[index]

Harmaline and Other Beta-carbolines

by Michael Valentine Smith

Although some of the compounds of this group occur in plants used as hallucinogens for millenia by the aborigines of South America and elsewhere, very little scientific work has been done on them. The Homa of Asia Minor appears to be syrian rue (Peganum harmala) from which harmaline was first isolated. Harmaline (1-methyl-7-methoxy-3,4-dihydro-beta-carboline) is about three times less potent than the 6-methoxy isomer, and very probably the 5-methoxy isomer will be even more active. The 6-methoxy isomer is also called 10-methoxy-harmalan. Activity appears to be greater when the methoxy group is replaced by a longer chain alkoxy group. If a double bond is also placed in the 3-4 position of harmaline, one obtains harmine. These compounds are active at about 200 mg orally. Most of these compounds are probably legal.

Harmaline and Isomers CJC 37,1856( 1959)

Dissolve 3.3 g 4,5, or 6 methoxy (or ethoxy, methyl, etc.)- tryptamine or its HCl salt in 350 ml 0.1 N HCl: heat on steam bath two hours with 1.1 g glycoaldehyde (reaction over when aliquot no longer gives a precipitate with dinitrophenylhydrazine). Filter, concentrate by heating on water bath or evaporate in vacuum; basify with 20% NaOH and extract with ether (best to do in an extractor for eighteen hours). Dry and evaporate in vacuum the extract to get about 5 g residue or oil which may precipitate on standing. Add 250 ml 90% phosphoric acid and heat on steam bath two hours. Evaporate in vacuum (or dilute with water, basify with 20% NaOH; extract with ether in extractor and dry, evaporate in vacuum the extract) to get about 2.5 g harmaline (or analog).

Norharmaline and Isomers JACS 72,2962(1950)

To 24 ml acetic anhydride in 80 ml formic acid add 22 g 4,5 or 6 methoxy (or analog) tryptophan and reflux 1/2 hour. Concentrate to thick syrup on steam bath with vacuum and add slowly with stirring 180 ml water and let stand twelve hours at Oø. Filter, wash with 2% HCl and water to get about 18 g N-formyl-methoxy-tryptophan (I) (recrystallize-benzene-ethanol). 10 g (I), 119 g polyphosphoric acid, 10 ml POCl3 mixed in 500 ml flask with vigorous stirring. Heat on oil bath at 125ø for eighty minutes (HCl and CO2 evolution). Add ice, cool, filter and neutralize filtrate with concentrated NH4OH to get about 5 g norharmaline or isomer. To get harmaline isomers, use 1.4 g N-acetyl-methoxy-tryptophan, 14 g polyphosphoric acid and 3 ml POCl3 and proceed as above.

Harmaline and Isomers JACS 70,223(1948)

Dissolve 27 g 4,5, or 6 methoxy (or ethoxy, methyl, etc.) tryptophan in 50 ml freshly distilled acetaldehyde and 1 L water and heat at 50ø in loosely stoppered flask three hours. Heat on steam bath five hours to remove acetaldehyde, then add 5 L water and heat to boiling. Add 1.2 L 1O% K-dichromate and 240 ml glacial acetic acid and continue heating three minutes. Cool and add excess Na-sulfite; take pH to 8 with Na carbonate Extract with 5 L ether and dry, evaporate in vacuum (or simply evaporate in vacuum after cooling) to get the harmaline isomer.

1,2-Dihydroharmaline JPS 57,269(1968)

Dissolve 4 g glyoxylic acid monohydrate in 220 ml water and add with stirring to a solution of 10 g 4,5, or 6 methoxy-tryptamine-HCl in 80 ml water. Adjust pH to 4 with 1O% KOH and stir five hours at room temperature. Filter and wash with water to get about 4.5 g precipitate. Melt to decarboxylate or to 4 g precipitate add 30 ml concentrated HCl and 100 ml water and heat at 65ø one hour. Add water to dissolve the solid and add excess 10% KOH. Filter to get the title compound or analog.

Harmaline analogs BSC 2262( 1962)

Brominate cyclohexanone-2-COOH (JACS 72,2127( 1950)) and cover to the ethyl ester. Add 1M ethyl-3-Br-cyclohexanone-2-carboxylate to 2M p-methoxy-aniline in cold benzene. Recrystallize the product from ether-petroleum ether and reflux sixteen hours in presence of ZnCl2 in dry ethanol. Filter, evaporate in vacuum and recrystallize-petroleum ether. Dehydrogenate with 5% palladium-carbon and then treat with NaOH (JCS 530(1945)). Heat at 180ø to get the analog of 6-methoxy-norharmine.

Sulfur Analogs ol Harman and Other beta-Carbolines JACS 72,4999(1950)

To synthesize 6-methoxy-3,4-dihydro-beta-carboline (10-methoxy- harmalan), add 5-methoxy-tryptamine to acetic anhydride and let stand twelve hours at 10ø. Dilute with water, basify and extract with methylene Cl and dry, evaporate in vacuum to get melatonin (I). Reflux (I) in xylene in the presence of P2O5 to get the title compounds. Other References: JMC 7,136(1964); JPS 57,1364 (1968), 59,1446(1970); JACS 70,219(1948); JCS 1602(1921), 1203(1951), 4589,4593( 1956); Organic Synthesis 51, 136 (1971). For the preparation of tryptophan-4-acetic acid from tryptophan see JACS 88,3941 (1966).

Sulfur isomeres of harmine, harmaline, etc. J.Het. Chem. 9,1265 (1972). Harmaline and analogs BSC 2058(1973). Beta-carbolines from sugars and tryptamines in 1 step BER 106,2943(1973)


[index]