Ephedrine-Ephedra vulgaris, Ephedra sinica, Ephedra equisetina

A. Ephedrine


Biological Source It occurs in the dried young stems of the Chinese wonder drug Ma HuangEphedra vulgarisEphedra sinica Stapf., Ephedra equisetina Bunge belonging to family Ginetaceae, and also in several other Ephedra species. This is also found in Ephedra geradiana Wall ex. Stapf. (Ephedraceae) (Pakistani Ephedra). There are two most important forage ephedras in the United States, namely: E. nevadensis and E. viridis. The former are is E. nevadensis S. Wats (Ephedraceae) and known as Mormon Tea and Nevada Jointfir.
Chemical Structure

Ephedrine
α-[1-(Methylamino)ethyl] benzene methanol (C10H15HO).
Isolation Ephedrine usually exists singly in Ephedra sinica (1-3%) and E. equisetina (2%).
However, it occurs in association with ~| -Ephedrine (i.e.pseudoephedrine) in E. vulgaris.
However, the ephedrine and pseudoephedrine may be extracted conveniently from the dried young stems of the plant material by adopting the ‘general procedures for alkaloid extraction’ (section 1.7.3), by the help of successive benzene and dilute HCl extractions.
Preparation Ephedrine may be prepared by two methods, namely:
(i) Fermentation method, and
(ii) Synthetic method.
(aFermentation Method: It can be prepared commercially by fermenting a mixture of molasses** and benzaldehyde. The reaction product i.e., methyl benzyl alcohol ketone i.e., C6H5-CH(OH)COCH3, a keto-alcohol is subsequently mixed with a solution of methyl amine and freshly prepared H2-gas is made to pass though it. Thus, we have:

 Fermentation Method
(b) Synthetic Method: Manske et al.*** (1929) synthesized (±)-Ephedrine by the catalytic reduction of 1-phenylpropane-1, 2-dione (or benzoylacetyl) in the presence of methylamine in methanol solution as given below:

Synthetic Method: synthesized (±)-Ephedrine
Stereochemistry Since the ephedrine molecule contains two dissimilar chiral centres, four optically active isomers (or two pairs of enantiomers) are possible theoretically. Freudenberg (1932) put forward the following configurations of ephedrine and ψ-ephedrine (mp 118°C, [α]D ± 51.2°) are as follows:

ephedrine and ψ-ephedrine
Foder et al. (1949, 1950) confirmed that the ephedrine has the erythro-configuration, and yephedrine the threo-configuration as stated below:


erythro-configuration, and yephedrine the threo-configuration
The carbobenzoxy derivative of nor-ψ-ephedrine undergoes intramolecular rearrangement to the O-derivative in an acidic medium. In case, nor-ψ-ephedrine possesses the threo-configuration, then this ultimately gives rise to the favourable trans-orientation of the phenyl and methyl groups in the cyclic intermediate i.e., the steric repulsions are at a bear minimum level. Likewise, the nor-ephedrine shall, therefore, exhibit essentially the crythroconfiguration; and it was further revealed that its corresponding N-carbobenzoxy derivative does not undergo any molecular rearrangement whatsoever in an acidic environment to produce the O-derivative. Therefore, one may infer that the steric repulsions that would take place between the phenyl and methyl groups in Foder et al. (1949, 1950) confirmed that the ephedrine has the erythro-configuration, and ψ-ephedrine the threo-configuration as stated below: the cyclic intermediate is evidently too high to allow its subsequent formation. Thus, it is absolutely possible, on this basis, to differentiate and distinguish between the stereoisomers of ephedrine and ψ-ephedrine.


nor-ephedrine
Characteristic Features The characteristic features of various forms of ephedrine and its salts are as stated under:

The characteristic features of various forms of ephedrine
Special Features
(iEphedrine does not yield a precipitate with Mayer’s Reagent except in concentrated solution.
(ii) Ephedrine in chloroform solution after long standing or on evaporation usually forms ephedrine hydrochloride and phosgene.
(iii) Both ephedrine and pseudoephedrine are fairly stable to heat and when heated at 100°C for several hours does not undergo any decomposition.
(ivEphedrine hydrochloride on being heated with 25% HCl gets partially converted to pseudoephedrine; and this conversion is reversible and soon attains on equilibrium.
Identification Tests
(iColour Test: Dissolve 0.1 g ephedrine in 1 ml water with the addition of a few drops of dilute HCl. Add to it two drops of CuSO4 solution (5% w/v) followed by a few-drops of NaOH (1N) solution when a reddish colour is obtained. Add to it 2-3 ml of ether and shake vigorously, the ethereal layer becomes purple and the aqueous layer turns blue.
(iiFormation of Ephedrine Hydrochloride: Dissolve 0.2-0.3g of ephedrine in 35 ml of chloroform in a stoppered test tube and shake vigorously. Allow it to stand for 12 hours and evaporate the chloroform, when crystals of ephedrine HCl are obtained, and
(iiiFormation of Benzaldehyde Odour: Take 0.05 g of ephedrine in a small porcelain dish and triturate it with a few crystals of pure potassium ferricyanide, [K3Fe(CN)6], add a few drops of water and heat on a water-bath, it gives rise to a distinct odour of benzaldehyde.
Biosynthesis of Ephedrine Alkaloids Interestingly, phenylalanine and ephedrine not only have the same carbon and nitrogen atoms but also have the same arrangement of C and N-atoms i.e., the skeleton of atoms. Noticeably, L-phenylalanine is a precursor, possessing only seven carbons, a C6C1 fragment, gets actually incorporated. It has been observed that phenylalanine undergoes metabolism, probably via cinnamic acid to benzoic acid; and this perhaps in the form of its coenzyme–A ester, which is acylated with pyruvic acid and undergoes decarboxylation during the addition as shown below.

Biosynthesis of Ephedrine Alkaloids
A thiamine PP-mediated mechanism is put forward for the formation of the diketone, and a transamination reaction shall give rise to cathinone. Further reduction of the carbonyl moiety from either face yields the diastereomeric norephedrine or norpseudoephedrine (Cathine). Ultimately,
N-methylation would give rise to ephedrine or pseudoephedrine.
Uses
1. The l-ephedrine is extensively used as a bronchodilator.
2. The d-psendoephedrine is employed widely as a decongestant.

comment 1 nhận xét:

Anonymous said...

Outstanding information - I've been looking for a straightforward ephedrine chemistry guide like this.

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