4-Methylaminorex (Fig. 1) (2-amino-4-methyl-5-phenyl-Δ²-oxazoline, 4,5-dihydro- 4-methyl-5-phenyl-2- oxazolamine, McN-822, "U4Euh," "ICE") is a potent anorectic^1-3 and central nervous system stimulant^2-8 possessing sympathomimetic⁹ hypertensive⁴, and norepinephrine potentiating¹⁰ properties. It has been observed with increasing frequency on the clandestine market^11,12 and was recently controlled (Schedule I) under the emergency scheduling procedures of the Controlled Substances Act^13,14.

The compound contains two chiral centers (C₄ and C₅); thus, there are four possible stereoisomers (trans-(4R,5R), trans-(4S,5S), cis-(4R,5S) and cis-(4R,5S)), and two racemates (dl-cis and dl-trans) (Fig. 2).

The individual stereoisomers and racemates are most conveniently synthesized via condensation of the respective 2-amino-1-phenyl- propanols with cyanogen bromide¹ (Figs. 3 and 4). The stereochemistry of the starting material is maintained through the course of the reaction; thus, the erythro amino-alcohol (norephedrine) gives the corresponding cis-4-methylaminorex, the threo amino-alcohol (norpseudoephedrine) the corresponding trans product (Fig. 4; note: C1/C2 in the starting material corresponds to C5/C4 in the product).

Pharmacological studies have shown similar anorectic^1,2 central nervous system stimulant⁴, hypertensive⁴, and norepinephrine potentiating¹⁰ activities regardless of stereochemistry. The racemic dl-cis free base is currently the most frequently encountered form in illicit samples of 4-methylaminorex³ and has been fully characterized in several reports¹²; however, only minimal physical data have been reported for any of the individual stereoisomers, the dl-trans racemate, or the corresponding hydrochloride salts.

Experimental Procedures

All precursor chemicals were obtained from Aldrich and used without additional purification. All other chemicals used were reagent grade or better.

Melting points were determined using a Fisher-Johns melting point apparatus and are uncorrected. Thin-layer chromatograms were run on silica gel (Baker-flex Silica Gel IB-F, J. T. Baker 4-4463), alumina (Baker-flex Alumina IB-F, J. T. Baker 4-4467), and C18-reverse phase (Whatman MKC18F, 4803-110) thin-layer plates. Gas chromatographic (GC) analyses were performed on a Perkin-Elmer Sigma 2000 Capillary Chromatograph equipped with a DB-1 30-m by 0.25-mm capillary column coated with a 0.25-µm film thickness (JAW Scientific) and a flame ionization detector. Hydrogen was used as the carrier gas (linear velocity 4.65 cm/s). Specific rotations were determined using a Perkin-Elmer 241 MC Polarimeter; all rotations were measured in ethanol (EtOH) at 25°C using a 1-dm cell and the sodium D line (589 nm). ¹H- and ¹³C-(NMR spectra were obtained in deuteriochloroform (CDCl₃) or deuterium oxide (D₂O) using a Bruker AM-300 WB NMR spectrometer (operating at 300 MHz for ¹H and 75.5 MHz for ¹³C); tetramethylsilane (Me₄Si) and dioxane were used as internal calibration standards (for samples in CDCl₃ and D₂O, respectively). ¹³C-NMR spectra were obtained in auto-recur mode (that is, a 35° pulse was utilized with a zero relaxation delay). Infrared (IR) spectra were obtained as KBr pellets using a Perkin-Elmer 1750 Infrared Fourier Transform Spectrometer; polystyrene was utilized as a calibration standard. High-resolution mass spectra (70-eV electron impact [EI]) were obtained using a Finnigan-MAT 8230 Mass Spectrometer (resolution = 7500; 5% valley). All samples were run using the solid-probe inlet.

Results and Discussion

Chemistry

Two of the six precursor 2-amino-1-phenylpropanols, dl-norpseudoephedrine and (1S,2S)-norpseudoephedrine, are (currently) commercially unavailable and were synthesized via a benzylic inversion route from racemic dl-norephedrine and (1R,2S)-norephedrine, respectively (Fig. 5)¹.

The individual enantiomers and racemates of 4-methylaminorex were synthesized via condensation of the respective 2-amino-1-phenylpropanols with cyanogen bromide¹. Recrystallization (chloroform/carbon tetrachloride 1:1) gave the free bases as white, crystalline powders. The corresponding hydrochloride (HCl) salts were precipitated from chloroform/diethyl ether 1:1 solutions of the free bases with anhydrous HCl gas. Recrystallization (iPrOH/CHCl₃/Et₂O 1:1:1) gave five of the six hydrochloride salts as white crystalline powders; the racemic dl-trans hydrochloride salt is hygroscopic, however, and rapidly "melted" following isolation from the reaction mixture. The resulting oil slowly crystallized over four weeks and was eventually isolated as an amorphous solid.

The free bases are readily liberated from the hydrochloride salts by solution in the minimum volume of distilled water (H₂O) followed by dropwise addition of excess saturated aqueous sodium carbonate (Na₂CO₃).

Melting Points

Melting points are presented in Table 1. In all cases, the melting ranges are unusually broad; that is, a gradual breakdown of crystal structure is observed over the final 15-20°C (sublimation evident), with complete dissolution occurring at the reported value. The close similarities between the diastereomeric cis and trans free bases (Δ=3°C) precludes differentiation via melting point except by mixed melting-point techniques¹⁵.

The reported melting point for the racemic dl-cis free base (139-142°C, Table 1) does not agree with the original literature (154.5-156°C¹). The racemic dl-cis-d₂ analogue was reported to be hygroscopic¹⁶; however, recrystallization from refluxing toluene with azeotropic removal of H₂O gave crystals with the same melting point (indicating that the prepared compound does not contain water of hydration). Recrystallization from boiling water, however, gave crystals with a melting point of 154-155°C. Chromatographic and spectroscopic evidence confirmed the structure as the hydrate. The individual cis enantiomers also give hydrates with slightly higher melting points (Table 1) from boiling water; however, the trans isomers did not give hydrates.

Interestingly, the crude free bases (precipitated from aqueous solutions by addition of aqueous base) are the anhydrous form - only cis products recrystallized from boiling water form hydrates. Several illicit samples of racemic cis-4-methyl-aminorex analyzed in this lab all gave melting points of approximately 140°C.

Thin-Layer Chromatography

The diastereomeric cis and trans free bases are marginally resolved on silica gel and alumina and unresolved on C₁₈-reverse-phase thin-layer plates (the hydrochloride salts give multiple spots and streaking on all three stationary phases). R_f values for three different solvent systems giving optimal development (0.4 to 0.7) are presented in Table 2. The more symmetrical (less polar) trans isomer migrates slightly faster on both silica gel and alumina; the most favorable resolution was observed on silica gel using an ammonium hydroxide- saturated chloroform/methanol 9:1 eluting solvent.

Gas Chromatography

The diastereomeric cis and trans free bases are sufficiently resolved for differentiation by capillary GC (Fig. 6). Retention times (R_t) are presented in Table 1. The more symmetrical (less polar) trans isomers elute prior to the cis isomers.

The hydrochloride salts undergo extensive thermally induced decomposition and give a more complex chromatogram; the free bases are, however, still apparent in the chromatogram (Fig. 6). Programmed injector port temperatures (from 75 to 280°C) only marginally improved performance.

Specific Rotation

The enantiomeric free bases and hydrochloride salts can be differentiated via specific rotation. Values are reported in Table 1. All compounds were determined in EtOH at 25°C using a 1-dm cell and the sodium D line (589 nm). The reported specific rotation for the cis-(4S,5R) free base ([α]_D²⁵ = -244.7°, Table 1) does not agree with the original literature ([α]_D²⁰ = -9.5°⁴); however, the latter value is incorrect. The reported rotations were scaled up from measurement (to three decimal places) of dilute solutions of differing concentrations - as the magnitudes of rotation for the enantiomers are internally self-consistent, that is, equal and opposite (+240.9 versus -244.7°, Table 1), the values are accurate. (The error in the original article is most likely due to measurement off-scale, that is, not -9.5 but rather -369.5°, a reasonable explanation in view of the high concentration (1 g/mL) used for the measurement⁴.)

NMR Spectroscopy

The ¹H-NMRs of the diastereomeric cis and trans free bases display significant variations in both chemical shifts (δ) and scalar coupling constants (J) (Fig. 7, Table 3). The most marked difference in chemical shift is observed with the 4-methyl substituent (δ cis = 0.73 ppm versus δ trans = 1.33 ppm); in the cis isomers, the methyl group lies within the shielding zone of the phenyl ring and is shifted 0.60 ppm upfield relative to the trans isomers. In addition, the aromatic ring protons display more fine structure in the cis isomer as a result of hindered rotation about and shielding from the methyl substituent. The largest variance in coupling constant is observed with the benzylic proton J_H5-H4 (trans): 7.36 Hz; (cis): 8.80 Hz); the observed values are in agreement with other 4-alkyl-5-aryl-substituted-Δ²-oxazolines (typical J_H5-H4 (trans): 7 to 8 Hz, (cis): 9 to 10 Hz¹⁷).

The ¹³C-NMRs display analogous variations in chemical shifts (Fig. 8, Table 3); in the cis isomers, the methyl substituent and the aliphatic oxazoline carbons (C₄ and C₅) are all shifted upfield relative to the trans isomers.

The hydrochloride salts display similar behavior (Figs. 9 and 10, Table 4); the principal differences observed between the free bases and the hydrochloride salts is the general downfield shift of all protons in the hydrochloride salts and specifically the marked downfield shift and integration of the ammonium substituent (-NH₂ versus -NH₂⁺).

IR Spectroscopy

The diastereomeric cis and trans free bases display similar but distinct IR spectra (Fig. 11). The principal absorptions include the amine stretch (v_N-H=3450 cm^-1), which surprisingly is a singlet, the imine stretch (v_C=N=1700 cm^-1), quite intense and shifted to higher than usual frequency by the amine substituent, and the mono-substituted phenyl ring stretching bands (v_C-C=1500, 1600 cm^-1). Similar results are obtained for the hydrochloride salts (Fig. 12); the principal differences are the broadening of the amine stretch and the higher frequency of the imine stretch.

Mass Spectroscopy

The diastereomeric cis and trans free bases display virtually identical mass spectra under 70-eV EI conditions (Fig. 13, Table 5). The first two fragment ions (m/z = 161.0715 and 132.0813) correspond to loss of methyl and carbonylamine, respectively. The base ion (m/z = 70.0531) corresponds to loss of benzaldehyde. Other ions include a C₇H₇ ion (m/z = 91.0548, possibly tropylium), a C₆H₅ ion (m/z = 77.0391, probably phenyl), and a C₂H₅N ion (m/z = 43.0422, possibly aziridine).

Somewhat unusually, the total ion current due to M (a measure of the relative stability of the parent molecules¹⁸ is greater for the cis isomer (the thermodynamically less stable isomer). This implies an alternate, more accessible fragmentation pathway for M in the case of the trans isomer; the M/total ion current ratios (Table 5) may thus be used (with caution) to differentiate diastereomers.

Color Test

The addition of one drop of 2% aqueous cobalt(II) thiocyanate to 1 mg of the free base or hydrochloride salt dissolved in 0.5 mL of EtOH gives an instantaneous deep blue color; the color is slightly less intense for the hydrochloride salt. The reagent is nonspecific with respect to stereochemistry.

No color change is observed upon addition of the reagent to an aqueous solution of the hydrochloride salt(s); however, subsequent addition of one drop of saturated aqueous Na₂CO₃ instantly precipitates a blue solid.

Microcrystalline Tests

Microcrystalline tests were performed on the hydrochloride salts with 5% aqueous platinous chloride (PtCl₂) and 5% aqueous gold trichloride (AuCl₃). Results are reported in Table 6. In all tests with PtCl₂, the addition of one drop of the reagent to one drop of an aqueous solution of the hydrochloride salt (2 mg/mL) gives microcrystals within 30 sec. Similar results are obtained from the free bases by dissolving them in the minimum volume of 5% HCl. Different microcrystalline precipitates are observed for each of the racemates and enantiomeric pairs (Table 6). In the case of AuCl₃, only the racemic dl-cis hydrochloride salt gives a microcrystalline precipitate; thus, AuCl₃ is a specific reagent for the racemic dl-cis hydrochloride salt.

It must be emphasized that microcrystal tests are often sensitive to concentration, pH, impurities, and technique; thus, positive identification should be attempted only via direct comparison with the known standards^19,20.