate needs of Somalia do not exceed 100 kg per year. At the time the present report was issued, Somalia had not yet replied to the enquiries about the shipment. The Board notes with concern that several African States are not in a position to respond in a timely manner to pre-export... 

---