Aminorex (cis (±)-4,5-dihydro-5-phenyl-2-oxazolamine)

aminorex (cis (±)-4,5-dihydro-5-phenyl-2-oxazolamine) 

(RS)-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine

Aminorex (Menocil, Apiquel, aminoxaphen, aminoxafen, McN-742) is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension. In the U.S., it is an illegal Schedule I drug, with no medical use and poor safety profile.

Aminorex, in the 2-amino-5-aryl oxazoline class, was developed by McNeil in 1962. It is closely related to 4-methylaminorex. Aminorex has been shown to have locomotor stimulant effects, lying midway between dextroamphetamine and methamphetamine. Aminorex effects have been attributed to the release of catecholamines.

It was discovered in 1962 by Edward John Hurlburt (U.S. Patent 3,115,494), and was quickly found in 1963 to have an anorectic effect in rats. It was introduced as a prescription appetite suppressant in Germany, Switzerland and Austria in 1965, but was withdrawn in 1972 after it was found to causepulmonary hypertension in approximately 0.2% of patients, and was linked to a number of deaths

The synthesis was first reported in a structure-activity relationship study of 2-amino-5-aryl-2-oxazolines, where aminorex was found to be approximately 2.5 times more potent than D-amphetamine sulfate in inducing anorexia in rats, and was also reported to have CNS stimulant effects. This racemic synthesis involved an addition/cyclization reaction of 2-amino-1-phenylethanol with cyanogen bromide (mechanism shown below).^[4] A similar synthesis has been also published.

The proton NMR spectrum for aminorex and its structural assignments are provided in Fig. 2. Unlike the spectrum of methylaminorex, no upfield (<3 δ) absorbances characteristic of a methyl group occur in the ¹H NMR spectrum of the confiscated sample.

The obtained spectrum is indicative of the assigned structure of aminorex, with the phenyl group appearing at 7.35 δ, a benzylic methine triplet at 5.46 δ, the exchangeable amino group at 5.2 δ, and the nonequivalent hydrogens of the methylene group β to the phenyl ring at 4.13 and 3.65δ. 






The ¹³C NMR spectrum is equally supportive of the 4,5-dihydro-5-phenyl-2-oxazolamine structure, with no upfield methyl signal and with the remaining carbon absorbances occurring at their expected 8 values (Fig. 3).
Decoupling analysis of this spectrum indicates quaternary and secondary carbons at 160.89 δ, 140.62 δ, and 60.63 δ, corresponding to the imine carbon (C-2), the phenyl carbon attached to C-5, and the methylene carbons (C-4). The remaining methine carbons manifested signals at 128.62 δ, 128.14 δ, 125.66 δ, corresponding to the phenyl carbons, and at 81.43 δ, which was assigned as the C-5 absorbance.

Mass spectrometric analysis was performed on the sample in question by probe distillation introduction. This technique indicated the presence of impurities which vaporized at higher temperatures than did the object compound. An El spectrum of the material is given in Fig. 4. The fragmentation pattern and the molecular ion are indicative of the aminorex structure and compare well with those of standard spectra¹². The M⁺peak is 162 m/z. Loss of the carboxamide group CONH₂ produces the fragment at 118 m/z, while generation of protonated benzyl alcohol results in the m/z = 107 fragment. Other important fragments include the tropylium ion (91 m/z) and the phenyl cation at 77 m/z. The base peak of the spectra (56 m/z) appears to be due to the imine structure, NH₂-C=N-CH₂⁺. 

1. Davis, F. T. and Brewster, M. E., "A Fatality lnvolving U4Euh, a Cyclic Derivative of Phenylpropanolamine," Journal of Forensic Sciences, Vol. 33, No. 2, March 1988, p. 549.
2. Yelnasky, J. and Katz, R., "Sympathomimetic Actions of cis-2-Amino-4-Methyl-5-Phenyl-2-Oxazoline," Journal of Pharmacology and Experimental Therapeutics, Vol. 141, 1963, p. 180
3. Wollueber, H., Hiltmann, R., Stoepel, K., and Kroneberg, H., "Stereochemische Untersuchungen über Arzneimittel, 1-Phenyl-3-imino-perhydro-3-H-oxazolo(3,4-a)pyridine, mit blutdrucksteigender Wirksamkeit," European Journal of Medicinal Chemistry, Vol. 15, 1980. p. 111.
4. Roszkowski, A. and Kelley, N., "A Rapid Method for Assessing Drug Inhibition of Feeding Behavior," Journal of Pharmacology and Experimental Therapeutics, Vol. 140, 1963, p. 367.
5. Poos, G., "2-Amino-5-Aryloxazoline Products," U.S. Patent No. 3,161,650 (1964).
6. Lawn, J. C., "Schedules of Controlled Substances; Temporary Placement of 3,4-Methylenedioxy-N-Ethylamphetamine, N-Hydroxy-3,4-Methylenedioxyamphetamine and 4-Methylaminorex into Schedule I," Federal Register, Vol. 52, Oct. 1987, pp. 38225-38226.
7. Lawn, J. C., "Schedule of Controlled Substances; Temporary Placement of 2-Amino-4-Methyl-5-Phenyl-3-Oxazoline (4-Methylaminorex) into Schedule I," Federal Register, Vol. 52, Aug. 1987, pp. 30174-30175.
8. Gurtner, H., "Aminorex and Pulmonary Hypertension," Cor et Vasa, Vol. 27, 1985, p. 160.
9. Gurtner, H., "Pulmonary Hypertension, 'Plexogenic Pulmonary Arteriopathy,' and the Appetite Depressant Drug Aminorex: Post or Propter?" Bulletin de Physio-pathologie Respiratoire, Vol. 15, Sept.-Oct. 1979, p. 897.
10. Seiler, K., "Aminorex and Pulmonary Circulation," Arzneimittel-forschung, Vol. 25, May 1975, p. 837.
11. Poos, G. I., Carson, J., Rosenau, J., Roszkowski, A., Kelly, N., and McGowir, J., "2-Amino-5-Aryl-2-Oxazolines: New Anorectic Agents," Journal of Medicinal Chemistry, Vol. 6, 1963 pp. 266-272.
12. Smith, F. P. and Kidwell, D. A., "Final Report: Designer Amphetamines - Their Synthetic and Detection," Naval Research Laboratory, US Department of the Navy, Washington, DC, August 1989, p. 11.