Phenylethylamine Alkaloids

2.7.1 Phenylethylamine Alkaloids

The important alkaloids belonging to this category are, namely: Ephedrine, Hordenine, Mescaline and Narceine, which shall be discussed as under:

A. Ephedrine

Biological Source It is obtained from the dried tender stems of the Chinese wonder drug Ma Huang which is being used in the Chinese systems of Medicine for more than five thousand years. It occurs in Ephedra vulgaris Hook. F. (E. gerardiana Wall); Ephedra sinica Stapf. (1-3%); Ephedra equisetina Bunge. (2%) belonging to the natural order Gentaceae; and several other Ephedra species. Besides, it is also found in the roots of Aconitum napellus L. (Ranunculaceae) (Aconite, Monkshood, Blue Rocket); and Ephedra nevadensis S. Wats. (Ephedraceae) (Mormon Tea, Nevada Jointfir).
Chemical Structure

α-[1-(Methylamino)-ethyl] benzene-methanol; (C10H15NO).
Isolation Both ephedrine and pseudoephedrine may be extracted from the plant source by general procedures described earlier under alkaloid extraction, through successive and dilute HCl extraction procedures.
However, the separation of ephedrine from pseudoephedrine may be accomplished by means of their corresponding oxalate salts; the ephedrine oxalate being comparatively less soluble in cold water than pseudoephedrine oxalate separates out first.
Note: Chloroform is not ragarded as an appropriate solvent for extraction of ephedrine as it forms its corresponding ephedrine hydrochloride salt after its dissolution in CHCl3 and subsequent evaporation of solvent.
Fermentation Method Ephedrine may be prepared on a commercial scale economically by the process of fermentation using a mixture of molasses (a by-product of sugar industry containing 8-10% of cane sugar i.e., C6H12O6) and benzaldehyde. The resulting keto-alcohol i.e., benzylhydroxy methyl ketone is subsequently mixed with a solution of methylamine and treated with hydrogen gas to yield a racemic mixture of ephedrine as given below:

Fermentation Method Ephedrine
Characteristic Features The characteristic features of some racemic forms, optical isomers and their respective salts are enumerated below:
1. dl-Ephedrine (Synonyms: Racephedrine; Racemic Ephedrine): The crystals have mp 79°C; and are soluble in oils, chloroform, ether, water, and ethanol.
2. dl-Ephedrine Hydrochloride (Synonyms: Ephetonin; Racephedrine Hydrochloride) (C10H15NO.HCl): The crystals have mp 187–188°C; and pH 6.0. Its solubility profile are: 1 g dissolves 4 ml water, 40 ml of 95% ethanol at 20°C; and practically insoluble in ether.
3. dl-Ephedrine Sulphate (Synonym: Racephedrine Sulphate) (C10H15NO.H2SO4): The crystals have mp 247°C, and are soluble in ethanol and water. Its solution has a pH of 6.0.
4. l-Ephedrine [L-Erythro-2(methylamino)-1-phenylpropan-1-ol): It is obtained as waxy solid, crystals or granules, having a soapy feel and the substance gradually decomposes on exposure to light. It may contain water upto ½ mole (5.2%). However, the anhydrous product is hygroscopic in nature having mp 34°C. Interestingly, the absorption of water enhances mp to 40°C; and bp 255°C. The pH of aqueous solution (1 in 200) is 10.8. 1 g of it dissolves in 20 ml water, 0.2 ml ethanol; and freely soluble in ether, chloroform and oils.
5. l-Ephdrine Hydrochloride (Synonyms: Ephedral; Senedrine): It is obtained as orthorhombic needles having mp 216-220°C, which are affected by light. Its specific optical rotation [α]D25 -33 to –35.5° (C = 5). The pH of aqueous solution (1 in 200) is 5.9. 1 g dissolves in 3 ml water, 14 ml ethanol; and is found to be practically insoluble in chloroform and ether.
6. l-Ephedrine Sulphate: Its orthorhombic needles have mp 245°C (decomposed) and are affected by light. Its specific optical rotation [α]D25 -29.5 to –32.0° (C = 5). 1 g dissolves in 1.2 ml water and 95 ml ethanol; and freely soluble in hot alcohol. Its pH is about 6.
Identification Tests
1. Dissolve 0.01 g of ephedrine in 1 ml water by adding a few drops of dilute HCl. To this add two drops of CuSO4 solution (5% w/v) followed by a few-drops of NaOH solution when a reddish colour is developed. Now, add 2-3 ml ether and shake the contents thoroughly; the ethereal layer turns purple while the lower aqueous layer becomes blue.
2. Dissolve 0.2 g of ephedrine in 30 ml of chloroform in a stoppered flask and shake the contents vigorously. Allow the mixture to stand for at least 12 hours at room temperature and then remove the chloroform over an electric water bath. The crystals of ephedrine hydrochloride separate out.
3. Triturate 0.05 g of ephedrine with a few crystals of [K3Fe(CN)6i.e., potassium ferricyanide, followed by a few drops of water and heat on a water bath slowly when a distinct odour of benzaldehyde (i.e., similar to the odour of bitter almonds) in given out.
l. l-Ehedrine is used extensively as a bronchodilator.
2. It also exerts excitatory action on the CNS and produces noticeable effects on skeletal muscles.
3. It is also employed as nasal decongestant.

B. Hordenine

Synonyms Anhaline; Eremursine; Peyocactine.
Biological Sources It is obtained from the plant of Lophophora williamsii (Lamaire) Coult. (Catctaceae) (Peyote) and Selenicereus grandiflorus Britt and Rose (Coctaceae) (Night Blooming Cereus).
Chemical Structure

4-[2-Dimethylamino) ethyl] phenol; (C10H15NO).
Isolation It is isolated from barley germs by the method suggested by Erspamer and Falconieri* (1952).
Characteristic Features
1. It is obtained as orthorhombic prisms from ethanol or benzene +ether; as needles from water having mp 117-118°C.
2. It sublimes at 140-150°C and has a bp11 173°C.
3. Solubility Profile: It is very soluble in chloroform, ethanol and ether; 7 g dissolves in 1 L of water; practically insoluble in petroleum ether; and sparingly soluble in benzene, xylene and toluene.
Identification Test Hrodenine readily forms its hydrochloride salt which is obtained as needles from ethanol having mp 177°C; and it is very soluble in water.
Uses It exhibits digitalis-like activity.

C. Mescaline

Synonym Mezcaline
Biological Sources It is obtained from Peyote (Mescal Buttons) the flowering heads of Lophophore williamsii (Lemaire) Coult. (Coctaceae) and the cactus Trichocereus pachanoi Britton and Rose (Cactaceae) (Achuma, San Pedro Aguacolli).
Chemical Structure

3, 4, 5-Trimethoxybenzeneethanamine; (C11H17NO3).
Isolation Mescaline has been successfully isolated from the plant source by Banholzer et al.* (1952).
Characteristic Features
1. The crystals have mp 35-36°C and bp12 180°C.
2. It is moderately soluble in water; freely soluble in ethanol, chloroform and benzene; and practically insoluble in ether and petroleum ether.
Identification Tests It forms readily a variety of salts, such as:
1. Mescaline Hydrochloride (C11H17NO3C11H17NO3.HCl): The needles have mp 181°C and freely soluble both in ethanol and water.
2. Mescaline Sulphate Dihydrate [(C11H17NO3)2.H2SO4.2H2O)]: It is obtained as prisms having mp 183-186°C; soluble freely in methanol and hot water; and sparingly soluble in ethanol and cold water.
3. Mescaline Acid Sulphate (C11H17NO3.H2SO4): The crystals have mp 158°C.
4. N-Acetylmescaline: It mostly occurs naturally, mp 94°C.
5. N-Methylmescaline: It occurs naturally, bp 130-140°C.
6. N-Benzoylmescaline: It is obtained as needles from aqueous ethanol having mp 121°C; and is found to be very soluble in ether and ethanol.
Note: This is a controlled substance (hallucinogen) listed in the US code of Federal Regulations
[Title 21 Part 1308.11 (1995)].
* Erspamer and Falconieri, Naturniss39, 431 (1952).

D. Narceine

Biological Source It is obtained from the dried latex (opium) by incision from the unripe capsule of Papaver somniferum Linn., (Papaveraceae) to the extent of 0.1-0.5%.
Chemical Structure

6-[[6-[2-(Dimethylamino) ethyl]-4-methoxy-1, 3-benzodioxol-5 yl] acetyl]-2, 3-dimethoxy benzoic acid; (C23H24NO8).
Isolation The isolation of nareceine from morphine mother liquors is tedious.** It may also be prepared from narcotine or gnoscopine.***
Characteristic Features
1. The anhydrous material is very hygroscopic in nature having mp 138°C; and it: uvmax (ethanol) is 270 nm (log € 3.98).
2. Usually the alkaloid is obtained as the trihydrate.
3. The clusters of silky and prismatic needles are obtained from water having mp 176°C.
4. Its dissociation constants are pKb at 20° = 10.7; Kb = 2 × 10–11; pka = 9.3; Ka = 5 × 10–10.
5. Th pH of its saturated solution is 5.8.
6. Solubility Profile: 1g dissolves in 770 ml water; 220 ml boiling water; moderately soluble in hot alcohol; almost insoluble in benzene, chloroform, ether, petroleum ether.
7. It forms salts with solutions of alkali hydroxide and also with dilute mineral acids.
Identification Test Ethylnarceine Hydrochloride (C25H32ClNO8) (Synonym: Narcyl): It is obtained as plates from water having mp 208-210°C. It is slightly soluble in cold water, insoluble in ether; and freely soluble in hot water, ethanol and chloroform.
1. Narcyl is used as a narcotic analgesic.
2. Narcyl is also employed as an antitussive agent.
Biosynthesis of Hordenine and Mescaline Decarboxylation of L-tyrosine via pyridoxal phosphate (PLP) yields the simple phenylethylamine derivative tyramine, which an di-N-methylation gives rise to hordenine. Besides, phenylethylamine derivatives commonly exhibit either 3, 4-di- or 3, 4, 5-trihydroxylation reactions, and are subsequently derived via dopamine i.e., the decarboxylation product obtained from L-DOPA (L-dihydroxyphenylalaline). The two variants of catecholamines, namely: first, a mammalian neurotransmitter noradrenaline (norepinephrine), and secondly, the most common ‘fight or flight’ hormone released in animals from the adrenal gland due to fear phychosis or stress adrenaline (epinephrine). Furthermore, these two compounds are formed due to β-hydroxylaton and N-methylation of dopamine.
Lastly, aromatic hydroxylation and O-methylation convert dopamine into mescaline. All these reactions have been shown sequentially as given below.
* Banholzer et al. Helv. Chim. Acta35, 1577 (1952).
** Merek, Chem. Ztg., 13, 525 (1889)
*** Roser, Ann. 247, 167 (1888).

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