Alkaloids methylephedrine

Nagai s ephedrine was obtained from Ma-Huang and the same alkaloid, together with its stereoisomeride pseudoephednne ( -ephedrine), was isolated by Merck from the European species, E. helvetica C. A. Meyer. From commercial Ma-Huang Smith prepared two additional bases, 1-W-methylephedrine and nnr-d- -ephedrine. Nagai and Kanao added two more, viz., d-W-methyl- -ephedrine and Z-norephedrine, and... 

The thought that transmethylation of noradrenaline may be an initial step in its deactivation in the body makes one wonder whether further transmethylation of adrenaline is also not a common biological process. As a result of studies of the various alkaloids of plants of the Ephedra species, it was noted that not only Z-ephedrine and its stereoisomer d-pseudoephedrine are present but also that -norephedrine, d-norpseudoephedrine, l-methylephedrine, and d-methylpseudoephedrine (8) are present. The quaternary tri-methylammonium compounds corresponding to these were not reported but very... 

The alkaloids dealt with in this section of the chapter are hyoscyamine (1), scopolamine (2), methylephedrine (3), norephedrine (4), ephedrine (5), pseudoephedrine (6), and cephalotaxine (7). 

To improve supercritical C02 solubilities of target alkaloidal salts, an appropriate modifier to raise the polarity of C02 had to be used. As previously mentioned, the most common modifier used in SFE is methanol because of its high solvation parameters, which can greatly increase the resultant polarity of C02. Water has been chosen as another modifier because some alkaloidal salts are freely soluble in water as well as methanol. Moreover, the addition of water into C02 has been reported to improve the extraction yield of some alkaloids [29]. Methanol or water as a modifier was added into the extractor at the concentration levels of 1, 5 and 10% (v/v), respectively. The effect of methanol and water on the solubilities of hyoscyamine (1) and scopolamine (2) is shown in Figure 5. Analogous information on ephedrine derivatives such as methylephedrine (3), norephedrine (4), ephedrine (5), and pseudopehedrine is illustrated in Figure 6. 

While increasing the concentration of water did not show any significant influence, the addition of a greater proportion of methanol yielded great enhancements in the resultant solubilities of the alkaloids, except for methylephedrine (3). These observations may be due to the fact that water is not so miscible as methanol in CO, (Figure 7). Therefore, water was less effective than methanol in terms of the enhancement of the SFE efficiency. Even though the addition of methanol in CO, resulted in slight improvements in solubilities, they were still poor, hence another modifier to enhance the solubilities of the alkaloidal salts was required. 

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. 

All ephedra plants contain phenylalanine-derived alkaloids, including ephedrine, pseu-doephedrine, methylephedrine, and trace amounts of phenylpropanolamine. Previously marketed herbal supplements typically stated total ephedra alkaloid content, although actual levels of individual alkaloid varied depending on raw material and production runs. 

Unlike most of the other alkaloids contained in ephedra (methylephedrine and cathinone are both psychoactive, but the amount contained in unadulterated ephedra is too low to be of clinical significance), ephedrine is also a... 

Figure 5 High-performance strong cation-exchange chromatography of ephedrine alkaloids and synephrine in dietary supplements. UV and fluorescence chromatograms of (A) standard solution ( 3 ng per component, except 1.6 tg of component 1), (B) Xenadrine RFA-1, (C) Xetalean, and (D) Ultra Diet Pep. Analytes 1, ( )-synephrine 2, (-)-norephedrine 3, (+)-norpseudoephedrine-HCI 4, (-)-ephedrine-HCI 5, (+)-pseudoephedrine 6, (-)-A/-methylephedrine 7, (+)-N-methylpseudoephedrine. Reproduced from R. A. Niemann M. L. Gay, J. Agric. Food Chem. 2003, 51, 5630-5638.

Ephedrine is the predominant alkaloid of ephedra plants. Other phenylalanine-derived alkaloids found in ephedra plants are (+)-pseudoephedrine, (—)-norephedrine, (-l-)-norpseudoephedrine, (l)-A-methylephedrine and phenylpropanolamines. Ephedrine is a potent central nervous system (CNS) stimulant. Because ephedra is both an a- and p-adrenergic agonist, ingestion of quantities over 50 mg lead to a rise in blood pressure, heart rate and cardiac output. 

Ephedrine and pseudoephedrine have been measured in guinea pig plasma using HPLC with fluorescence detection, following precolumn derivatization with 5-dimethylamino-napthalene-1-sulfonyl chloride in acetonitrile. The mobile phase was 0.6% phosphate buffer (pH 6.5)-methanol (3 8 v/v). Jacob et al. developed an LC-atmospheric pressure chemical ionization MS-MS method for the quantitaion of various alkaloids found in ephedra-containing dietary supplements and also in plasma and urine from subjects using these supplements. Using this method, the concentrations of ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine, methylpseudoephedrine and caffeine were determined in low nanogram quantities in plasma and urine. The analytical cycle time for this method was 12 min. 

All ephedra plants contain phenylalanine-derived alkaloids. These include (-)-ephedrine, (+)-pseudoephedrine, (-)-norephedrine, (+)-norpseudo-ephedrine (also called cathine because it is a major alkaloid of Catha edulis or khat, a plant used as a stimulant in North Africa), (-)-A-methylephedrine and (+)-A-methylpseudoephedrine, (+)-pseudoephedrine, and (+/-)-norephedrine (phenylpropanolamine). Significant enantioselective differences with regard to both pharmacokinetic and pharmacodynamic effects of these agents are possible. All of these alkaloids have important effects on the cardiovascular and respiratory systems, but not to the same degree. 

E. intermedia collected in one area and in E. gerardiana. Specimens of E. intermedia collected in other areas contained N-methylephedrine in addition, as did E. gerardiana var. sikkimensis, E. nebrodensis var. procera, an unidentified Ephedra sp., and various commercial samples of the drug Ma-Huang. The cactus Opuntia clavata has been shown to contain iV-methyltyramine. Whereas no alkaloids could be detected in a number of Thelocactus spp., seven cacti of the genus Gymnocactus were found to contain various amounts of N-methyl- -phenethylamine, in some cases accompanied by hordenine and iV-methyltyramine. ... 

Several bases, other than ephedrine and i -ephedrine, have been identified in Ma Huang. Smith found 1-iV-methylephedrine (146) and nor-d-i -ephedrine (147) in the sirupy alkaloidal residue obtained in the manufacture of ephedrine. Nagai and Kanao (149), working up thoroughly a Ma Huang extract, confirmed Smith s observations and separated another new alkaloid, d-A-methyl- f -ephedrine. Kanao (150) succeeded in isolating a sixth ephedra base, 1-norephedrine. 

Seven ephedrine alkaloids (synephrine, norephidrine, ephedrine, pseudoephi-drine, norpseudoephidrine, iV-methylephedrine, -methylpseudoephedrine) were extracted fiom various herbal formulations and baseline resolved on a phenyl column (A = 255nm). The use of a 98/2 water (0.1 M sodium acetate pH 4.8)/acetonitrile mobile phase resulted in a 14-min analysis. Synephrine eluted very close to the system void volume [1598]. Aworking curve from 4 to 150 pg/tnL was used and sample detection limits of 0.05 mg/g were reported. 

Fig. 36.6 Optimization of MEKC conditions for cmantioseparation of ephedrine alkaloids using polysodium iV-tmdecenoxycarbonyl-L-leucinate (poly-L-SUCL) as chiral surfactant. In the elec-tropherogram, the effect of surfactant c

Stem (AuaHUANG) contains 1-2% alkaloids composed mainly of /-ephedrine and f-pseudoephedrine, with ephedrine ranging from 30% to 90%, depending on the source. Thus, E. sinica contains ca. 1.3% alkaloids with more than 60% ephedrine E. intermedia contains ca. 1.1% alkaloids with 30-40% ephedrine and E. equisetina contains ca. 1.7% alkaloids with 85-90% ephedrine. Other alkaloids include /-A-methylephedrine, (/-A-methylpseudoephedrine, /-norephedrine, /-norpseudoephedrine (cathine), ephedine, ephedroxane, and pseudoephedroxane (imm-4). The alkaloids are concentrated in the intemodes, with lesser amount (ca. 50%) in the nodes and none in the root (zhou). 

A few years later Marco [17] investigated the Baylis-Hillman reaction of MVK with aliphatic aldehydes (e.g., cyclohexanecarboxaldehyde) under 10-11 kbar with cinchona alkaloids, N-methylprolinol, and N-methylephedrine (Scheme 21.2b). 

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