The basic formula for cocaine starts by purchasing or making tropinine,
converting the tropinone into 2-carbomethoxytropinone (also known as
methyl-tropan-3-one-2-carboxylate), reducing this to ecgonine,
and changing that to cocaine.
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 t
aken 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.
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 0* and add 15 ml of water that contains 2.5 g of ammonium chloride.
Extract the solution after shaking with 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 1/2 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 precipetate.
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 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 (the 2 should be on a lower level) 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 isopropanol
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 1/2 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 1 1/2 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 cocain 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 in 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 potassiumpermanganate
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
1 hour. A large excess of NaOH is added and the reaction is steam distilled
until 1 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 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 convering 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.
