N-Methylamphetamine

Verster, J., and Van Praag, H.M. A comparative investigation of methylamphetamine and 4-chloro-N-methylamphetamine in healthy test subjects. Pharmako-Psychiatric Neuropsychopharmacologie 3 239-248, 1970. 

Paetsch PR, Baker GB, Caffaro LE, Greenshaw AJ, Rauw GA, et al. 1991. An electron-capture gas chromatographic procedure for simultaneous determination of amphetamine and N-methylamphetamine. J Chromatogr Biomed Appl 573 313. 

This synthetic procedure, using the hydrochloride salt of the amine and sodium cyanoborohydride in methanol, seems to be quite general for ketone compounds related to 3,4-methylenedioxyphenylacetone. Not only were most of the MD-group of compounds discussed here made in this manner, but the use of phenylacetone (phenyl-2-propanone, P-2-P) itself appears to be equally effective. The reaction of butylamine hydrochloride in methanol, with phenyl-2-propanone and sodium cyanoborohydride at pH of 6, after distillation at 70-75 °C at 0.3 mm/ Hg, producedN-butylamphetamine hydrochloride (23.4 g from 16.3 g P-2-P). And, in the same manner with ethylamine hydrochloride there was produced N-ethyl-amphetamine (22.4 g from 22.1 g P-2-P) and with methy lamine hydrochloride there was produced N-methylamphetamine hydrochloride (24.6 g from 26.8 g P-2-P). The reaction with simple ammonia (as ammonium acetate) gives consistently poor yields in these reactions. 

Fogassy, E., Acs, M., Faigl, F., Simon, K., Rohonczy, J., and Ecsery, Z. Pseudosymmetry and chiral discrimination in optical resolution via diastereoisomeric salt formation. The crystal structures of (R)- and (5)-N-methylamphetamine bitartarates, J. Chem. Soc. Perkin Trans 2. 1986, 1881-1885 Acta Cryst. S. 1985, 40A C81. 

Kozma, D., and Fogassy, E. Solvent-free optical resolution of N-methylamphetamine by distillation after partial diastereoisomeric salt formation, Chirality, 2001,13, 428-430. 

MDA (3,4-methylenedioxyamphetamine) was available in the 1960 s. The molecule produces empathy in human subjects. In the 1970 s, MDMA(3,4-methylenedioxy-N-methylamphetamine) appeared, followed by MDEA(3,4-methylenedioxy-N-ethylamphetamine) in the 1980 s. All of these molecules were placed in schedule 1 because they were being abused. 

Unlike dopamine, 5-HT is released into the general neuronal regions, not just into synapses, and diffuses over a much larger area to activate neuronal 5-HT receptors. 3,4-Methylenedioxy-N-methylamphetamine (MDMA), cocaine, tricyclic antidepressants, and SSRIs all inhibit the removal of 5-HT from neuronal sites. 

There were generated glistening crystals of 4-methoxy-N-methylamphetamine hydrochloride (METHYL-MA or DOONE) that weighed, after washing with Et20 and air drying to constant weight, 11.0 g and which had a mp of 177-178 °C. The same base can be made by the action of ethyl chloroformate on 4-MA in the presence of triethylamine to make the carbamate, or the action of formic acid to make the formamide. These can then be reduced with LAH to this same end product. 

MDMA MDM ADAM ECSTASY 3,4-METHYLENEDIOXY-N-METHYLAMPHETAMINE SYNTHESIS (from MDA) A solution of 6.55 g of... 

After filtering, Et20 washing, and air drying, there was obtained 6.2 g of 2,5-dimethoxy-N-methylamphetamine hydrochloride (METHYL-DMA) as fine white crystals with a mp of 117-118 deg C. The mixed mp with 2,5-DMA (114-116 deg C) was depressed to 96-105 deg C. An alternate synthesis gave the same overall yield of an identical product, but started with 2,5-DMA. It required two synthetic steps. The free base amine was converted to the crystalline formamide with formic acid in benzene using a Dean Stark trap, and this intermediate was reduced to METHYL-MDAwith LAH. 

This phenolic amine, 5-hydroxy-2-methoxy-N-methylamphetamine is just a methyl group away from METHYL-DMA it could either be methylated to complete the synthesis, or METHYL-DMA could be demethylated to form this phenol. There is plentiful precedent for both of these reactions occuring in the body. It is always intriguing when drugs which show distinctly different actions can, in principle, intersect metabolically at a single structure. One wonders just what the pharmacology of that common intermediate might be. 

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