The Identification of Cathinone and Methcathinone

THE IDENTIFICATION OF CATHINONE AND METHCATHINONE

TERRY A. DAL CASON NORTH CENTRAL LABORATORY CHICAGO, ILLINOIS 60607

The seizure of several clandestine methcathinone (ephedrone, N-methylcathinone, a-methylaminopropiophenone, "CAT") laboratories in the Upper Peninsula (U.P.) of Michigan and the continued availability of the compound in that area may be preliminary indicators of future epidemic abus~. Most recently a clandestine methcathinone laboratory was seized in the Seattle, Washington area. The former Soviet Union [1,2] has also experienced an abuse problem with "CAT". In, an effort to prevent wide spread manufacture and use of "CAT" in the United States, the compound was recently placed as a temporary Schedule I drug under the Federal Controlled Substances Act [3].

Although no clandestine laboratories manufacturing cathinone (a-aminopropiophenone) have been seized by federal authorities, at least one state (Florida) lists cathinone as a controlled substance within its jurisdiction.

In order to rapidly reach a large segment of the interested forensic community, this analytical data is being presented for identification purposes with little comment. Only the synthesis routes known to have been used in clandestine laboratories are covered. Additional information and analytical data are available from Reference [1].

Synthesis and Purification

Although Zhingel [1] reported that the permanganate oxidation [Fig. 1] is used by "Russian" clandestine laboratory chemists for the conversion of ephedrine to methcathinone, all of the clandestine laboratories seized to date within this country have used the dichromate oxidation [4]. With either synthetic variation, optically active precursors should lead to optically active products: (-)IR,2S-ephedrine or (+)IS,2S-pseudoephedrine yields (-)IS-Methcathinone and (-)IR,2S-norephedrine and (+)IS,2S-norpseudoephedrine yields (-)IS-cathinone.

The amino ketones produced in this laboratory by dichromate oxidation have retained their optical activity [4]. However, Glennon et ale [5] experienced racemization using the same general technique [6]. Berrang et ale [7] report racemization of optically active cathinone during processing and Zhingel et ale [1] report that racemization can occur during synthesis or processing depending on the reaction conditions. The parameters effecting the racemization, both during synthesis and/or processing, are currently being investigated as well as the optical activity of the exhibits now being encountered in the U.P.

In any case, cathinone/methcathinone samples require care during processing since dimerization of these compounds occurs quite

MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Page 313

-----,,',.- ._._-,-- readily under certain conditions [7,8,9]. These amino-ketones are stable if kept protected as the salt of a strong acid such as hydrochloric acid. However, both racemization and dimerization will occur [7] in hydroxylic solvents such as methanol, and as the free base.

The samples examined in this laboratory have been submitted as white powders, as residues or traces of material, and as liquid reaction mixtures having a dark brown to black appearance. Because the a- aminopropiophenones are sensitive to strong base, extraction of cathinone or methcathinone from aqueous mixtures using saturated sodium carbonate (pH 11) to basify the solution is preferred. Saturated sodium bicarbonate (pH 8.5) is less harsh but the evolution of larger volumes of gas, and commensurate foaming of the solution, are drawbacks to its use.

Chloroform and dichloromethane are suitable extraction solvents although clandestine laboratory operators generally use toluene. Shaking the basified aqueous solution with one of the above solvents in a separatory funnel will effect transfer of the cathinone or methcathinone as the free base into the organic solvent. The solvent should then be passed through a layer of anhydrous' sodium sulfate to remove any basic aqueous phase remaining in the extraction solvent. Addition of an isopropyl or ethyl alcohol: hydrochloric acid mixture (4:1) to the extracted base, and subsequent solvent evaporation with a steam bath, is suitable to provide the hydrochloride salt. If available, a rotary vacuum evaporator is useful at this stage. Recrystallization may be accomplished, if necessary, from isopropyl alcohol to which diethyl ether or THF is added.

Instrumentation

Acquisition of the ultraviolet (UV) spectra in ethanol was accomplished with a Perkin-Elmer Lambda 6 Spectrophotometer. Infrared (IR) spectra were obtained using a Perkin-Elmer 1800 Fourier Transform Infrared Spectrophotometer. Melting points were recorded on material dried over silica gel under vacuum using a Thomas-Hoover "unimelt" apparatus. Gas Liquid Chromatographic retention times were acquired using a Hewlett-Packard 5890 with FID. The Mass Spectra were obtained from a Hewlett-Packard 5970 Mass Selective Detector having a 10 m x 0.25 mm x l~m DB-l column.

Color Tests

The color tests were performed on approximately 5 mg of the pure hydrochloride salts in a porcelain spot plate. (Table 1).

Ultraviolet Spectrophotometry (UV)

Cathinone HCl or methcathinone HCl (Fig. 2A) in ethanol display a UV spectrum markedly different than the typical UV spectra for the amphetamine HCI, methamphetamine HCl, norephedrine HCl, and ephedrine HCl (Fig. 2B) series of compounds. Cathinone and methcathinone have extended conjugation due to the carbonyl group adjacent to the phenyl ring and show maxima at 245 and 203 nm and a minima at 217 nm.

Page 314 MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Infrared Spectroscopy (IR)

The IR Spectra of cathinone HCl and methcathinone HCl are provided in Fig. 3A and 3B respectively using the standard potassium bromide matrix. An intense_l carbonyl absorption can be seen in bot~l compounds at 1688 cm . The weak absorption at about 3360 cm is probably due to a small amount of the enol tautomer being present, rather than contamination from unreacted aminoalcohol precursors.

Melting Points

Optically active cathinone HCl melted at 179-180 °c turning red and effervescing. Optically active methcathinon~ melted at 176-178 °c turning brown and effervescing.

Although either HP-1 or HP-17 columns are suitable for quantitation using propiophenone (phenyl-1-propanone, P-1-P) or phenyl-2-butanone (P-2-B) as internal standards, both screening and quantitations have been on the HP-1 column at this laboratory (Table 2).

GC-MS

The hydrochloride salts of cathinone, amphetamine, norephedrine, norpseudoephedrine, methcathinone, methamphetamine, ephedrine and pseudoephedrine were dissolved in water, basified with sodium carbonate, extracted with chloroform and passed through anhydrous sodium sulfate. The representative mass spectra are presented in Fig. 4A. Because the mass spectra of some of the above compounds are similar, acetylated mass spectra are shown in Fig. 4B. The formula weights for both groups of compounds are shown in Table 3.

Acetylation was accomplished by one of two procedures. The solutions, extracted as above, were placed in a beaker and evaporated to near dryness. Sufficient acetic anhydride was added to cover the material which was heated on a steam bath until the excess acetic anhydride evaporated. A simpler procedure yielding identical results was to draw a 1/2 ~L plug of the extracted sample into a micro syringe followed by a 1/2 ~L plug of acetic anhydride. The simultaneous injection of the two components into the hot injection port provides "on column" acetylation. Acetylated norephedrine, ephedrine and their diastereomeric pseudo isomers show multiple GLC peaks with the corresponding mass spectra indicating reaction at the hydroxyl or the amino group, or both groups. Due to the similarity of the mass spectra of norephedrine and ephedrine with their diastereomeric pseudo compounds, the latter are not included in Figure 4A and 4B. The mass spectra are provided for comparative purposes without further comments.

Discussion

Cathinone and methcathinone are potent stimulants which are structurally related to the controlled substances amphetamine and methamphetamine. All four stimulants can be synthesized from the respective precursors, norephedrine or norpseudoephedrine, and pseudoephedrine or ephedrine. Infrared spectroscopy provides an excellent means of distinguishing between these compounds.

MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Page 315 Identification of the aminoketones by GC-MS is somewhat more difficult. The use of an acetylating technique will give the analyst more easily distinguishable mass spectra, in addition to a second retention time. Additionally the combination of the color tests previously described, especially when used in conjunction with UV spectroscopy, should leave no doubt which class of compounds is being analyzed.

As noted earlier, cathinone and methcathinone require care during purification. Extractions should proceed as rapidly as possible and the organic phase, containing the free base aminoketone, should be dried with anhydrous sodium sulfate. Although it is preferable to immediately convert the compounds into a stable salt form, the free bases in chloroform or dichloromethane kept at O°C showed no obvious signs of decomposition after 48 hours. "Not~ceable decomposition" is evident by a yellowing of the solution. Lack of stability of both the base and hydrochloride forms of the aminoketones in alcohol solutions has also been mentioned and storage in these solvents is not recommended. Breakdown, however, has not been found to be so rapid as to preclude the use of alcohols as solvents for UV spectra.

REFERENCES

[1] Zhingel, K. Y., Dovensky, W., Crossman, A., and Allen, A., "Ephedrone: 2-Methylamino-l-Phenylpropan-l-one(Jeff)," Journal of Forensic Sciences, Vol. 36, No.3, May 1991, pp. 915-920.

[2] Savenko, V.G., Semkin, E.P., Sorokin, V.I., and Kazankov, S.P., "Expert Examination of Narcotic Substances Obtained from Ephedrine", The All-Union Scientific Research Institute of the U.S.S.R. Ministry of the Interior. Moscow, 1989; pp. 1-24.

[3] Federal Register, Vol. 57, May 1, 1992, 57FR188824.

[4] U.S. Patent 2,802,865, L'Italien, Yvon J., and Rebstock, Mildred C., assigned to Parke, Davis and Co., Detroit, Michigan, Aug. 13, 1957.

[5] Glennon, R. A., Yousif, Mamoun, Naiman, Norren, and Kalix, Peter "Methcathinone: A New and Potent Amphetamine-Like Agent," Pharmacology Biochemistry & Behavior, Vol.26, 1986, pp.547-551.

[6] British Patent 768.772, Feb. 20, 1957.

[7] Berrang, B.D., Lewin, A.H., and Carroll, F.I., "Enantiomeric a-Aminopropiophenones(cathinone):Preparation and Investigation," The Journal of Organic Chemistry, Vol. 47, 1982, pp. 2643-2647.

[8] Hartung, Walter H., Munch, James C., Deckert, W. Allen, Crossley, Frank, "Amino-Alcohols. II. Homologs and Analogs of Phenylpropanolamine", Journal of the American Chemical Society, Vol. 52, Aug. 1930, pp. 3317-3322.

[9] MNAR/ll/75 "Studies on the Chemical Composition of Khat. III. Investigations on the phenylalkylamine Fraction." Report on research being carried out at the United Nations Narcotics Laboratory, Geneva.

Page 316 MICROGRAM, VOL. XXV, NO. 12, DECEMBER 19~

-_ .. _-_._- ._------,------oxidation •• {AI or (Bl

R = H for norephedrine or norpseudoephedrine and Cathinone R = CH3 for ephedrine or pseudoephedrine and Methcathinone

A) Potassium permanganate I acetic acid B) Sodium dichromate I sulphuric acid

Figure 1 - Synthesis of Cathinone and Methcathinone

TABLE 1: COLOR TESTS

MARQUIS1 SECONDARy2 CHEN'S3 AMINE

Cathinone No reaction No reaction Slow forming, yellow-orange

Amphetamine Orange to brown No reaction No reaction

Norephedrine No reaction No reaction Purple

Methcathinone No reaction SIt. ppt. of Slow forming, blue flecks or yellow-orange blue ring formed

Methamphetamine Orange to brown Dark blue No reaction

Ephedrine No reaction No reaction Purple

1 Marquis Reagent: 2 drops of formaldehyde solution (37%) with 1 mL of concentrated sulfuric acid. Ref.: E.G.C. Clarke, ed., Isolation and Identification of Drues, London, Pharmaceutical Press, 1969, p. 801.

2 Secondary Amine Reagents: Reagent 1- 1% sodium nitroprusside in water to which 10% by volume of acetaldehyde is added; Reagent 2 - 2% solution of sodium carbonate. Ref.: Fiegel, F., Spot Tests in Oreanic Analysis, Elsevier Publishing Co., New York, 1966, p. 251.

Directions: Add 1-2 drops of Reagent 1 to the sample followed by 1-2 drops of Reagent 2.

3 Chen's Reagents: Reagent 1-1 % acetic acid in water; Reagent 2 - 1% copper sulfate in water; Reagent 3 - 2N sodium hydroxide solution Ref.: (See Ref. 2 above) p. 131. Directions: Add 1-2 drops of Reagent 1 to the sample, followed by 1-2 drops of Reagent 2, followed by 1- 2 drops of Reagent 3.

MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Page 317 TABLE 2: GLC DATA

HP_11 HP-172 RT IN MIN RT IN MIN

Amphetamine 1.51 1.15 P-1-P 1.84 1.52 Methamphetamine 2.19 1.33 P-2-B 2.64 1.-98 Cathinone 4.57 3.55 Methcathinone 5.55 3.54 Norephedrine 5.93 3.90 (Tailing) Ephedrine 7.18 4.24 (Tailing)

1) HP-1 5 m X 0.53 mm X 2.65 urn, 80°C initial temp. 8.5 min., rate 25°C/min to 250°C, 1 min hold. FID detector at 265°C. Injector temperature at 250°C. Split mode.

2) HP-17 10 m X 0.53 mm X 2.0 urn, 140°C initial temp. 6.0 min., rate 30°C/min. to 250°C, 1 min hold. FID detector at 265°C. Injector temperature at 250°C. Split mode.

TABLE 3

Formula Weights (F.W.) for methcathinone and related compounds.

COMPOUND F.W.

1. Cathinone 149 la. N-acetylcathinone 191 2. Amphetamine 135 2a. N-acetylamphetamine 177 3. Norephedrine 151 3a. N-acetylnorephedrine 193 3b. O-acetylnorephedrine 193 3c. N,O-diacetylnorephedrine 235 4. Methcathinone 163 4a. N-acetylmethcathinone 205 5. Methamphetamine 149 5a. N-acetylmethamphetamine 191 6. Ephedrine 165 6a. N-acetylephedrine 207 6b. O-acetylephedrine 207 6c. N,O-diacetylephedrine 249

Page 318 MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 u

ILDD :no m 2111 •• Ita •• •• .uI ~ ------FIGURE 2A - UV SPECTRA (CATHINONE/METHCATHINONE TYPE) t.a

ILl

IL7 ••

ILl

Clot

ILDD :no m MIl 2111 aD •• ItO a •• _0 ~ - - - - - FIGURE 2B - UV SPECTRA (EPHEDRINE/METHAMPHETAMINE TYPE)

MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Page 319

-----_ .._-----_ ... -~~------\QQ tOO I (rI\ -' %r ';fl' ~ r~ 1\ " f ~ BO BO f- t ' V

- 60 60 f--

- 40 40 I--

- 20 20 f--

o L- -L ~ ~ ~ ~ ~ ~ ~ ~ ~ 0

4000 3500 3000 2500 2000 1750 1500 1250 1000 750 450 c. -1

FIGURE 3A - IR SPECTRA CATHINONE HCL 100 ,...- --.- .,...... - --.. -.----...----T ..,..- --T ..,..- --r --, 100 ~1 f\ BO

60 I-- - 60

40 f-- - 40

- 2!l 20 f-

o L- -L ~~ __ ~~ ~ __ ~_L ~.' ~ ~ ~~ ~O 4000 3500 3000 2500 2000 1750 1500 1250 1000 750 450 ell! -1

FIGURE 3B - IR SPECTRA METHCATHINONE HCL

Page 320 MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Scan 241 (3.818 rmn) of caUl0801008A

2000000

1500000

1000000

500000

133 147 148 '\. ""/ 0 40 60 60 100 1ZD 140 160 Mass/Olarge

4A-l methcathinone

Scan zn (4.155 mill) of cath130100zA Abundance

1BOOOOO- 56

1600000-

1400000- . 1200000- . 1000000-

800000-

1iOOOOO-

400000- - 200000- 77 42 105 146 91 117 132 ,,,, .11 [I .- \ .- .- \ 0 , , I I 40 60 60 100 1Zo 140 160 Mass/Olarge

4A-2 ephedrine

FIGURE 4A - MASS SPECTRA OF METHCATHINONE AND SOME RELATED COMPOUNDS

MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Page 321

------~~-~-- ~~~~~--~~~~------Scan LU!J pAOlO rnmj 01 ca\llu I U IUU I." ~»n~iVlI;e

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600000

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51 200000 " 105 63 89 " 134 0 40 60 80 100 120 140 MasslOIarlJe

4A-3 cathinone

Scan zzs (3.&83 milt) of cathZ1D1001.d Abundance

1200000 -

1000000-

800000-

600000-

400000-

zooooo- 77 51 63 1.1 91 105 118 ,I II J " 0 I I T " I " I 40 GO 60 1110 120 140 MasslOIarge

4A-4 norephedrine

FIGURE 4A - MASS SPECTRA OF METHCATHINONE AND SOME RELATED COMPOUNDS

Page 322 MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992

------Scan 72 (1.920 rrnn) ot catnzaut 001 .d PlJunadllce

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2000000

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91 65 ~ 120 103 1;5 / 134 0~~~-+~~~U4~~-r~--~~~r-'-~~~-r~~~-.--r-~~--r--r-- 40 60 80 100 120 140 Mass/Otarge

4A-5 amphetamine

Scan 119 (2.448 min) of cathll01011.d Abundance

2000000- .

1500000-

1000000- .

00-סס50

91 134 77 146 103 1'5 133/ ,I 11.1 ~ .- / I r I I " 40 80 100 120 140 160 Mass/Olarge

4A-6 methamphetamine

FIGURE 4A - MASS SPECTRA OF METHCATHINONE AND SOME RELATED COMPOUNDS

MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Page 323 ._..- Scan 487 (GoS80 min) of cath0901009.d - Abundance

zOOOOOO- 56

1800000 : · 1600000-

1400000- · 1ZOO0oo-

1000000-

- 800000-· 100 · .- 600000- : 43 400000- .- 77 · .- zooooo- 106 133 148 162 205 ,I J ,- , , .. 0 'f 1/ I 40 sO 80 100 120 140 1SO 1110 ZOO MasslOlarge

4B-1 acetylmethcathinone

Scan 435 (6.030 mm) of cath1Z01001.d Abundance

1400000-

lZoo000- .

1000000-

800000- 100-, 600000-

400000- 43 .- zooooo- 117 '01 134 - 77 191 - ( / ( I , 0 J .1 I " r. I J I m, 40 m 100 1Zo 140 160 180 MassJOIarge

4B-2 acetylmethamphetamine

FIGURE 4B - MASS SPECTRA OF ACETYLMETHCATHINONE AND SOME RELATED COMPOUNDS

Page 324 MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992

------_ .._----_ .. __ ..._-----, ---..--.-~---.-.- ..-.- ... - Scan 466 (6.345 mill) of caUl1lZ0101lZ.d

44 1600000--

1400000- .- 1200000-

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410000- 77 " 105 ZIJOOOO- " 132 134 149 - 55 191 I " "-I / o I I I I I I " 40 60 80 100 1m 140 160 MasslO1artJe

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Scan 37&(5.334 rrun) of cath0401004.d Abundance

1000000- 44

900000-

600000-

700000-

600000-

500000-

400000:

300000- 86, monoo- 118 65 " 00-סס10 ,.I 77 103 134 177 ,I .1 " " 0 I I . " " I " I ~ 60 80 100 120 140 160 180 MasslO1artJe

4B-4 acetyl amphetamine

FIGURE 4B - MASS SPECTRA OF ACETYLMETHCATHINONE AND SOME RELATED COMPOUNDS

MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Page 325 TIC Of caUll40101J3.C1 ~e\ylvpll~; Run at" ~7 AM CDT on Thu Oct lZ, tasz Abundance 2

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4B-5 TIC of acety1ated ephedrine

scan SS6 (1.355 min) of cath1401 003.d Abundance 58 lZOOOO

000סס1 100 /

80000

60000

40000

zoooo 77, 105 / 133 ,/ 189 / I 1".1 .. II 1 1 .1,1 I,ll II I 0 I I I I 50 100 150 zoo Z50 MasslOUIrge

4B-6 acety1ated ephedrine peak 1

FIGURE 4B - MASS SPECTRA OF ACETYLMETHCATHINONE AND SOME RELATED COMPOUNDS

Page 326 MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 scan ~ (7.7Zli nun) Of caUll4tllUu::I.a 1'MIJm_ 5ff 000-סס16

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48-7 acetylated ephedrine peak 2

ncer catb0601006.d acety".lIorephedrt; Run at 06:1 Z PM COT on W8d Oct Z1 • 199Z AbUndance 2

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48-8 TIC of acetylated norephedrine

FIGURE 4B - MASS SPECTRA OF ACETYLMETHCATHINONEAND SOME RELATED COMPOUNDS

MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Page 327

,", ,------,------.. _._ ..... Scan 516 (6.305 min) of cathZ901001.d Abundance

100000

80000

87 / 60000

40000

ZOOOO \

105 133 / I II I I I I I I I 40 60 80 100 1Z0 140 160 180 ZOO ZZO Z40 Mass/Otlll1le

4B-9 acetylated norephedrine peak 1

Scan 551 (7299 min) of cathZ901001.d Abundance

lZOOO00-

0000-סס1

800000-

134 176 149 I ,I / .( I , 140 160 180 ZOO ZZO 240 Mass/Otlll1le

4B-10 acetylated norephedrine peak 2

FIGURE 4B - MASS SPECTRA OF ACETYLMETHCATHINONE AND SOME RELATED COMPOUNDS

Page 328 MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 ,...- :--::--::c: _ Scan 598 (7.827 min) of cath2901001 .d AlWrItUfte!

90000 43

80000

70000

60000 86 /

50000

40000

30000 128 /

20000 77 107 / 10000 \

0 40 60 80 100 120 140 160 Mass/Olarge

4B-11 acetylated norephedrine peak 3

FIGURE 4B - MASS SPECTRA OF ACETYLMETHCATHINONE AND SOME RELATED COMPOUNDS

MICROGRAM, VOL. XXV, NO. 12, DECEMBER 1992 Page 329

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