Pseudoephedrine, enantiomers

Duddu, S.P. Khin-Khin, A. Grant, D.J.W. Suryanarayanan, R. A novel X-ray powder diffractometric method for studying the reaction between pseudoephedrine enantiomers. J. Pharm. Sci. 1997, 86 (3), 340-345. 

Higher differences for the interaction of both the biological and the synthetic receptors with the two enantiomers are found for the propanol-derivatives than for the ethanol-derivatives (Norephedrine, Metaraminol vs. Octopamime, Noradenaline Pseudoephedrine, Ephe-drine vs. Synephrine, Adrenaline). 

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. 

Notice that ephedrine has two chiral carbons. This would give rise to four possible optical isomers- two pairs of enantiomers and four sets of diastereomers. One of the diastereomers is called pseudoephedrine. 

Fast chiral separations were carried out in a quartz chip using a linear imaging UV detector. Figure 6.11 shows the chiral separation of a tocainide derivative (an antiarrhythmic drug). UV imaging with a diode-array detector located along the 25-mm-long separation channel reveals the separation between the two enantiomers. Another chiral separation of pseudoephedrine was achieved in 13 s. The... 

Diastereomeric complexes can also be formed by ion-pairing of an enantiomer with a chiral counterion. In order to form this diastereomeric complex, it has been postulated that at least three interaction points between the ion pair are required [250]. Nearly all of these form weak complexes in aqueous mobile phases. Consequently, the chromatographic methods that have been developed have been either silica or diol columns with low-polarity mobile phases. Enantiomeric amines, such as the beta-blockers, have been optically resolved when (-l-)-lO-camphorsulfonic acid was used as the chiral counterion [251]. Enantiomers of norephedrine, ephedrine, pseudoephedrine, and phenyramidol have all been resolved from their respective enantiomers with n-dibutyltartrate [252]. Enantiomers of naproxen, a chiral carboxylic acid, are resolved from each other by either using quinidine or quinine in the mobile phase [253]. In these studies, silica... 

The basis of the method is akin to the Pfeiffer effect [8] except that, in this instance, the roles of the ligands are reversed and reorganization of the inner sphere and not the outer sphere of the metal is intimately involved. The racemate originates in the solution environment and the enantiomer is part of the coordination compound (vide infra). Calculation of the enantioexcess is most easily done using spectral differences. Figure 5 shows the CD spectrum for the parent complex (lowest curve) where M is Cu(II) and L is L-tartrate in strong base together with a series of curves in which the L-pseudoephedrine concentration has been systematically increased. An isosbestic point at 538 nm is obvious [51]. 

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. 

Early in this chapter, we said that most of the molecules in nature are chiral, arid that Nature usually produces these molecules as single enantiomers. We ve talked about the amino acids, the sugars, ephedrine, pseudoephedrine, and tartaric acid—all compounds that can be isolated from natural sources as single enantiomers. On the other hand, in the lab, if we make chiral compounds from achiral starting materials, we are doomed to get racemic mixtures. So how do chemists ever isolate compounds as single enantiomers, other than by extracting them from natural sources We ll consider this question in much more detail in Chapter 45, but here we will look at the simplest way using nature s enantiomerically pure compounds to help us separate the components of a racemic mixture into its two enantiomers. This process is called resolution. 

Asymmetric Alkylation. 4-Pseudoephedrine ([IS, 2S]-(+)) is a commodity chemical employed in over-the-counter medications with annual worldwide production in excess of 300 metric tons. The enantiomer, /-pseudoephedrine, is also readily available in bulk and is inexpensive. Pseudoephedrine has been shown to be highly effective as a chiral auxiliary in asymmetric alkylation reactions. Treatment of either enantiomer of pseudoephedrine with carboxylic acid chlorides and anhydrides leads to efficient and selective iV-acylation to form the corresponding tertiary amide derivatives (Table 1). Typically, the only by-product in the acylation reactions is a small amount (<5%) of the A,0-diacylated product, which is easily removed by crystallization or flash column chromatography. Because intramolecular 0- -N acyl transfer within pseudoephedrine 3-amino esters occurs rapidly, and because the A-acyl form is strongly favored under neutral or basic conditions, products arising from (mono)acylation on oxygen rather than nitrogen are not observed. 

Figure 5 The structures of the diastereomeric molecules ephedrine and pseudoephedrine (only one enantiomer of each substance is presented).

More accurate results were achieved by exchanging both the enantiomers in prepared non-racemic mixtures of ephedrines and pseudoephedrines with the coordinated L-tartrate ligand of the Cu(II)-L-tartrate host complex dissolved in 0.10 M aqueous base. ... 

The enantiomers of pseudoephedrine were observed to react in the solid state to form the racemic compound.f While the powder patterns of the... 

The rate at which any of the enantiomers is eliminated depends upon the urinary pH. At high pHs, excretion time is prolonged. At low pH ranges, excretion is accelerated. In controlled laboratory studies, where volunteer subjects were given either bicarbonate or ammonium chloride, the higher the urine pH, the more slowly the ephedrine and pseudoephedrine were excreted. Conversely, when the urine pH is low, excretion is accelerated (71). The importance of these observations is hard to assess, because without the addition of bicarbonate, urine pH values in the general population rarely approach 8.0. A study of pseudoephedrine pharmacokinetics in 33 volunteers who were not treated with drugs to alter urine pH found that these parameters could not be... 

Pseudoephedrine concentrations, but not measurements for ephedrine or any of the other enantiomers, have been published by the National Association of Medical Examiners in their Annual Registry report. In 15 children diagnosed with sudden infant death syndrome, the mean blood pseudoephedrine concentration was 3.55 mg/L, the median 2.3 mg/L, with a range of 0.07-13.0 mg/L (SD = 3.36 mg/L). The authors of the study take pains to point out that The data do not allow definitive statements about the toxicity of pseudoephedrine at a given concentration (129). 

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