Harmine

Other Names l-Methyl-7-methoxy-P-carboline 7-Methoxy-l-methyl-9H-pyrido[3,4-b]indole Ban-isterin Banisterine Harmin Hamiine Leucoharmine Telepathin Telepathine Yagein Yageine CA Index Name 9H-Pyrido[3,4-b]indole, 7-methoxy-l-methyl-CAS Registry Number 442-51-3 Merck Index Number 4616 Chemical Structure 

Chemical/Dye Class Fluorescent, Heterocyclic Molecular Formula C13H12N2O Molecular Weight 212.25 pH Range 7.2-8.9 

Color Change at pH Blue fluorescence (7.2) to yellow fluorescence (8.9) pKa 7.7 

Physical Form White to off-white crystals Solubility Slightly soluble in water, ethanol, ether, chloroform UV-Visible 241 nm, 301 nm, 336 nm Melting Point 261°C (decompose) 

Boiling Point (Calcd.) 421.4 40.0°C Pressure 760 Torr Synthesis Synthetic methodsi  

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On reduction harmaline yields tetrahydroharmine, C13HJ5ON2, m.p. 199°, and on gentle oxidation is converted into harmine. ... 

Harmine, C13H12ON2, crystallises from methyl alcohol in colourless rhombic prisms, m.p, 266°, [a]D 0°. The hydrochloride, m.p. 269-5-270-5° (Chen ), nitrate, platinichloride, m.p. 264-6°, acid chromate and oxalate crystallise well. The salts show a deep blue fluorescence in dilute solution. Harmine behaves as a monoacidic base. It gives a methiodide, from which methylharmine, needles, m.p. 209°, may be prepared, and this in turn yields methylharmine methiodide. On demethylation harmine yields the phenolic base harmol, C12H10ON2, m.p. 321°.i ... 

Constitution of Harmine and Harmaline. Harmaline is a dihydro-harmine. Both bases on reduction yield tetrahydroharmine and in both the single oxygen atom is present as methoxyl. Knowledge of the constitution of the two alkaloids is mainly due to the work of O. Fischer and his colleagues, and more recently to the researches of Perkin and Robinson. 

In view of its possible interest as the mode of formation of harman, harmine and harmaline in plants, Kermack, Perkin and Robinson investigated the conversion of tryptophan (II) into harman (I) and nor-harman (IV). The latter is produced when tryptophan is condensed with formaldehyde in presence of dilute sulphuric acid and the product (III) oxidised by potassium dichromate. Harman is formed when formaldehyde in this process is replaced by acetaldehyde. 

Since 1921 much work has been done to confirm the formula for harmine and that provisionally assigned to harmaline, both by synthetic methods and by reactions to explore and explain peculiarities in the... 

Spath and Lederer have published a simplified synthesis of harmaline consisting in treating the acetyl derivative of 6-methoxytryptamine (XXIX) with phosphorus pentoxide in boiling xylene, the harmaline thus produced being converted into harmine by catalytic dehydrogenation at 200°. 

To these alkaloids Asahina and Mayeda assigned formulae, based on the reactions described, and on the first assumption, referred to above, that 2- -aminoethylindole was the scission product of evodiamine. Kermack, Perkin and Robinson pointed out that the evidence did not exclude the possibility that the base produced was in reality 3-)3-amino-ethylindole, in which case evodiamine and rutascarpine could be represented by the following formulas, which would bring them into line with harmine. 

The crude drug, Adhatoda vasica, is used in India as a remedy for asthma. According to Chopra, vasicine produces broncho-dilation and might be used clinically as an expectorant. A detailed pharmacological examination of peganine in comparison with harmine has been made by Tutaev and Makarova. ... 

The nomenclature used to describe the fused benzene-pyrrole-pyridine system of the compounds under discussion has been repeatedly modified, and the compounds have been numbered in an astonishing variety of ways since Perkin and Robinson introduced the name carboline for the ring system, which was encountered for the first time in the harmala alkaloids. In the earliest version of carboline nomenclature, the parent compound of the series, whose trivial name was norharman, was referred to as 4-carboline and numbered as in 1. Harmine (2) then became ll-methoxy-3-methyl-4-carboline. 

The numbering of the carboline system was later modified to that shown in 4, and the position of the basic nitrogen in the pyridine ring was designated by a Greek letter. Harmine thus became 8-methoxy-2-... 

According to the Ring Index, the system is classified as pyrido-indole and numbered as in 6 (harmine = 7-methoxy-1-methyl-9 -pyrido[3,4-fc]indole). This is the nomenclature adopted by Chemical Abstracts, according to which a-carboline (5) is 9 -pyrido[2,3-6]indole, jS-carboline (6) is 9jy-pyrido[3,4-6]indole, y-carboline (7) is pyrido[4,3-6]indole, and S-carbohne (8) is 5jy-pyrido[3,2-fc]indole. 

The numbering used in 6 was introduced also in conjunction with the carboline nomenclature (harmine = 7-methoxy-l-methyl-jS-carbo-line). This is the system which, at the present time, appears to be most widely adopted. The same numbering has been used without the Greek letter conventions (harmine = 7-methoxy-l-methyl-2-carbo-line). 

The bromination of 7-methoxy-l-methyl-j8-carboline (harmine) was studied by Fischer. He obtained a compound, Ci3Hi2Br4N20, which he called tetrabromoharmine, by the action of bromine water on a dilute sulfuric acid solution of harmine. The bromination of harmine was reinvestigated by Hasenfratz, who found that two products (both hydrobromides) could be isolated when harmine was treated with bromine in aqueous acetic acid. The major component formed colorless needles and was called bromoharmine hydrobromide (free base colorless needles, m.p. 275°), while the product obtained in lesser amount was a canary-yellow dihydrate which was named isobromoharmine hydrobromide (free base colorless needles, m.p. 

The alkylation of carboline derivatives has been repeatedly studied. The first quaternary A-alkyl carbolinium salts to be described were those prepared in connection with the elucidation of the structure of harmine (methiodide, methochloride, and methosulfate Other j8-carbolinium salts were subsequently prepared in connection with systematic studies of the site of alkylation and of the... 

In the course of structural investigations of a number of jS-carboline alkaloids, reactions leading to ring cleavage have been encountered. Oxidation of harmine (271) and of harmaline... 

A similar oxidative ring opening is reported to take place when 7-methoxy-l-styryl-j8-carboline is oxidized. The product, which was reported to be identical with harminic acid, is presumably the related compound 283 (R = CO2H or H). 

These authors formulated the major steps in the biogenesis of the harmala bases as a condensation of a tryptamine derivative (460) with acetaldehyde to yield a l,2,3,4-tetrahydro-)3-carboline (461), which on oxidation in two stages would give harmaline (462 R = OCH3) and then harmine (463 R = OCH3). 

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