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- Welcome to the complete guide of how to make cocaine. If you do
- everything right you are going to be king of the world, either in your
- own world or in the real world. Please read the disclaimer at the end of
- this text.
- Now, let's get to action!
- 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.
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