http://www.freepatentsonline.com/7855296.

html

A Practical Total Synthesis of Cocaine's Enantiomers

John F. Casale

Forensic Science International 33, 275-298 (1987)

HTML by Rhodium

Summary

A simplified total synthesis of the single enantiomers of cocaine and racemic cocaine is outlined.
The synthesis employs common laboratory glassware, reagents, and methods which can be
performed in most forensic laboratories. The procedure for the isolation and purification of the
dextrorotatory enantiomer of cocaine is presented.

Introduction

In many jurisdictions cocaine is listed as a controlled substance under statutes covering coca
leaves and their extracts. Therefore only the levorotatory isomer of cocaine would be
controlled. These laws do not include optical isomers and diastereoisomers. The question of
enantiomeric composition has recently become popular with defense attorneys. (-)-Cocaine is
the naturally occurring alkaloid extracted from coca leaves. Racemic and (+)-cocaine can only be
obtained through a chemical synthesis.

The molecular structure of cocaine was first described by Willsttter and Muller1 in 1898. It was
not until the early 1950's that the, principles and methodologies of stereochemistry were
applied to cocaine's tropane ring skeleton. Findlay2, Fodor3,4, and others established the
stereochemistry of the tropane alcohols and their esters. Once this groundwork was laid, the
three-dimensional structures of cocaine and its diastereoisomers (pseudococaine, allococaine,
and allopseudococaine) were elucidated by Findlay5-7 and Hardegger et. al.8 Findlay's three-
dimensional structures were confirmed in 1968 by Sinnema et. al.9using NMR spectral analysis.
Electron impact fragmentation patterns of the tropane alkaloids were later established by
Blossey et. al.10 These workers identified the major mass spectral fragmentation patterns by
deuterium and substituent labelling. Fragmentation patterns for various tropinone analogs have
also been determined by Kashman and Cherokee11.

Methods for detection of cocaine diastereoisomers have been established by Allen et. al.12,
Olieman et. al.13, Sinnema et. al.9, and Lewin et. al.14 These methods incorporate IR, GC, GC-
MS, NMR, and HPLC. Identification of the different enantiomeric mixtures can be done as
illustrated by Eskes15 and Allen et. al.12 One report has been published concerning the
detection of cocaine co-synthetics. This work by Cooper and Allen16 lists and identifies the three
most reoccurring substances.

Fig. 1.

Synthetic route to 2-CMT.

The first total synthesis of cocaine was accomplished by Willsttter et. al.17 Cocaine is prepared
following a 3-5-step synthesis which includes one separation of epimers. This route is usually
()-2-carbomethoxytropinone (2-CMT) ()-ecgonine methylester (EME) ()-cocaine. The
reduction of 2-CMT with sodium amalgam yields a mixture of ()-EME and ()-pseudoecgonine
methylester (PEME). If this epimeric mixture is not separated prior to benzoylation, a mixture of
()-cocaine and ()-pseudococaine results. Any unreacted tropinone or 2-CMT will become
benzoylated to yield two co-synthetics identified by Cooper.

It has been shown by Findlay18, Cooper and Allen16, and myself (unpublished) that direct
synthesis of 2-CMT gives greater yields than the carbomethoxylation of tropinone.
Preobrashenski19 and Wallingford20 synthesized 2-CMT and other beta-keto esters from
condensation of alkyl carbonates with ketones. Findlay, Cooper, and myself found that such a
route gives poor yields with resinous by-products. It is noteworthy that Carroll et al.21 obtained
2-CMT in 80% yield through an alkyl condensation.

Methylamine, acetonedicarboxylic acid, and succindialdehyde are potential starting materials

for the synthesis of 2-CMT. 2-CMT is synthesized by first converting acetonedicarboxylic acid
into its anhydride (84%) and then preparing the methyl ester from the anhydride (99%). These
compounds can be synthesized following the procedures of Adams et al.22, Kaushall23 and
Findlay18, respectively. The mono-methyl ester of acetonedicarboxylic acid is reacted with
methylamine and succindialdehyde via the Mannich condensation to yield 2-CMT (86%) (Fig. 1).
Thus the overall yield of 2-CMT is 71%.

Data has not been published concerning optimum conditions for 2-CMT synthesis. However an
analogy can be drawn from tropinone and 2-CMT to pseudopelletierine optimum synthetic
conditions. Pseudopelletierine is a ring homolog of tropinone having an eight-membered ring as
opposed to the seven-membered ring of tropinone. Optimum conditions for its synthesis were
established by Cope et al.24. Those workers found that a buffered solution at pH 3-4 and 25C
gave highest yields. Data by Schoph and Lehmann25 show highest yields at pH 5-7. Preliminary
experiments in our laboratory to synthesize 2-CMT, via the conditions of Cope and Schoph's
pseudopelletierine synthesis, indicated the optimum conditions for 2-CMT synthesis were at pH
4-4.5 and 25C (unpublished). I also found that a buffered reaction is critical for good yields of
product. Cope stated that without buffered reactions the pseudopelletierine condensation
reaction had a pH rise of 3.5 units. Keagle and Hartung26 found that tropinone was prepared in
highest yield with 0.0225 mol succindialdehyde per liter of solution. My work has shown an 86%
yield of 2-CMT from 0.053 mol succindialdehyde per liter of solution. Mastering the ring
coupling Mannich reaction is the key step in producing synthetic cocaine.

All practical routes to cocaine have used 2-CMT as the common intermediate. These routes
include procedures by Findlay18, Keagle26, Kashman11, Bazilevshaya27, Sinnema9, Schopf25,
Robinson28,29, Mannich30, Preobazhenskii19, Zeigler31, Zeile32 and Willsttter17,33,34. New
synthetic methods for entry into the tropane skeleton have been reported by Tufariello35-37,
Hawakawa38, Noyori39, Parker40, Peterson41, Iida42 and Kashman11 but are novel approaches
with complicated synthesis.

Fig. 2.

Reduction and benzoylation of 2-CMT

(Single enantiomers are depicted for simplification,

i.e. (-)-EME, (+)-PEME, (-)-cocaine and (+)-pseudococaine).

The reported sequence of synthesis (Figs. 1 and 2) combines several procedures found in the
literature. Clean-up procedures are based on the desired intermediate's solubilities in organic
solvents.
2-CMT exists largely as the enol when hydrated and all three keto-enol isomers are present in
solution. The keto nature allows it to be reduced by sodium amalgam to EME and PEME. The
reduction is carried out at near the freezing point of water in an acid medium to yield the
equatorial 3-hydroxy isomers of EME and PEME. The C-2 axial epimer EME is thermodynamically
less stable and is easily irreversibly epimerized under basic conditions to PEME. Clarke et al.43
attempted to influence the ratio of axial to equatorial C-2 epimers in their initial reactions but
were unsuccessful.

EME is a colorless oil which is hydroscopic and any water absorbed causes slow hydrolysis to
ecgonine. Aqueous alkaline solutions will also cause slow saponification. The conversion of EME
into cocaine was studied at length by DeJong44,45. Various solvents and alkaline drying agents
were used in his benzoylations. Sinnema et al.9 also reported benzoylations with high yields.

Resolution of cocaine's enantiomers is accomplished through bitartrate recrystallizations. This

resolution can be performed with 2-CMT prior to reduction and benzoylation as demonstrated
by Carroll (pers. comm.), Clarke et al.43, and Lewin et al.46,47.

Synthesis
Acetonedicarboxylic acid anhydride

To a solution of 30 ml glacial acetic acid and 22 ml of acetic anhydride (Fisher) at 10C was
slowly added 20g (0.684 mol) of 1,3-acetonedicarboxylic acid (Aldrich). The temperature was
not allowed to rise above +12C until the reaction was complete. For runs where precipitation of
product had not occurred within 3 h, it was induced by the addition of benzene. The product
was filtered by suction filtration, washed with 100 ml of glacial acetic acid, and next washed
with 100 ml of benzene. It was allowed to dry yielding 14.8 g of white powder (84%).

Succindialdehyde

To 400 ml of 0.2 N sulfuric acid was slowly added 44.2 g (0.334 mol) of 2,5-
dimethoxytetrahydrofuran (Aldrich) and stirred for 15 min. The succindialdehyde was allowed to
stand for 4 h without further treatment.
Acetonedicarboxylic acid monomethyl ester

To a flask containing 41.0 g (0.32 mol) of acetonedicarboxylic acid anhydride was added 160 ml
of cold dry methanol. The mono-methyl ester solution was allowed to stand for one hour and
filtered.

()-2-Carbomethoxytropinone

Six liters of 4.4 pH citrate buffer was made by diluting 35.3 g of citric acid and 38.8 g of sodium
citrate dihydrate to volume. To the buffer was added 32.0 g (0.48 mol) of methylamine
hydrochloride (Fisher) and 12.8g (0.32 mol) of sodium hydroxide. The succindialdehyde solution
was added dropwise to the buffer over 10 min with stirring at room temperature. The mono-
methyl ester solution was next added dropwise over 10 min with stirring. The reaction was
stirred 48 h at room temperature. The reaction was extracted in 250-ml portions by making the
pH 12 with concentrated ammonium hydroxide and extracted 4 times with 200 ml of
chloroform. The extracts were dried over sodium sulfate and evaporated in vacuo. The resulting
yellow oil was dissolved in 200 ml of dry diethyl ether and filtered. The filtrate was evaporated
in vacuo. The oil was next dissolved into 200 ml of petroleum ether and filtered. The filtrate was
evaporated in vacuo and the resulting oil was allowed to hydrate upon standing. The crude
hydrate was 95% pure and purified further by sublimation to yield snow white flakes, mp 96-
98.5C. Yield: 58.9 g (86%).

Resolution of ()-2-carbomethoxytropinone

To a solution of 26.60 g (0.124 mol) of sublimed racemic 2-CMT in 106 ml of absolute ethanol
was added dropwise a solution of 18.57 g (0.124 mol) of (-)-tartaric acid in 133 ml of absolute
ethanol. After 48 h the mother liquor was decanted and set aside. The crystals were washed
with 50 ml of absolute ethanol and then dissolved into a minimal amount (approx. 200 ml) of
hot dry methanol. The solution was filtered while hot into an Erlenmeyer flask and covered. The
solution was left undisturbed for 72 h. The solution was decanted off and combined with the
first mother liquor. The crystals of anhydrous (-)-2-CMT bitartrate were washed with 100 ml of
dry acetone and dried yielding 6.8g (30%), []D24 -16.9 (c=2, H2O). Findlay18 reported []D20 -
16.9 (c=2, H2O). The mother liquors were evaporated to dryness and dissolved into 200 ml of
water, made pH 8 with sodium carbonate, and extracted 5 times with 200 ml of methylene
chloride. The extracts were dried over sodium sulfate and evaporated in vacuo. The (+)-enriched
2-CMT was hydrated yielding 17.5 g of powder.

To a solution of 17.2 g (0.08 mol) of (+)-enriched 2-CMT in 70 ml of absolute ethanol was added
a solution of 12.0 g (0.08 mol) of (+)-tartaric acid in 86 ml of absolute ethanol. Subsequent
recrystallizations yielded 6.95 g of anhydrous (+)-2-CMT bitartrate (30%), []D24 +16.9 (c=2,
H2O). Freebasing the mother liquors and retreatment with (-)-tartaric acid yielded 6.0 g more
anhydrous (-)-2-CMT bitartrate, []D24 -17.0 (c=2, H2O). Thus the overall yield of anhydrous (-)-
2-CMT bitartrate was 12.8 g (57%).

(+)-Ecgonine methyl ester

Into a three-neck 500 ml round bottom flask was placed 7.70 g (0.036 mol) of (-)-2-CMT hydrate
with 51 ml of ice cold 10% sulfuric acid. Bromophenol blue (approx. 2 mg) indicator was added.
With stirring the solution was treated with 1028 g of 1.5% sodium amalgam in small portions
over 2.5 h. The temperature was kept under +5C. The pH was monitored via the indicator and
kept between pH 3 and 4 with cold 30% sulfuric acid. Periodic addition of water was necessary
to dissolve sodium sulfate salts. The reaction was stirred an additional 45 min after the addition
of amalgam was complete. The solution was separated from the mercury, adjusted to pH 12
with sodium hydroxide and extracted three times with 200 ml of chloroform. The extracts were
dried over sodium sulfate and evaporated in vacuo to a light green oil containing a 3:1 ratio of
EME to PEME. The oil was dissolved into 200 ml of petroleum ether and filtered. The filtrate was
evaporated in vacuo. The resulting oil was dissolved into 500 ml of dry diethyl ether and the
hydrochloride salts were made with ethereal HCl. The salts were filtered and immediately
dissolved into a minimal amount of dry methanol. The methanol was evaporated in vacuo and
120 ml of dry chloroform was added to the crystals. The slurry of crystals was filtered and dried
yielding 2.28 g of (+)-ecgonine methyl ester hydrochloride (27%). The product was recrystallized
from methanol and diethyl ether to yield 2.2 g of pure product []D24 +52.3 c=1, MeOH), mp
213-214C. Lewin et al.47 reported mp 213.5-214.5C, []D24 +52.3 (c=1, MeOH).

Racemic and (-)-EME can be synthesized by the same reduction procedure and clean-up using
()-2-CMT and (+)-2-CMT respectively.

(+)-Cocaine

In an oven-dried 100-ml round bottom flask was added 1.00g (4.25 mmol) of (+)-ecgonine
methyl ester HCl with 7 ml of dry pyridine and stirred in an ice bath. The reaction was protected
from moisture with argon. Dropwise over 5 min was added a solution of 0.8 ml (6.85 mmol) of
benzoyl chloride in 5 ml of pyridine. After addition was complete the ice bath was removed and
the reaction was stirred 24 h under argon. Dry acetone (200 ml) was added and the slurry was
filtered by suction filtration. The crude (+)-cocaine hydrochloride was washed with an additional
100 ml of dry acetone. The product was dried yielding 1.28 g (89%). The hydrochloride was
dissolved into 20 ml of water, made pH 8 with 5% ammonium hydroxide, and extracted 4 times
with 50 ml of methylene chloride. The solvent was dried over sodium sulfate and evaporated in
vacuo. The free base was recrystallized from diethyl ether and petroleum ether yielding 1.01 g
(78%) of pure (+)-cocaine base, []D24 +35.8 (c=1, 50% aqueous EtOH), mp 96.0-97.5C. The
literature48 lists the (-)-enantiomer at []D24 -35 (c=1, 50% aqueous EtOH), mp 98C.

Racemic and (-)-cocaine can be synthesized using the same benzoylation procedure and clean-
up using (+)-EME and (-)-EME respectively.

Experimental Procedure

Melting points were determined on a Mel-Temp capillary tube apparatus. Optical rotations were
recorded at the sodium D line with a Rudolph Autopol III Automatic Polarimeter (1 dm cell).
Infrared (IR) spectra were recorded in potassium bromide disks with a Beckman Microlab 600
spectrometer. A Finnigan Model 5100 GC-MS with Supelcos Data System was used for producing
the mass spectra. A 30-m fused silica, SE 54 capillary column (i.d. 0.25 mm) (Supelco) was
employed with helium (99.99% VHP) as the carrier gas. The injection port temperature was
250C and the sample was injected in the splitless mode. The initial column temperature was
120C and was ramped at 10C/min to 260C. The quadrupole mass analyzer operated under
electron impact conditions at 70 eV.

Figures 3-11 present infrared spectra of the intermediates and final products. Figures 12-17
present mass spectra of the same compounds.

Fig. 3. Infrared spectrum of ()-2-CMT hydrate.

Fig. 4. lnfrared spectrum of ()-2-CMT anhydrous base.

Fig. 5. lnfrared spectrum of (-)-2-CMT hydrate.

Fig. 6. Infrared spectrum of ()-EME hydrochloride.

Fig. 7. lnfrared spectrum of (+)-EME hydrochloride.

Fig. 8. Infrared spectrum of ()-PEME base.

Fig. 9. Infrared spectrum of (+)-PEME base.

Fig. 10. lnfrared spectrum of ()-cocaine base.

 Fig. 11. Infrared spectrum of (+)-cocaine base.

Fig. 12. Electron impact mass spectrum of tropinone.

Fig. 13. Electron impact mass spectrum of 2-CMT.

Fig. 14. Electron impact mass spectrum of EME.

Fig. 15. Electron impact mase spectrum of PEME.

Fig. 16. Electron impact mass spectrum of cocaine.

Fig. 17. Electron impact mass spectrum of pseudococaine.

Discussion

(+)-Cocaine base was obtained overall in 8.6% of theoretical yield. Isolation and purification of
intermediates and final product were performed through their solubilities in organic solvents
and recrystallizations. Liquid chromatography was not used in this procedure but could be used
to increase the yield of EME.

Extracting 2-CMT from the Mannich reaction at pH 12 restricts gummy tar-like substances from
co-extracting. The extraction must be performed quickly since the product will undergo self-
condensation at this pH. Conversely a very acidic pH will cause decarboxylation to tropinone.
Dissolution of 2-CMT in diethyl ether and petroleum ether precipitates any resinous by-
products. 2-CMT was found to be more stable as the hydrate. The anhydrous base would turn
dark brown within one week if it was not hydrated.

EME hydrochloride is practically insoluble in chloroform. This property allows PEME

hydrochloride and other impurity hydrochlorides to be separated. EME will slowly hydrolyze to
ecgonine in water. Its extractions from aqueous alkaline solutions must be done promptly to
prevent saponification.

Cocaine hydrochloride is insoluble in dry acetone. This allows cocaine to be separated from
unreacted benzoyl chloride, EME, and pyridine.
(+)-Cocaine gives an identical microcrystalline precipitate to that of (-)-cocaine in gold chloride-
HOAc. When the separate enantiomers are mixed they give racemic crystals in gold chloride-
HOAc as described by Allen et. al.12 and identical crystals to a sample of racemic cocaine
synthesized from this procedure.

The infrared spectra of levo-, dextro- and racemic cocaine hydrochloride are identical. The
infrared spectra of racemic cocaine base and its single enantiomers have definite differences
(Figs. 10 and 11).

It is my hope that this procedure will allow other forensic laboratories to synthesize their own
(+)-cocaine and ()-cocaine without the use of expensive and sophisticated equipment.

References

R. Willsttter and W. Muller, Chem. Ber., 31, 1202-1214 (1898)

S. Findlay, J. Am. Chem. Soc., 75, 1033-1035 (1953)

G. Fodor, Nature, 170, 278-279 (1952)

G. Fodor and O. Kovacs, J. Chem. Soc., 724-727 (1953)

S. Findlay, J. Org. Chem., 24, 1540-1550 (1959)

S. Findlay, J. Am. Chem. Soc., 76, 2855-2862 (1954)

S. Findlay, J. Am. Chem. Soc., 75, 4624-4625 (1953)

E. Hardegger and H. Ott, Helv. Chem. Acta, 38, 312-320 (1955)

A. Sinnema, L. Maat, A. Van Der Gugten and H. Beyer, Rec. Trav. Chim., Pays-Bas, 87, 1027-
1041 (1968)

E. Blossey, M. Ohashi, G. Fodor and C. Djerassi, Tetrahedron, 20, 585-595 (1964) [Abstract]

Y. Kashman and S. Cherkez, Tetrahedron, 28, 155-165 (1972) [Abstract]

A. Allen, D. Cooper, W. Kiser and R. Cottrell, J. Forensic Sci., 26, 12-26 (1981)

C. Olieman, L. Maat and H. Beyerman, Rec. Trav. Chim., Pays-Bas, 98, 501-522 (1979)

A. Lewin, S. Parker and I. Carroll, J. Chromatog., 193, 371-380 (1980)

 D. Eskes, J. Chromatog., 152, 589-591 (1978)

D. Cooper and A. Allen, J. Forensic Sci., 29, 1045-1055 (1984)

R. Willsttter, D. Wolfes and M. Mader Annalen., 434, 111-139 (1923)

S. Findlay, J. Org. Chem., 22, 1385-1394 (1957)

N. Preobazhenskii, M. Schtschukina and R. Lapina, Chem. Ber., 69(7), 1615-1620 (1936)

V. Wallingford, A. Homeyer and D. Jones, J. Am. Chem. Soc., 63, 2252-2254 (1941)

I. Carroll, M. Coleman and A. Lewin, J. Org. Chem., 47, 13-19 (1982)

R. Adams, H. Chiles and C. Rassweiler, Org. Synth. Coll. Vol. 1, 10-12 (1941) [Full Text]

R. Kaushal, J. Indian Chem. Soc., 17, 138-143 (1940)

A. Cope, H. Dryden, C. Overgerger and A. D'Addieco, J. Am. Chem. Soc., 73, 3416-3418 (1951)

C. Schopf and G. Lehmann, Annalen., 518, 1-36 (1935)

L. Keagle and W. Hartung, J. Am. Chem. Soc., 68, 1608-1610 (1946)

G. Bazilevskaya, M. Bainova, D. Gura, K. Dyumaev and N. Preobazhenskii, Izvest. Vyssh. Uch.

Zave. Khim. Khim. Tekn., 2, 75 (1958); Chem. Abs. 53, 423 (1959)

R. Robinson, J. Chem. Soc., 111, 762-776 (1917)

Menzie and R. Robinson, J. Chem. Soc., 125, 2163-2172 (1924)

C. Mannich, Arch. Pharm., 272, 323-359 (1934)

Ziegler and Wilms, Annalen, 567, 31-43 (1950)

K. Ziele and W. Schultz, Chem. Ber., 89, 678-679 (1956)

R. Willsttter and A. Pfannenstiel, Annalen., 422, 1-15 (1921)

R. Willsttter and M. Bonner, Annalen., 422, 15-35 (1921)

J. Tufariello and G. Mullen, J. Am. Chem. Soc., 100, 3638-3639 (1978)

J. Tufariello, J. Tegeler, S. Wong and A. Ali, Tetrahedron Lett., 20, 1733-1736 (1978) [Abstract]

J. Tufariello. G. Mullen, J. Tegeler, S. Wong and A. Ali, J. Am. Chem. Soc., 101, 2435-2442
(1979)

Y. Hayakawa, Y. Baba, S. Makino and R. Noyori, J. Am. Chem. Soc., 100, 1786-1791 (1978)
 R. Noyori, Y. Baba and Y. Hayakawa, J. Am. Chem. Soc., 96, 3336-3338 (1974)

W. Parker, R. Raphael and D. Wilkinson, J. Chem. Soc., 2433-2437 (1959)

J. Petersen, S. Toteberg-Kaulen and H. Rapoport, J. Org. Chem., 49, 2948-2953 (1984)

H. lida, Y. Watanabe and C. Kibayashi, J. Org. Chem., 50, 1818-1825 (1985)

R. Clarke, S. Daun, A. Gambino, M. Aceto, J. Pearl and E. Bogado, J. Med. Chem., 16, 1260-
1267 (1973)

A. Dejong, Rec. Trav. Chim., Pays-Bas, 62, 54-58 (1942)

A. Dejong, Rec. Trav. Chim., Pays-Bas, 59, 27-30 (1940)

A. Lewin, R. Clanton and C. Pitt, Synthesis and Applications of Isotopically Labeled

Compounds. Proceedings of an International Symposium, 1982, p. 421

A. Lewin, T. Nasaree, I. Carroll and F. Ivy, J. Heterocycl. Chem. 24, 19-21 (1987) [Full Text]

The Merck Index, M. Windholz (Ed)

Cocaine Synthesis
From "Recreational Drugs" by Professor Buzz

HTML by Rhodium

Although this drug is categorized as a local anesthetic, I have chosen to put it in with the
hallucinogens because of the psychotomimetic effects that it produces. Cocaine is not a
phenylethylamine, but it produces central nervous system arousal or stimulant effects which
closely resemble those of the amphetamines, the methylenedioxyamphetamines in particular.
This is due to the inhibition by cocaine of re-uptake of the norepinepherine released by the
adrenergic nerve terminals, leading to an enhanced adrenergic stimulation of norepinephrine
receptors. The increased sense of well being and intense, but short lived, euphoric state
produced by cocaine requires frequent administration.

Cocaine does not penetrate the intact skin, but is readily absorbed from the mucus membranes,
creating the need to snort it. This accounts for the ulceration of the nasal septum after cocaine
has been snorted for long periods.

The basic formula for cocaine starts by purchasing or making tropinone, converting the
tropinone into 2- carbomethoxytropinone (also known as methyl-tropan-3-one-2-carboxylate),
reducing this to ecgonine, and changing that to cocaine. Sounds easy? It really is not very simple,
but with Reagan's new drug policies, cracking down on all of the drug smuggling at the borders,
this synthetic cocaine may be the source of the future. This synthesis is certainly worth
performing with the high prices that cocaine is now commanding. As usual, I will start with the
precursors and intermediates leading up to the product.

Succindialdehyde

This can be purchased, too. 23.2 g of succinaldoxime powder in 410 ml of 1 N sulfuric acid and
add dropwise with stirring at 0C a solution of 27.6 g of sodium nitrite in 250 ml of water over 3
hours. After the addition, stir and let the mixture rise to room temp for about 2 hours, taking
care not to let outside air into the reaction. Stir in 5 g of Ba carbonate and filter. Extract the
filtrate with ether and dry, evaporate in vacuo to get the succindialdehyde. This was taken from
JOC, 22, 1390 (1957). To make succinaldoxime, see JOC, 21, 644 (1956).

Complete Synthesis of Succindialdehyde

JACS, 68, 1608 (1946)

In a 2 liter 3 necked flask equipped with a stirrer, reflux condenser, and an addition funnel, is
mixed 1 liter of ethanol, 67 g of freshly distilled pyrrole, and 141 g of hydroxylamine
hydrochloride. Heat to reflux until dissolved, add 106 g of anhydrous sodium carbonate in small
portions as fast as reaction will allow. Reflux for 24 hours and filter the mixture. Evaporate the
filtrate to dryness under vacuo. Take up the residue in the minimum amount of boiling water,
decolorize with carbon, filter and allow to recrystallize in refrigerator. Filter to get product and
concentrate to get additional crop. Yield of succinaldoxime powder is a little over 40 g, mp is
171-172C.

5.8 g of the above powder is placed in a beaker of 250 ml capacity and 54 ml of 10% sulfuric acid
is added. Cool to 0C and add in small portions of 7 g of sodium nitrite (if you add the nitrite too
fast, nitrogen dioxide fumes will evolve). After the dioxime is completely dissolved, allow the
solution to warm to 20C and effervescence to go to completion. Neutralize the yellow solution
to litmus by adding small portions of barium carbonate. Filter off the barium sulfate that
precipitates. The filtrate is 90% pure succindialdehyde and is not purified further for the reaction
to create tropinone. Do this procedure 3 more times to get the proper amount for the next step,
or multiply the amounts given by four and proceed as described above.

Take the total amount of succinaldehyde (obtained from 4 of the above syntheses combined)
and without further treatment or purification (this had better be 15.5 g of succindialdehyde) put
into an Erlenmeyer flask of 4-5 liters capacity. Add 21.6 g of methylamine hydrochloride, 46.7 g
of acetonedicarboxylic acid, and enough water to make a total volume of 2 liters. Adjust the pH
to 8-10 by slowly adding a saturated solution of disodium phosphate. The condensate of this
reaction (allow to set for about 6 days) is extracted with ether, the ethereal solution is dried
over sodium sulphate and distilled, the product coming over at 113C at 25 mm of pressure is
collected. Upon cooling, 14 g of tropinone crystallizes in the pure state. Tropinone can also be
obtained by oxidation of tropine with potassium dichromate, but I could not find the specifics
for this operation.
2-Carbomethoxytropinone

A mixture of 1.35 g of sodium methoxide (this is sodium in a minimum amount of methanol), 3.5
g of tropinone, 4 ml of dimethylcarbonate and 10 ml of toluene is refluxed for 30 min. Cool to
0C and add 15 ml of water that contains 2.5 g of ammonium chloride. Extract the solution after
shaking with four 50 ml portions of chloroform, dry, evaporate the chloroform in vacuo. Dissolve
the oil residue in 100 ml of ether, wash twice with a mixture of 6 ml of saturated potassium
carbonate and three ml of 3 N KOH. Dry and evaporate in vacuo to recover the unreacted
tropinone. Take up the oil in a solution of aqueous ammonium chloride and extract with
chloroform, dry, and evaporate in vacuo to get an oil. The oil is dissolved in hot acetone, cool,
and scratch inside of flask with glass rod to precipitate 2-carbomethoxytropinone. Recrystallize
16 g of this product in 30 ml of hot methyl acetate and add 4 ml of cold water and 4 ml of
acetone. Put in freezer for 2.5-3 hours. Filter and wash the precipitate with cold methyl acetate
to get pure product.

Methylecgonine

0.4 mole of tropinone is suspended in 80 ml of ethanol in a Parr hydrogenation flask (or

something that can take 100 psi and not react with the reaction, like stainless steel or glass). 10
g of Raney Nickle is added with good agitation (stirring or shaking) followed by 2-3 ml of 20%
NaOH solution. Seal vessel, introduce 50 psi of hydrogen atmosphere (after flushing vessel with
hydrogen) and heat to 40-50C. After no more uptake of hydrogen (pressure gauge will hold
steady after dropping to its lowest point) bleed off pressure and filter the nickle off, rinse out
bottle with chloroform and use this rinse to rinse off the nickle while still on the filter paper.
Make the filtrate basic with KOH after cooling to 10C. Extract with chloroform dry, and
evaporate the chloroform in vacuo to get an oil. Mix the oil plus any precipitate with an equal
volume of dry ether and filter. Add more dry ether to the filtrate until no more precipitate
forms, filter and add to the rest of the precipitate. Recrystallize from isopropanol to get pure
methylecgonine. Test for activity. If active, skip down to the step for cocaine. If not active,
proceed as follows. Stir with activated carbon for 30 min, filter, evaporate in vacuo, dissolve the
brown liquid in methanol, and neutralize with 10% HCl acid in dry ether. Evaporate the ether
until the two layers disappear, and allow to stand for 2 hours at 0C to precipitate the title
product. There are many ways to reduce 2-carbomethoxytropinone to methylecgonine. I chose
to design a Raney Nickle reduction because it is cheap and not as suspicious as LAH and it is
much easier than zinc or sodium amalgams.
Cocaine

4.15 g of methylecgonine and 5.7 g of benzoic anhydride in 150 ml of dry benzene are gently
refluxed for 4 hours taking precaution against H2O in the air (drying tube). Cool in an ice bath,
acidify carefully with hydrochloric acid, dry, and evaporate in a vacuum to get a red oil which is
treated with a little portion of isopropanoi to precipitate cocaine.

As you can see, this is quite a chore. The coca leaves give ecgonine, which as you can see, is only
a jump away from cocaine. If you can get egconine, then dissolve 8.5 g of it in 100 ml of ethanol
and pass (bubble) dry HCl gas through this solution for 30 min. Let cool to room temp and let
stand for another 1.5 hours. Gently reflux for 30 min and evaporate in vacuo. Basify the residue
oil with NaOH and filter to get 8.4 g of methylecgonine, which is converted to cocaine as in the
cocaine step above.

Below is given a somewhat easier method of producing tropinone by the general methods of
Willstatter, who was instrumental in the first synthetic production of cocaine and several other
alkaloids. After reviewing this method, I found it to be simpler than the above in many respects.

Tropinone

10 g of pyrrolidinediethyl diacetate are heated with 10 g of cymene and 2 g of sodium powder,

the reaction taking place at about 160C. During the reaction (which is complete in about 10
min) the temp should not exceed 172C. The resulting reaction product is dissolved in water,
then saturated with potassium carbonate, and the oil, which separates, is boiled with dilute
sulfuric acid. 2.9 g of tropinone picrate forms and is filtered.

Here are two more formulas devised by Willstatter that produce tropinone from tropine. Take
note of the yield differences.
Tropinone

To a solution of 25 g tropine, dissolved in 10 times its weight of 20% sulfuric acid are
added 25 g of a 4% solution of potassium permanganate in 2 or 3 g portions over 45 min
while keeping the temp at 10-12C. The addition of permanganate will cause heat (keep
the temp 10-12C) and precipitation of manganese dioxide. The reaction mixture is
complete in I hour. A large excess of NaOH is added and the reaction is steam distilled
until I liter of distillate has been collected. The tropinone is isolated as the dibenzal
compound by mixing the distillate with 40 g of benzaldehyde in 500 cc of alcohol and 40
g of 10% sodium hydroxide solution. Let stand several days to get dibenzaltropinone as
yellow needles. Yield: 15.5 g, 28%. Recrystallize from ethanol to purify.

Tropinone

A solution of 12 g of chromic acid in the same amount of water (12 g) and 60 g of glacial
acetic acid is added dropwise with stirring over a period of 4 hours to a solution of 25 g
of tropine in 500 mL of glacial acetic acid that has been warmed to 60-70C and is
maintained at this temp during the addition. Heat the mixture for a short time on a
steam bath until all the chromic acid has disappeared, cool and make strongly alkaline
with NaOH. Extract with six 500 mL portions of ether and evaporate the ether in vacuo
to get an oil that crystallizes readily. Purify by converting to the picrate or fractionally
distill, collecting the fraction at 224-225C at 714 mm vacuo.

The tropinones can be used in the above formula (or in a formula that you have found
elsewhere) to be converted to cocaine. Remember to recrystallize the 2-
carbomethoxytropinone before converting to methylecgonine.
B. Illicit Synthetic Cocaine
The classic total synthesis of cocaine involves three synthetic, one enantiomeric
resolution and one diastereomeric purification steps (Figure 112,22), and requires a
significantly high level of synthetic expertise and well-equipped laboratory facilities. The
synthesis will produce a pair of racemic diastereomers (of which only one, i.e., (-)-
cocaine, is physiologically active) if the enantiomeric resolution and diastereomeric
purification steps are omitted. To date, there have been only three seizures of illicit
synthetic cocaine laboratories in the United States. All three followed the classic
synthesis; however, none of the three performed the enantiomeric resolution step. Two
of these laboratories were run by clandestine operators with advanced chemical
training, and successfully produced very low yields of racemic cocaine.

The first step involves a ring coupling Mannich reaction using methylamine,
succindialdehyde, and acetonedicarboxylic acid monomethyl ester in high dilution in a
buffered, aqueous solution at 25C. After 2 days, the reaction mixture is made basic and
extracted with chloroform to give racemic 2-carbomethoxytropinone; tropinone is the
major impurity. Enantiomeric resolution of the racemate can be accomplished at this
point with (+)- and (-)-tartaric acid; however, as noted above, none of the operators of
the three clandestine laboratories seized to date attempted such a resolution.

In step two, the 2-carbomethoxytropinone is dissolved in a minimal volume of ice-cold

dilute sulfuric acid and reduced to methyl ecgonine with a 1 to 1.5% Na/Hg amalgam at
pH 3.5 and 5C. Reaction conditions are critical; poor pH and/or temperature control
results in both decarboxylation of 2-carbomethoxytropinone to tropinone (which is, in
turn, reduced to tropine and pseudotropine) and C-2 epimerization of methyl ecgonine
to pseudoecgonine methyl ester. After several hours, the reaction is made basic,
extracted with chloroform, and evaporated to an oil containing methyl ecgonine and
pseudoecgonine methyl ester in an approximate 3:1 ratio. Additional impurities usually
include tropinone, tropine, pseudotropine and unreacted 2-carbomethoxytropinone.
The majority of pseudoecgonine methyl ester is precipitated from the oil by the addition
of diethyl ether and removed via filtration. The filtrate is evaporated to dryness,
dissolved in diethyl ether and converted to the hydrochloride. None of the operators of
the three clandestine laboratories seized to date attempted to purify their methyl
ecgonine any further than the pseudoecgonine methyl ester precipitation step.

In step three, the methyl ecgonine hydrochloride is benzoylated with benzoyl chloride in
pyridine near 0C. After 24 h, the reaction mixture is allowed to warm to room
temperature and is diluted with diethyl ether, which precipitates a cocaine HCl/pyridine
HCl complex. This precipitate is filtered and washed with additional ether to remove
excess pyridine, dissolved in water, and extracted with additional ether to remove
benzoic acid. The resulting aqueous solution is made basic with dilute ammonium
hydroxide (causing dissociation of the cocaine HCl/pyridine HCl complex), and
repeatedly extracted with methylene chloride. The combined extracts, which also
contain the remaining free pyridine, are evaporated to dryness to give cocaine base,
which is re-dissolved in diethyl ether/acetone 1:1 and converted to the hydrochloride
via addition of a stoichiometric amount of concentrated hydrochloric acid. As noted
above, the clandestine manufacture of illicit synthetic cocaine is extremely unusual. This
is not surprising, because - even when attempted by a skilled chemist - the preparation
of (-)-cocaine via total synthesis proceeds in less than 10% overall yield. This is clearly
economically infeasible in view of the relatively low cost and ready availability of illicit
natural cocaine.