                             Cocaine Synthesis
    Scanned From _Recreational Drugs: A Complete Guide to Manufacturing_
 
                                  COCAINE
 
 
  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 0! 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 171-172!.
 
  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 0! 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 20! 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 113! 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. Coo] to
0! 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 2l/2 to 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
40-50!. 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 10!. 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% HCI acid in dry ether. Evaporate the
ether until the two layers disappear, and allow to stand for 2 hours at
0! 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 H20 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 8l/2 g of it in 100 ml of ethanol and pass
(bubble) dry HC1 gas through this solution for 30 min. Let cool to room
temp and let stand for another 11/2 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
160!. During the reaction (which is complete in about 10 min) the temp
should not exceed 172!. 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
10-12!. The addition of permanganate will cause heat (keep the temp
10-12!) 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 cc of glacial acetic acid that has been warmed to 60-70! 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 cc
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 224-225! 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.
 
