(pHantasticant)
11-22-03 02:24
No 472459
(Rated as: excellent)
TFSE shows that the article was mentioned in Post 127122 (Acme: "A new breath?", Tryptamine Chemistry). However it is not possible to reply to that post.
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Herein presented procedure is similar to the one from JOC for preparation of phenetylamines from phenylacetic acid. Only in this case methyl acetate derivative is made rather than acetyl chloride as precursor for acetamide which is later on reduced with LAH to corresponding phenetylamine.
Sintas Jose A. ; Vitale Arturo A. Journal of Labelled Compounds and Radiopharmaceuticals 41; 1; (1998) 53-61 (http://pharmacist.the-hive.tripod.com/m
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(Chief Bee)
11-22-03 09:46
No 472505
(Rated as: good read)
Synthesis of Mescaline
Jose A. Sintas and Arturo A. Vitale
Journal of Labelled Compounds and Radiopharmaceuticals, 41(1), 53-61 (1998)
Mescaline and its derivatives have been isolated from plants like peyote and other psychoactive cacti13. Several synthetic methods have been developed to obtain them for pharmacological purposes with low yields (between 12-35%). Condensation of the substituted benzaldehyde with nitroethane readily afforded the corresponding nitropropene, which was further reduced with LiAlH4/THF14-17 to yield the amine.
3,4,5-Trimethoxybenzoic acid chloride has also been used as a starting material in a reaction with diazomethane with the formation of the corresponding diazoketone, which was then subjected to Hoffman19 conditions (AgNO3/NH3) to yield the amide, which was further reduced with LiAlH4/THF, leading finally to mescaline. A similar method for preparing the phenethylamines was used by Hadácek et. al.20 who obtained a low yield of the amine. The diazoketone was converted into the corresponding methyl ester of the 3,4,5-trimethoxyacetic acid, which was hydrolyzed and transformed into the acid chloride. After the amide formation with NH3, it was reduced with LiAlH4/THF to obtain the amine.
Preparation of phenethylamines
In this paper we describe an easy method of preparing some derivatives of phenethylamine under mild conditions with yields higher than those reported in the previous methods, using commercial 3,4,5-trimethoxyphenylacetic acid as starting material. The main metabolite of mescaline is 3,4,5-trimethoxyphenylacetic acid, which appears to be produced enzymatically by a diamine oxidase3. We used this compound as starting material for the synthesis of mescaline, using a similar reaction sequence to that previously developed in our laboratories28. The acid was esterified with methanol and the product was added to an excess of aqueous ammonia. After isolation of the amide it was reduced with lithium aluminum hydride in THF (Scheme 1). The overall yield was 55%.
Synthesis of Mescaline
3,4,5-Trimethoxyphenylacetate methyl ester (1)
A solution of 1.20 g (5.3 mmol) of 3,4,5-trimethoxyphenylacetic acid in 70 ml of methanol with a few drops of concentrated sulfuric acid was heated under reflux for 2 h until complete disappearance of the acid as checked by TLC on silica gel plates, eluting with ethyl acetate: Rf (acid) 0.7, Rf (ester) 0.9. The solution was neutralized with CaCO3, filtered and the solvent was evaporated under reduced pressure. The crude product was recrystallized from methanol to give 1.20 g (5.0 mmol, 96%), mp 40-41°C.
3,4,5-Trimethoxyphenylacetamide (2)
The ester 1 (1.07 g, 4.8 mmol) was dissolved in 20 ml of concentrated aqueous ammonia and stirred at 20 °C for 24 h; the reaction was tested by TLC on silica gel plates eluting with ethyl acetate Rf (amide) = 0.1. To avoid hydrolysis the excess of ammonia was extracted under reduced pressure. The product crystallized from methanol to give 0.90 g (4.0 mmol, 84%), mp 125-126°C.
3,4,5-Trimethoxyphenethylamine (Mescaline) (3)
To a stirred suspension of LiAlH4 (0.40 g, 10.5 mmol) in dry THF (15 ml), the amide 2 (0.44 g, 1.98 mmol) in dry dichloromethane (25 ml) was added slowly. The mixture was refluxed for 36 h under nitrogen until complete disappearance of the amide as checked by TLC, silica gel, eluting with methanol (Rf (amine) 0.2, Rf (amide) 0.8). The mixture was cooled in an ice bath, and treated with several drops of water to decompose the excess of LiAlH4 reagent. The reaction mixture was filtered to remove any remaining solids, dried over anhydrous MgSO4, and solvents removed. The yield was 76% (0.32 g, 1.5 mmol) of a colorless oil, which crystallized in the freezer (-20°C), mp 35-36°C, hydrogen sulfate salt mp 157-158°C .
References
[3] Shulgin, A. T. Hallucinogens, In: Wolff, M. E. Burger's Medicinal Chemistry, 4th. Ed. New York; Wiley and Co. (1981).
[13] Gottlieb, A. Peyote and other Psychoactive Cacti. Kistone Press (1977).
[14] Nichols, D. E., Kostuba, L. J. J. Med Chem. 22, 1264 (1979)
[15] Glennon, R. A., Liebowitz, S. M., Leming-Doot, D. J. Med. Chem. 23, 990 (1980)
[16] Comins, D. L., Brown, J. D. J. Org. Chem. 49, 1078 (1984)
[17] Johnson, M. J., Frescas, S. P., Oberlender, R., Nichols, D. E. J. Med. Chem. 34, 1662 (1991)
[19] Banholzer, K., Campbell, T. W., Schmid, H. Helv. Chim. Acta. 35,1577 (1952)
[20] Hadácek, J., Michaksky, J., Malcholán, L. Chem. Listy. 49, 271 (1955)
[28] Sintas, J. A., Vitale, A. A. J. Lab Comp. Radiopharm. In press. (1997)