Technical Note

Synthesis of trans-4-Methylaminorex from
Norephedrine and Potassium Cyanate

Walter R. Rodriguez,* M.S. and Russell A. Allred, Ph.D.
U.S. Department of Justice
Drug Enforcement Administration
Southeast Laboratory
5205 NW 84th Avenue
Miami, FL 33166
[email: walter.r.rodriguez -at- usdoj.gov]

ABSTRACT: An unusual and previously undocumented synthesis for trans-4 methylaminorex was determined to be in use at a clandestine laboratory. Conventional references unanimously describe the use of norephedrine (phenylpropanolamine, 2-amino-1- phenylpropan-1-ol) and cyanogen bromide to synthesize cis-4-methylaminorex. In this case, use of norephedrine and potassium cyanate gave predominantly trans-4-methylaminorex. This new synthesis is explored, and its intermediates and byproducts are characterized.

KEYWORDS: 4-Methylaminorex, Oxazoline, Norephedrine, Phenylpropanolamine, Potassium Cyanate, Diastereomers, Clandestine Laboratory, Controlled Substance Analogue, Isomer, Forensic Chemistry

Introduction

In December 2004, a clandestine laboratory raid was conducted at a private residence in Ft. Lauderdale, Florida. The operator was an educated chemist (degree in Chemical Engineering). In his post Miranda statements, he indicated that he had been synthesizing “Euphoria” (4-Methylaminorex, also known as: U4Euh, Ice*, 4-MAR, Intellex) in his home since June 2004, and stated that he was capable of producing batches as large as 1 kilogram. He also admitted to manufacturing lesser quantities of amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine. The chemicals and materials seized at the site supported his claims.

Of particular interest was 20 kilograms of a white powder alleged to be potassium cyanate (later confirmed to be a cyanate salt (cation not identified)). This compound had never been previously reported as a primary reagent at a clandestine laboratory. By the cook’s account, he followed an internet recipe for synthesis of trans-4-methylaminorex from norephedrine and potassium cyanate.

This statement was surprising in that exhaustive literature searches indicated that the only reported syntheses starting with norephedrine used cyanogen bromide (not potassium cyanate) and produced cis (not trans) 4-methylaminorex [1]. The internet recipe (which had been posted on a website dedicated to drug abuse) was derived from the work of Fodor and Koczka [2], who investigated the stereochemistry of the conversion of 2-ureidoalcohols to oxazolidines. Included were the conversions of ephedrine and pseudoephedrine to the corresponding 2-ureidoalcohols, followed by their cyclization to their corresponding oxazolidines. Extrapolating from these results, the internet author theorized that the same reaction sequence could be applied to norephedrine, resulting in trans-4-methylaminorex [3] (Figure 1).

Klein et al. reported that the cyanogen bromide method is stereoselective and proceeds with retention of configuration at the benzylic carbon (C-1) of norephedrine [4]. Thus, norephedrine produces cis-4-methylaminorex and norpseudoephedrine yields trans-4-methylaminorex (Figure 1). Therefore, if the classic synthesis (with cyanogen bromide) had been used, the trans isomer could only have been synthesized from norephedrine if stereochemical inversion was first performed on norephedrine to produce norpseudoephedrine [4]. This “stereoinversion” requires a tedious series of steps that is unlikely to ever be attempted in a clandestine setting. In contrast, in the potassium cyanate synthesis, trans-4-methylaminorex is allegedly generated directly from norephedrine without preliminary “stereoinversion” at C-1.

trans-4-Methylaminorex	cis-4-Methylaminorex

Figure 1. The Diastereomers of 4-Methylaminorex (the Corresponding
Enantiomers Have Been Omitted for Clarity).

Analysis of the seized exhibits confirmed that trans-4-methylaminorex was in fact the major product. Herein, the synthesis of trans-4-methylaminorex from norephedrine and potassium cyanate is characterized.

Legal Issues

When 4-methylaminorex was first temporarily controlled [5] in the summer of 1987, very little was known regarding the individual optical isomers of both the cis and trans forms [6]. Since the clandestine procedure employed at the time resulted in the production of the racemic cis isomer, there was no evidence that the trans isomer had any abuse potential, much less if it even existed in the clandestine market. As a result, only the cis isomer was explicitly controlled [7]. This marked the first and to date the only time a specific diastereomer has been listed as a controlled substance.

The production of trans-4-methylaminorex therefore raised an interesting legal issue. Since cis-4-methyl-aminorex is a Schedule I controlled substance, it can be inferred that “...its salts, isomers, and salts of isomers...” would also be Schedule I controlled substances. However, the term isomer, as defined in 21 CFR 1300.01(b)(21) means “...the optical isomer except as used in... [Schedules I(d) and II(b)].” cis-4-Methylaminorex is specifically listed as a stimulant in Schedule I(f). Since trans-4-methylaminorex is not an optical isomer of cis-4-methylaminorex, the “isomer” provision does not apply and it is not formally controlled.

Therefore, the legal issue is whether trans-4-methylaminorex is a controlled substance analogue. Under the Controlled Substance Analogue provision of the Controlled Substances Act, it must first be demonstrated that trans-4-methylaminorex has a chemical structure that is substantially similar to the chemical structure of controlled substance in Schedule I or II. The controlled substance in this case is cis-4-methylaminorex. The diastereomeric relationship between these two compounds clearly satisfies the requirements of the first “prong” of the provision.

Secondly, trans-4-methylaminorex must exhibit a stimulant effect that is substantially similar to or greater than the stimulant effect of cis-4-methylaminorex -OR- must be represented or intended to have a stimulant effect that is substantially similar to or greater than the stimulant effect of cis-4-methylaminorex. The rank order of potencies of the four enantiomers of 4-methylaminorex has been shown to be:

trans-4S,5S > cis-4S,5R ~ cis-4R,5S > trans-4R,5R

in several pharmacological studies [6,8-11]. One group of researchers suggested that the trans-4S,5S isomer may have sufficient abuse potential to warrant its classification as a Schedule I controlled substance [10]. Thus, the second “prong” of the Controlled Substance Analogue provision is also met.

Finally, the trans-4-methylaminorex seized in this case was specifically stated by the clandestine chemist to be “Euphoria,” which is the generic street nomenclature for 4-methylaminorex without any stereochemical (cis or trans) designation [12,13]. Therefore, all three “prongs” of the Controlled Substance Analogue provision are satisfied, and it is virtually certain that Federal prosecution of trans-4-methylaminorex as a “controlled substance analogue” would be successful. In this case, the clandestine chemist was convicted of manufacture of a controlled substance.

Experimental

Reagents were obtained from Sigma Aldrich, and were used without further purification.

Gas chromatograph/mass spectrometry (GC/MS) data was obtained from an Agilent 6890 Gas Chromatograph (GC) coupled to an Agilent 5973 Mass Selective Detector (MSD) operating in electron impact (EI) mode. The mass spectral scan range was m/z 34 to 520. The ion source and quadrupole temperature zones were set to 230 °C and 150 °C, respectively. The interface was heated to 280 °C. The GC was equipped with a 30 meter ZB-1 column with an internal diameter of 0.25 mm and a 0.25 µm film thickness (Phenomenex). The inlet was set to 250 °C and the carrier gas was Helium with a constant flow rate of 1.3 mL/min. The oven was ramped from 100 °C - 295 °C at 35 °C/min, with a 6.43 minute hold at 295 °C, for a total run time of 12 minutes.

Fourier Transform ¹H Nuclear Magnetic Resonance (FT-NMR) analyses were performed on a Varian Mercury plus spectrometer operating at 400 MHz. Eight scans were collected for each sample. Internal reference standards were not used.

Fourier Transform Infrared (FTIR) spectra were collected on a Thermo Nicolet Nexus 470 FTIR equipped with a SensIR Technologies Durascope 3-bounce ATR attachment. The scan range was 4000 cm ^-1 to 550 cm^-1, with a 4 cm^-1 resolution. 32 scans were collected for each sample.

Molecular drawings, 3-D optimizations, and IUPAC names were generated with ACD Labs ChemSketch software, version 7.0.

Preparation of trans-4-Methylaminorex
Because this synthesis is no longer readily accessible on the internet, experimental details have been omitted, in accordance with Microgram Journal policy. Law enforcement personnel with a legitimate need to know should contact the authors for further information.

Results and Discussion

It is uncommon for trained, professional chemists to produce illicit drugs. It is even more unusual that a genuinely new clandestine manufacturing process is encountered. It was helpful in this case that the cook not only documented his reaction, batch, and
scale-up information, but also was willing to discuss his “work” in a proffer hearing. As detailed above, the synthesis of
trans-4-methylaminorex was performed using a procedure partially described on the internet and further expanded by the clandestine chemist [14]. A scaled-down version of this method was used in this study.

Analysis of the reaction mixture from the illicit method after the first 2.5 hours revealed the presence of N-(2-hydroxy-1-methyl-2 phenethyl) urea, 4-methyl-5-phenyl-1,3-oxazolidin-2-one and unreacted norephedrine (see Figure 2). No trans-4-methylaminorex was detected up to this point.

Figure 2. The Components of the Reaction Mixture from the Illicit Method after the First
2.5 Hour Reflux Period. Only One of Each Enantiomeric Pair Is Shown.

The final reaction mixture was similar in composition to the actual evidence seized from the clandestine laboratory. In addition to trans-4-methylaminorex, small amounts of cis-4-methylaminorex were also found. The crude mixture also contained 4-methyl-5- phenyl-1,3-oxazolidin 2-one, N-(2-hydroxy-1-methyl-2-phenethyl)urea, and unreacted norephedrine. For this study, this mixture was cleaned up prior to isolation of the final product.

It is likely that the synthesis occurs through the intermediate 2-ureidoalcohol alpha-methyl-beta-hydroxyphenethylurea [15] which cyclizes to the oxazoline with inversion of configuration at C-1 [2]. Therefore, the synthesis was also conducted by the initial production and isolation of N-(2-hydroxy-1-methyl-2-phenethyl)urea intermediate. The general stoichiometric reaction is shown below:

Norephedrine + Potassium Cyanate + H2O —> Norephedrine-Urea + KOH (Equation 1)

The pH of the solution immediately upon complete dissolution of the reactants was about 5-6. After the reaction had gone to completion, the pH of the remaining liquid was about 10-11, supporting Equation 1.

It is generally accepted that the reaction of cyanates in water does not proceed via the cyanate but via isocyanic acid [16-18]. This scenario (Scheme 1) involves nucleophilic attack by the amino group of norephedrine on the somewhat positively polarized carbon of isocyanic acid, with a subsequent proton shift from the amino group of norephedrine.

Scheme 1

This mechanism shows that the chiral centers remain unchanged during the formation of the urea intermediate. Since norephedrine produces trans-4-methylaminorex, inversion of configuration must occur via an intramolecular SN₂-type attack at the benzylic carbon by the carbonyl group of the urea portion of the intermediate. This can occur because N-(2-hydroxy-1-methyl-2-phenethyl)urea can achieve a favorable conformation to allow the reaction to occur [2]. The pseudo 5-membered ring conformation places the carbonyl oxygen in proximity to the benzylic carbon, enabling the SN₂ type attack. This conformation is depicted in the 3-D image shown below (Figure 3).

Figure 3. Three Dimensional Image of N-[(1S,2R)-(2-Hydroxy-1-methyl-2-phenethyl)]urea
in a Conformation Enabling SN2 Attack at the Benzylic Carbon (C-2) by the Ureido Carbonyl.

Note the changes in the numbering system of the various compounds. The benzylic carbon in norephedrine is designated as C-1. The same carbon is labeled as C-2 in the urea intermediate, and as C-5 in 4-methylaminorex. Thus, the (1R,2S) isomer of norephedrine becomes the (1S,2R) isomer of the urea intermediate, which is subsequently converted to the trans-(4S,5S)-isomer of 4-methylaminorex.

Figure 4. Summary of Absolute Configurations of Chiral Centers of Key Molecules.
One of Each Enantiomeric Pair Is Shown.

The small amount of the oxazolidinone detected in the reaction mixture at the half way point is probably formed by the attack of the benzylic hydroxyl on the carbonyl of the urea (Figure 5), liberating a molecule of ammonia into the solution (presumably as NH₄OH), which may also contribute to the already moderately high pH observed at the end of the reaction (Equation 1).

Figure 5. Formation of cis-4-Methyl-5-phenyl-1,3-oxazolidin-2-one from the Urea Intermediate.

This results in retention of configuration. The phenyl and methyl groups of the oxazolidinone by product must be cis since no change in the configuration at C-4 or C-5 could occur. This is confirmed by NMR data. The coupling constant for the C-5 proton is consistent with a cis configuration (J_4-5 = 8.02 Hz). This value is comparable to literature values for the electronically similar
3,4-dimethyl-2-imino-5-phenyloxazolidine [19].

Acknowledgements

The authors would like to thank DEA Librarians RoseMary Russo and Lavonne Wienke for their assistance in searching for and providing the literature references cited herein.

References

1. Poos GI, Carson JR, Rosenau JD, Roszkowski AP, Kelley NM, McGowin J. 2-Amino-5-aryl-2-oxazolines. Potent new anorectic agents. Journal of Medicinal Chemistry 1963;6:266 272.

2. Fodor G, Koczka K. The stereochemical course of the conversion of 2-ureido-alcohols into oxazolidines. Part I. Journal of the Chemical Society 1952;850 854.

3. 4-Methylaminorex synth w/o CNBr. www.thehive.org 2001 (Note: Lapsed Website).

4. Klein RFX, Sperling AR, Cooper DA, Kram TC. The stereoisomers of 4-methylaminorex. Journal of Forensic Sciences 1989;34(4):962-979.

5. Lawn JC. Schedules of controlled substances; temporary placement of 2-amino-4-methyl-5-phenyl-2-oxazoline (4- methylaminorex) into Schedule I. Federal Register 1987;52:30174.

6. Glennon RA, Misenheimer B. Stimulus properties of a new designer drug: 4-Methylaminorex (“U4Euh”). Pharmacology Biochemistry and Behavior 1990;35(3):517-521.

7. Lawn JC. Schedules of controlled substances; placement of (+/-)-cis-4-methylaminorex into Schedule I. Federal Register 1989;54:14799.

8. Batsche K, Ashby Jr. CR, Lee C, Schwartz J, Wang RY. The behavioral effects of the stereoisomers of 4-methylaminorex, a psychostimulant, in the rat. Journal of Pharmacology and Experimental Therapeutics 1994;269(3):1029-1039.

9. Ashby Jr. CR, Pan H, Minabe Y, Toor A, Fishkin L, Wang RY. Comparison of the action of the stereoisomers of the psychostimulant 4-methylaminorex (4-MAX) on midbrain dopamine cells in the rat: An extracellular single unit study. Synapse 1995;20:351-361.

10. Kankaanpää A, Ellermaa S, Meririnne E, Hirsjärvi P, Seppälä T. Acute neurochemical and behavioral effects of the stereoisomers of 4-methylaminorex in relation to brain drug concentrations. Journal of Pharmacology and Experimental Therapeutics 2002;300:450-459.

11. Roszkowski AP, Kelley NM. A rapid method for assessing drug inhibition of feeding behavior. Journal of Pharmacology and Experimental Therapeutics 1963;140:367-374.

12. Inaba D, Brewer LM. U4Euh. Microgram 1987;20:55-61 (Note: Law Enforcement Restricted).

13. Davis FT, Brewster ME. A fatality involving U4EuH, a cyclic derivative of phenylpropanolamine. Journal of Forensic Sciences 1988;33:549-553.

14. One pot synthesis of 4-methylaminorex. www.thehive.org 2003 (Note: Lapsed Website).

15. McCasland GE. N ---->O Acyl migration in epimeric acetyl inosamines. Journal of the American Chemical Society 1955;73:2295-2297.

16. Taillade J, Boiteau L, Beuzelin I, Lagrille O, Biron J P, Vayaboury W, Vandenabeele Tranbouze O, Giani O, Commeyras A. A pH dependent cyanate reactivity model: Application to preparative N-carbamoylation of amino acids. Journal Chemical Society, Perkin Transactions 2 2001;1247-1254.

17. Shorter J. The conversion of ammonium cyanate into urea - a saga in reaction mechanism. Chemical Society Reviews 1978;7:1-14.

18. Williams A, Jencks WP. Urea synthesis from amines and cyanic acid: Kinetic evidence for a zwitterionic intermediate. Journal Chemical Society, Perkin Transactions 2 1974;1753-1759.

19. Carson JR, Poos GI, Almond Jr. HR. 2-Amino-5-aryl-2-oxazolines. Tautomerism, stereochemistry, and an unusual reaction. Journal of Organic Chemistry 1965;30:2225-2228.

Figure 6. EI Mass Spectra. Top: 4-Methyl-5-phenyl-1,3-oxazolidin-2-one; Middle: N-(2-Hydroxy-1-methyl-2-phenethyl)urea; Bottom: trans-4-Methylaminorex.

 

Figure 7. ¹H NMR, 8 scans, trans-4-Methylaminorex.

 

Figure 8. ¹H NMR, 8 scans, N-(2-Hydroxy-1-methyl-2-phenethyl)urea.

Figure 9. FTIR. 32 scans, trans-4-Methylaminorex.

Figure 10. FTIR. 32 scans, N-(2-Hydroxy-1-methyl-2-phenethyl)urea.

 

[* In the late 1980's and early 1990's, “Ice” was a street name for 4-methylaminorex. Since then, however, it has shifted to a street name for high purity methamphetamine hydrochloride in large crystal form.]