Author Topic: MDA - Precursors, Intermediates, and Impurities  (Read 2877 times)

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Rhodium

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MDA - Precursors, Intermediates, and Impurities
« on: February 10, 2004, 08:20:00 PM »
Spectroscopic and Chromatographic Identification of Precursors, Intermediates, and Impurities of 3,4-Methylenedioxyamphetamine Synthesis
Theodore Lukaszewski

J. Assoc. Off. Anal. Chem. 61(4), 951-967 (1978)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/forensic/mda.lukaszewski.pdf)

Abstract
The ultraviolet, infrared, nuclear magnetic resonance, and mass spectra of a number of precursors, intermediates, and impurities of 3,4-methylenedioxyamphetamine (MDA) synthesis are presented as well as gas-liquid and thin layer chromatographic data. Test results are given on the precursors safrole, isosafrole, and piperonal; the intermediates isosafrole glycol, N-formyl-MDA, and 1-(3,4-methylenedioxyphenyl)-2-nitro-1-propene; the impurities di[1-(3,4-methylenedioxyphenyl)-2-propyl]amine, di[1-(3,4-methylenedioxyphenyl)-2-propyl]methylamine, and 3,4-methylenedioxyphenylpropane; and the product MDA. The data are discussed and 2 methods of MDA synthesis are summarized, in which the precursors, intermediates, and impurities are encountered.


In Canada, 3,4-methylenedioxyamphetamine (MDA) continues to be a popular illicit drug. Because no legitimate therapeutic use exists for this amphetamine, MDA is produced almost exclusively by illicit or clandestine laboratories. Chemicals seized from such laboratories often contain precursors, intermediates, or impurities in addition to, or in the absence of, MDA. Presence of impurities in illicit MDA samples can interfere with some methods of analysis. The identification of these impurities can, however, assist in establishing the method of MDA synthesis being used and can be used in the comparison of samples of diverse origin. Identification of precursors and intermediates helps to establish the synthetic route employed and the potential quantity of MDA that could be produced.

Experimental

Isosafrole, safrole, and piperonal were purchased from Matheson Coleman and Bell Chemicals, Norwood, OH; 3,4-methylenedioxyphenylpropane and 1-(3,4-methylenedioxyphenyl)-2-nitro-1-propene from Alfred Bader Chemicals, Milwaukee, WI; and 3,4-methylenedioxyphenyl-2-propanone from Terochem Laboratories, Edmonton, Alberta, Canada. MDA hydrochloride was obtained from the Health Protection Branch, Department of Health and Welfare, Ottawa, Ontario, Canada. Isosafrole glycol was synthesized by the method of Fujisawa and Deguchi (1). Following the completion of the reaction, the reaction mixture was divided into 2 portions. One portion was evaporated under vacuum to remove the acetone; the residue was taken up in ether and washed with 5% NaHCO3 to remove excess formic acid. The ether was evaporated on a steam bath, and the residue was taken up in a small volume of methanol and hydrolyzed with 10% aqueous NaOH.

Isosafrole glycol was extracted into ether and puri fied by preparative thin layer chromatography (TLC) on silica gel G plates, using benzene as the solvent and Marquis reagent (H2SO4 and formaldehyde) as the visualizing agent. The second portion was prepared according to the method of Fujisawa and Deguchi (1), treated with 15% H2SO4, and extracted with ether to yield 3,4-methylenedioxyphenyl-2-propanone.

N-Formyl-MDA was synthesized from 3,4-methylenedioxyphenyl-2-propanone, formic acid, and formamide in a molar ratio of 1:2.5:5, by heating 7 hr at 160-170°C on an oil bath (2). The reaction solution was diluted with water and extracted with ether which was washed with water and 5% NaHCO3. The ether was evaporated on a steam bath and the N-formyl-MDA was purified by preparative TLC using silica gel C plates and the solvent n-butyl ether-ethyl ether-diethylamine (45+45+5). The visualizing agent was acidified iodoplatinate.

Results and Discussion

Synthesis of MDA from Safrole via the Leuckart Reaction

Safrole is a naturally occurring compound found in oil of sassafras. The treatment of safrole with an ethanol-potassium hydroxide solution causes isomerization of the double bond (3) resulting in the conversion of safrole into isosafrole (Fig. 1). Although the mass spectra of safrole and isosafrole (Fig. 2) are similar due to the facile isomerization of the double bond, the compounds can easily be distinguished by UV (Table 1) or IR spectrophotometry (Fig. 3), The compounds can also be distinguished by gas-liquid chromatography (GLC) (Table 2). Gas chromatograms of isosafrole formed by the base-catalyzed isomerization of safrole or of practical grades of isosafrole show 2 peaks due to the resolution of the cis and trans isomers. The cis isomer elutes from an SE-30 column before the trans isomer (4).

Reaction of isosafrole with formic acid and hydrogen peroxide followed by treatment with sulfuric acid yields 3,4-methylenedioxyphenyl-2-propanone (1,5). Oxidation of an olefinic compound with formic acid and hydrogen peroxide results in the formation of the trans glycol (6). The IR, NMR, and mass spectra of isosafrole glycol are illustrated in Figs 4, 5, and 6, respectively. Figure 6 shows that although the methyl resonance signal at 1 ppm appears as a triplet, expansion of this signal reveals that it actually consists of 2 doublets. This phenomenon is likely caused by the presence of both the threo and erythro forms of the glycol. Although isosafrole glycol is converted to 3,4-methylenedioxyphenyl-2-propanone by treatment with sulfuric acid, it can also be converted to piperonal by reaction with paraperiodic acid (7). This reaction results in the cleavage of the glycol and the formation of piperonal and acetaldehyde. Also, although 3,4-methylenedioxyphenyl-2-propanone is most easily synthesized from isosafrole, it can be prepared from piperonal (8). The IR and mass spectra of 3,4-methylenedioxyphenyl-2-propanone are illustrated in Figs 7 and 8.

The Leuckart reaction is a convenient method for synthesizing amines from ketones and aldehydes. Although numerous reactants and reaction conditions have been used (9), good yields have been reported using a ketone, formic acid, and either ammonia or formamide (2). Reaction of 3,4-methylenedioxyphenyl-2-propanone under reflux conditions results in the formation of N-formyl-MDA (Fig. 1). Hydrolysis of N-formyl-MDA with hydrochloric acid yields MDA. Incomplete hydrolysis can result in the presence of N-formyl-MDA as an impurity of MDA synthesized by the Leuckart reaction. The IR and mass spectra of N-formyl-MDA and MDA are presented in Figs 9 and 10. The NMR spectrum of N-formyl-MDA is shown in Fig. 11.

Synthesis of MDA from Piperonal

Aromatic aldehydes can also be synthesized from corresponding aromatic propenes by treatment with ozone (22-24). Hydrogenation of the resultant ozonide gives the best yields of the aromatic aldehyde (25). Recently, this laboratory has identified 3,4-methylenedioxyphenylpropane in solutions of isosafrole, piperonal, and 1-(3,4-methylenedioxyphenyl)-2-nitro-1-propene seized at a clandestine laboratory. This compound was probably formed as a result of incomplete ozonolysis of isosafrole. Subsequent hydrogenation of the mixture of isosafrole and isosafrole ozonide resulted in the formation of 3,4-methylenedioxyphenylpropane and piperonal. The IR and mass spectra of 3,4-methylenedioxyphenylpropane are illustrated in Figs 18 and 19.

References

(1) Fujisawa, T., & Deguchi, Y. (1954) J. Pharm. Soc. Jpn. 74, 975-977
(2) Crossley, F. S., & Moore, M. L. (1944) J. Org. Chem. 9, 529-536
(3) Fieser, L. F., & Fieser, M. (1961) Advanced Organic Chemistry, Reinhold Publishing Corp., New York, NY, p. 828
(4) Shulgin, A. T. (1967) J. Chromatogr. 30, 54-61
(5) Fujisawa, T., Okada, M., & Deguchi, Y. (1956) Japanese Patent 8573; thru (1958) Chem. Abstr. 52, 11965b
(6) Roberts, J. D., & Caserio, M. C. (1965) Basic Principles of Organic Chemistry, W. A. Benjamin Inc., New York, NY, p. 420
(7) Vogel, A. I. (1970) A Text-Book of Practical Organic Chemistry Including Qualitative Organic Analysis, 3rd Ed., Longman Group Ltd, London, UK, p. 1070
(8) Hirao, I. (1952) Japanese Patent 1770; thru (1954) Chem. Abstr. 48, 2097c
(9) Moore, M. L. (1949) Org. React. 5, 301-330
(10) Barron, R. P., Kuegel, A. V., Moore, J. M., & Kram, T. C. (1974) J. Assoc. Off. Anal. Chem. 57, 1147-1158
(11) Bailey, K., Boulanger, J. G., Legault, D., & Taillefer, S. L. (1974) J. Pharm. Sci. 63, 1575-1578
(12) Lomonte, J. N., Lowry, W. T., & Stone, I. C. (1976) J. Forensic. Sci. 21, 575-582
(13) Monney, E. F. (1968) Annu. Rev. NMR Spectrosc. 1, 6-8
(14) Paudler, W. W. (1971) Nuclear Magnetic Resonance, Allyn & Bacon Inc., Boston, MA, pp. 162-168
(15) Benington, F., Morin, R. D., & Clark, L. C. (1954) J. Org. Chem. 19, 11-16
(16) Benington, F., Morin, R. D., Clark, L. C., & Fox, R. P. (1958) J. Org. Chem. 23, 1979-1984
(17) Gilmen, H., & Blatt, A. H. (1941) Organic Syntheses, Collective Vol. I, John Wiley & Sons Inc., New York, NY, pp. 413-415
(18) Hoover, F. W., & Hass, H. B. (1947) J. Org. Chem. 12, 501-505
(19) Shulgin, A. T. (1966) J. Med. Chem. 9, 445-446

Post 190333 (missing)

(Rhodium: "Shulgin: The Six Trimethoxyamphetamines", Chemistry Discourse)

(20) Ramirez, F. A., & Burger, A. (1950) J. Am. Chem. Soc. 72, 2781-2782
(21) Kawanishi, M. (1955) Japanese Patent 5172; thru (1957) Chem. Abstr. 51, 15574g
(22) Anderson, B. F., Briggs, L. H., Cebalo, T., & Trotman, M. A. (1964) J. Chem. Soc., 1026-1029
(23) Challis, A. A. L., & Clemo, G. R. (1947) J. Chem. Soc., 1692-1697
(24) Subluskey, L. A., Harris, G. C., Maggiolo, A., & Tumolo, A. L. (1959) Adv. Chem. Ser. 21, 149-152
(25) Fieser, L. F., & Fieser, M. (1961) Advanced Organic Chemistry, Reinhold Publishing Corp., New York, NY, pp. 193-195


Rhodium

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Analysis of performic oxidation rxn mixture
« Reply #1 on: April 23, 2004, 03:05:00 PM »
Analysis of 3,4-Methylenedioxyphenyl-2-Propanone and 3,4-Methylenedioxyamphetamine Prepared From Isosafrole
C. Randall Clark, F. Taylor Noggle, Jack DeRuiter and Shridhar Andurkar

Journal of Chromatographic Science, Vol. 32, 393-402 (1994)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/forensic/isosafrole.mdp2p-mda.pdf)

Abstract
The intermediates, products, and by-products obtained in the synthesis of MDA from isosafrole are identified by gas chromatography-mass spectrometry. The initial oxygenation of the conjugated double bond in isosafrole produces a number of products, and the product distribution varies with the reaction solvent. If acetone is used as a cosolvent, the major product is the diol acetonide, while without acetone the product mixture contains the diol, the ketone (methylenedioxyphenyl-2-propanone, MDP-2-P), and mono- and diformates of the diol. These oxygenated products, upon treatment with sulfuric acid, are all converted to the expected ketone, MDP-2-P. Amination of MDP-2-P with formamide (Leuckart conditions) yields the desired amine, MDA, and a pyrimidine by-product, 4-methyl-5-(3,4-methylenedioxyphenyl)pyrimidine, which is characteristic of these reaction conditions.


Rhodium

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MDMA Precursors, Intermediates and Byproducts
« Reply #2 on: June 11, 2004, 09:58:00 AM »
A Study of the Precursors, Intermediates and Reaction Byproducts in the Synthesis of MDMA
R.J. Renton, J.S. Cowie and M.C.H. Oon

Forensic Science International 60, 189-202 (1993)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/mdma.impurity.study.html)

Abstract
3,4-Methylenedioxymethylamphetamine (MDMA) was prepared by three synthetic routes. Analytical data from thin-layer chromatography, gas chromatography and gas chromatography-mass spectrometry of the precursors (safrole and isosafrole), intermediates (isosafrole glycol, piperonylmethylketone, N-formyl-3,4-methylenedioxymethylamphetamine, N-formyl-3,4-methylenedioxyamphetamine and 1-(3,4-methylenedioxyphenyl)-2-bromopropane), reaction by-products and the product MDMA were obtained. Further analyses of MDMA using other techniques including 1H- and 13C-nuclear magnetic resonance spectroscopy, X-ray diffraction, infrared spectroscopy, ultraviolet spectroscopy and high performance liquid chromatography were also carried out. The results were then used as reference data for the identification of MDMA in case samples and also to establish the route of synthesis of illicitly prepared MDMA by the study of trace impurities.