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             Enantiomeric alpha-Aminopropiophenones (Cathinone)
                         Bertold D. Berrang et. al.
                     J. Org. Chem. 47, 2643-2647 (1982)
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The preparation of the optical antipodes of alpha-aminopropiophenone
(cathinone) from norephedrine and an improved large-scale resolution of
norephedrine are described. The characterization of cathinone and its salts
is discussed.

The chewing of the leaves of Catha edulis Forsk (Khat) by the natives of
several Asian and African countries to provide rapid stimulation is
extremely prevalent (1) and has been considered to be a serious problem of
drug dependence not unlike that associated with amphetamine (2). In fact,
on the basis of the observations of Eddy et al. (3) the United Nations
Narcotics Laboratory undertook research on the chemistry of Khat and its
components (2).

Earlier in this century (+)-norpseudoephedrine, a CNS-active compound, was
identified among the basic alkaloid components of Khat (4). Later
investigations (5-8) revealed the presence of other bases, but the
isolation and characterization of the main constituent has only been
reported within the last few years by the United Nations Narcotics
Laboratory (9,10). Specifically, the presence of (-)-alpha-aminopropiophenone
(9) and its absolute configuration (10), as well as the presence of
3,6-dimethyl-2,5- diphenylpyrazine (9) were reported. Since this information
is only available in the United Nations Documents which are somewhat hard
to come by (11), it will be briefly summarized here. Extraction of
freeze-dried plant material with methanol, followed by separation of the
nonpolar and weakly basic species and purification by acid-base extractions
gave an odiferous yellow oil which, after treatment with oxalic acid, gave
a solid: mp 157-160 °C (9). This compound was identified as alpha-amino-
propiophenone oxalate by its UV, IR, 1H-NMR, and mass spectra (9). In
another reports the absolute configuration of the plant extract was deduced
from comparison of the CD curve observed for a separately isolated sample
of oxalate salt with those of model compounds. It was concluded (10) that
natural alpha-aminopropiophenone has the S configuration, which is
biogenetically consistent with the configurations of both (+)-norpseudo-
ephedrine and (-)-norephedrine at the corresponding asymmetric center.

These reports do, however, contain some puzzling results. The stereospecific
synthesis of (-)-alpha-aminopropiophenone by bromination of propiophenone
followed by the Gabriel synthesis is claimed (10). Indeed, the melting
point (175°C) reported for the hydrochloride salt of the synthetic product
differs substantially from that reported previously for racemic alpha-amino-
propiophenone hydrochloride (184°C (12), and 187°C (13) and is in agreement
with the melting point reported by Takamatsu (175-176°C (14)) for (+)-alpha-
aminopropiophenone hydrochloride. Furthermore, it was reportedly that when
this salt was converted to an amine oxalate, a solid with a melting point
of 172-175°C, which showed no melting point depression with natural cathinone
oxalate, was obtained.

These results seem to suggest that the stereospecific synthesis of (-)-alpha-
aminopropiophenone hydrochloride from propiophenone had been accomplished
without the benefit of optically active reagents, solvents, or resolution.
Other apparent inconsistencies appear in the literature relating to alpha-
aminopropiophenone. For example, the report (14) that treatment of alpha-
aminopropiophenone with ethanolic hydrochloric acid gave (+)-alpha-amino-
propiophenone hydrochloride, mp 175-176°C, would appear to be an error
presumably the l-mandelate salt of (+)-alpha-aminopropiophenone was treated
with ethanolic hydrochloric acid.

In the light of increased interest in expanding the pharmacological and
medical investigations of the major constituents of Khat (2) and because
known methods of resolution of racemic alpha-aminopropiophenone were
inadequate for the preparation of gram quantities of the required antipodes
of alpha-aminopropiophenone, we undertook the development of an improved
synthetic pathway to optically active alpha-aminopropiophenone. At the same
time, having pure alpha-aminopropiophenone and its optical antipodes in
hand, we were able to establish some of the properties and chemical
behavior of alpha-aminopropiophenone and of its salts and to explain some
of the literature discrepancies.

Results and Discussion

Attempts to resolve (-)-alpha-aminopropiophenone via the mandelate salt by
following the reported procedures (7,14) yielded only minute quantities of
product in spite of the care taken to exclude light. Somewhat better
results were obtained with tartaric acid. Thus, (+)-alpha-aminopropiophenone
crystallized with (-)-tartaric acid and the (-) enantiomer crystallized
with (+)-tartaric acid. For both antipodes the yields were small, probably
due to the strong tendency of alpha-aminopropiophenone to cyclize to
3,6-dimethyl-2,5-diphenyldihydropyrazine, with subsequent oxidation to
3,6-dimethyl-2,5-diphenylpyrazine when it is not stabilized by the presence
of strong acids (13).

Consequently, an alternative route to optically active cathinone was developed.
Norephedrine was resolved in high yield into its (+) and (-) antipodes with
O,O-dibenzoyl-d-tartaric acid (15). Each enantiomer was converted to its
N-formyl derivative and oxidized with chromium trioxide in pyridine.
Hydrolysis with 20% hydrochloric acid at 40°C gave optically pure alpha-
aminopropiophenone hydrochloride without racemization. In this manner there
was obtained, from racemic norephedrine, (-)-alpha-aminopropiophenone in
39% overall yield and the (+) enantiomer in 40% overall yield. It should be
noted that use of an N-acetyl blocking group in the oxidation of norephedrine
to alpha-aminopropiophenone was unsuitable because removal of the acetyl
group led to racemization (~60%). Similarly, if deprotection of N-formyl-
alpha-aminopropiophenone was carried out with weaker acid (<20% HCI) and at
higher temperature (>40°C), racemization was observed.

An approach to the stereospecific synthesis of (S)-cathinone from
(S)-N-(methoxycarbonyl)alanine has been recently published (17). The
Friedel-Crafts yield was reported to be 50-60%; assuming a 90% yield in
removal of the N- methoxycarbonyl protecting group, the overall yield
obtained would be slightly higher than that obtained by our method.
However, whereas our approach leads to both enantiomers on using a natural
(and therefore relatively inexpensive) tartaric acid derivative,
preparation of (R)-cathinone by the procedure of McClure et al (17)
requires nonnatural alanine.

Surprisingly, the melting points obtained by us for racemic and optically
active alpha-aminopropiophenone hydrochloride were practically the same
(racemic, mp 190-191°C; optically active, mp 189-191°C). Furthermore, our
melting points for the optical antipodes were substantially higher than
those previously reported (175-176°C)(13). Our experiments suggest that the
low melting point was observed when the samples were insufficiently dried.

Because it had been found that optically active alpha-aminopropiophenone
racemized readily in the absence of strong acids (18), it occurred to us
that the plant extract obtained by using dilute acetic acid at room
temperature might have racemized to some extent during the extraction
procedure and/or while present as the salt of a weak acid such as oxalic
acid. The hydrochloride salts of (-)-alpha-aminopropiophenone and of the
racemate were therefore converted to the oxalate salts. The optically
active and racemic oxalate salts had very similar melting points (optically
active, mp 173-175°C; racemic, mp 172-173°C), as we had found for the
hydrochloride salts. In addition, they did not exhibit melting point
depression when admixed. Thus, although optical resolution by direct
crystallization of mixtures of interconverting enantiomers is possible in
principle (19), the strong tendency of alpha-aminopropiophenone to racemize
and/or cyclize when it is not stabilized by the presence of a strong acid
(13, 18) may account for the apparent identity of the oxalate salt of the
plant extract and of synthetic alpha- aminopropiophenone observed (10).
Clearly, in this case the melting points cannot serve as criteria for
optical purity. 


Conclusions

(1)     The optical antipodes of alpha-aminopropiophenone can be prepared in
        high yield by oxidation of optically active N-formylnorephedrine,
        followed by deblocking of the amino group. The resolution of nor-
        ephedrine is best carried out by using O,O-dibenzoyltartaric acid.
(2)     Melting points cannot be used as criteria of the optical purity of
        cathinone derivatives because of the (a) similarity of the melting
        points of the racemic and optically active compound and (b) lack of
        melting point depression upon admixing of opposite antipodes and/or
        racemic and optically active compounds.
(3)     The cathinone free base racemizes and dimerizes readily in a hydroxylic
        medium. Similar behavior is observed for solutions of the oxalate salt
        but at a somewhat reduced rate; therefore, the plant extract of Schorno
        (10) may have been partially racemized.
(4)     The cathinone free base is fairly stable as a dilute solution in
        nonpolar, nonhydroxylic media, and, consequently, strong acid salts of
        optically active cathinone can be interconverted without racemization.


Experimental Section


Resolution of Norephedrine  

A solution of 80 g (0.53 mol) of (-)-norephedrine in 400 mL of EtOH was
combined at 60 °C with a solution of 95 g (0.27 mol) of O,O-dibenzoyl-
d-tartaric acid in a mixture of 100 mL of EtOH and 250 mL of i-PrOH. When
the mixture had cooled slightly, some seed crystals were added, and the
salt was allowed to crystallize undisturbed for 3 days.
The clear supernatant was carefully decanted from the crystal cake of
(+)-norephedrine O,O-dibenzoyl-d-tartrate. The solid was washed thoroughly
with EtOH-i-PrOH, and the washings were filtered into the supernatant. This
operation usually caused the crystallization of (-)-norephedrine O'O-dibenzoyl-
d-tartrate in the filtrate. After 2 days, the (-)-norephedrine salt was
collected by filtration, washed with THF and dried at 120°C. The yield was
75 g (86%) of (-)-norephedrine O,O-dibenzoyl-d-tartrate and 68 g (78%) of
(+)-norephedrine O,O-dibenzoyl-d-tartrate. Both products had a melting
point of 190-200°C (dec). For conversion to the corresponding hydrochlorides,
the salts were each treated with 150 mL of 7% ethanolic hydrochloric acid
at 60°C for 30 min. After evaporation of the solvent, the residue was
triturated with THF which caused spontaneous crystallization. The solid was
washed with THF and EtOH and vacuum dried. From the filtrates was obtained
a second crop upon cooling.
The following results were obtained. (-)-Norephedrine hydrochloride: 40 g
(81%); mp 170-172°C; (c 1, H2O) (lit. 15 mp 171-172°C). (+)-Norephedrine
hydrochloride: 37 g (74%); mp 170-172°C (c 1, H2O) (lit. 15 mp 171-172°C).


(+)-N-Formylnorephedrine 

A solution of 110 g (0.73 mol) of (+)-norephedrine in 250 mL of THF was
cooled in an ice bath while a mixture of 35 g (0.73 mol) of 95% formic acid
was added dropwise with stirring over 1 h. The pasty product was diluted
with ether to give 134 g (94%) of the crystaLine formate of (+)-norephedrine.
The formate was dissolved in 700 mL of toluene and refluxed for 2 days,
with the water produced being separated in a Dean-Stark trap. The syrupy
product (+)-N-Formylnorephedrine, which remained after evaporation of the
solvent ich remained after evaporation of the solvent and vacuum drying,
weighed 115g (92%): 


(+)-N-Formyl-alpha-Propiophenone (23) 

An ice-cold mixture of 3 L of CH2Cl2 and 190 g (2.4 mol) of pyridine was
treated with 120 g (1.2 mol) of dry CrO3 which was added in portions within
a 30-min period. The purple-brown mixture was stirred at room temperature
for 2 h. A solution of 38 g (0.21 mol) of (+)-N-Formylnorephedrine in 200
mL CH2Cl2 was added to the CrO2 mixture all at once with vigorous mechanical
stirring. After 15 min, the yellow solution was decanted from a black, sticky
precipitate and immediately extracted with 1 L of 5% NaOH solution followed
by 1 L of 10% HCI solution. The organic phase was filtered through a bed of
Na2SO4 and evaporated to a clear, light yellow syrup. After vacuum drying
overnight, the product (+)-N-Formyl-alpha-Propiophenone weighed 31 g
(83% yield). The material was sufficiently pure for further synthesis.


(+)-alpha-Aminopropiophenone Hydrochloride 

A suspension of 21 g (0.12 mol) of (+)-N-Formyl-alpha-Propiophenone in 200
mL of 20% HCI was vigorously stirred at 40 °C until a clear solution
resulted (~5 h). The mixture was evaporated to dryness, and the residue was
crystallized from i-PrOH-Et2O. After the sample was dried overnight
(P2O5-KOH), 16 g (72%) of (+)-alpha-Aminopropiophenone HCl was obtained: mp
186-189°C. One recrystallization from i-PrOH-THF gave a product: mp 186-189°C.


(-)-N-Formylnorephedrine 

The free base isolated from 115 g (0.62 mol) of (-)-norephedrine hydrochloride
by CHCl3-aqueous NaHCO3 partition was dissolved in 250 mL of THF. While a temp
of 5°C was maintained, a mixture of 30 g (0.7 mol) of 95% formic acid and
30 mL of THF was added dropwise over 2 h. The resulting thick suspension
was diluted with 520 mL of Et2O and stored at room temperature for 1 h.
Filtration and washing with Et2O gave 122 g of (-)-norephedrine. Filtration
and washing with Et2O gave 122 g of (-)-norephedrine formate, mp 144-145°C.
The dried formate was refluxed for 2.5 days with 800 mL of toluene in a
Dean-Stark trap until all the water was removed. The solvent was then
evaporated, and vacuum drying gave 106 g (96%) of (-)-N-formylnorephedrine
as a nd vacuum drying gave 106 g (96%) of (-)-N-formylnorephedrine as a
slightly yellow syrup.


(-)-alpha-Aminopropiophenone Hydrochloride

The oxidation of  (-)-N-Formylnorephedrine was carried out in four portions
of 26.5 g with chromium trioxide-pyridine complex as described for the
(+) antipode. The corresponding (-)-N-formyl-alpha-aminopropiophenone produced
(91g, 83%) had the same NMR characteristics as (+)-N-formyl-alpha-aminopropio-
phenone. Hydrolysis of 90g (0.5 mol) of (-)-N-formyl-alpha-aminopropiophenone
with 6 N hydrochloric acid (500 mL, 3 mol) at 40°C and evaporation of the
excess acid provided (-)-alpha-Aminopropiophenone HCI as a tan solid, 65 g
(69.5%). Two recrystallizations from i-PrOH-Et2O gave pure product (mp
175-176°C) which after vacuum drying over P2O5-KOH had a melting point of
188-190°C (dec). The salt weighed 56 g (60%). A mixture melting point with
the other antipode or with racemic alpha- her antipode or with racemic
alpha-Aminopropiophenone gave a depression to 176-177°C dec.


Resolution of alpha-Aminopropiophenone With d-Tartaric Acid. 

A solution of 1.8 g (0.01 mol) of alpha-Aminopropiophenone HCI in 10 mL
water was added all at once to an emulsion prepared by shaking 100 mL of
CH2CI2 and 10 mL of 1 M NaHCO3 solution. After the mixture was shaken for
20 s, the organic phase was separated as soon as possible and immediately
added to a solution of 0.8 g (0.005 mol) of d-tartaric acid in 35 mL of
EtOH. After 2 days at room temperature, 450 mg (17%) white crystals (mp
162-164°C (dec)), were separated. Treatment of the salt with ethanolic HCl
gave (+)-alpha-Aminopropiophenone atment of the salt with ethanolic HCl
gave (+)-alpha-Aminopropiophenone HCl: 280 mg (75%) from tartarate); mp 176°C.

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References:

(1)     Krikorian, A., A. Econ. Bet. 1973, 27, 378.
(2)     United Nations Document MNAR/3/79.
(3)     Eddy, N., N. H. Bull. W. H. O. 1965, 32, 721.
(4)     Wolfes, 0., Arch. Pharm. 1930, 268, 81.
(5)     Parris, M. R., Ann. Pharm. Fr: 1957,15, 89.
(6)     Ristic, Th., Arch. Pharm. 1962, 295, 254.
(7)     Karawya, M., J. Pharm. Sci. UAR. 1968, 9,147.
(8)     Racker, G. Planta Med. 1973, 24, 61
(9)     United Nations Document MNAR/11/1975.
(10)    United Nations Document MNAR/7/1978.
(11)    These documents were umavailable from either the United Nations
        Library in New York or from the document library of the University
        of North Carolina at Chapel Hill which serves as a regional
        depository of the United Nations Documents. We obtained copies of
        the documents from the National Institute on Drug Abuse.
(12)    Behr-Bergowski, L. Chem. Ber. 1897, 30, 1515.
(13)    Gabriel, S. Chem. Ber. 1908, 41, 1127-1156.
(14)    Takamatsu, H., Yakugaku Zasshi 1956, 76, 1219-1222, CA 1957, 51, 4303c.
(15)    The resolution of norephedrine with tartaric acid has been reported
        (16). In our hands O,O-dibenzoyltartaric acid was a more satisfactory
        resolving agent.
(16)    Nagai, W., Justus Liebigs Ann. Chem. 1929, 470, 156-182.
(17)    McClure, D., J. Org. Chem. 1981, 46, 2431-2433.
(18)    Takamatsu, H., Yakugaku Zasshi 1956, 76,1223-1226.
(19)    Collet, A., J. Chem. Rev. 1980, 80, 215-230.
(20)    Rice, K. C., J. Org. Chem. 1980, 45, 592-601.
(21)    Rice, K. C., private communication.
(22)    The material supplied by Aldrich has the incorrect configurational
        assignment. Thus the catalog reads "(R)-(-)-2-methylbenzyl
        isocyanate" it is in fact the (S)-(-) enantiomer. This has been
        confirmed by Aldrich.
(23)    Ratcliffe, R., J. Org. Chem. 1970, 35, 4000-4002.

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