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> Any one know how Ketamine can be produced?
AngelD
post Sep 13, 2007, 08:49 AM
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Hi, I'm new to this site, but have been looking for a place to discuss certain things for a while.
While I was searching for a recipe for K I found you guys and liked the look of the site, thought I'd join and see what people have to say.

I'm a relatively experienced tripper and enjoy pushing myself... sometimes a little too far, but thats all part of the fun.
What I'm trying to work out is, is it feasible to produce ketamine at a domestic level?
I can't seem to find a description of the process for making it anywhere and was wondering if anyone here knew where I could find it? As far as I know, its not all that chemically removed from salt, but I could be totally wrong. As my interest's now piqued, I'm on a hunt to find out what I can about the breakfast of choice!
Any help would be much appreciated.
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lucid_dream
post Sep 13, 2007, 05:13 PM
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QUOTE(AngelD @ Sep 13, 2007, 09:49 AM) *
As far as I know, its not all that chemically removed from salt

Ketamine's hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. The chemical structure bears absolutely no resemblance to common salts.

Though I don't think home-based ketamine synthesis is realistic (usually, ketamine is obtained from vet suppliers), here are the instructions, just for kicks:

Step 1: (o-chlorophenyl)-cyclopentyl ketone

119.0 g of cyclopentyl bromide and 19.4 g of magnesium are reacted in ether or THF to give a cyclopentyl Grignard reagent. The best yields are obtained if the ether solvent is distilled from the Grignard under vacuum and replaced with hydrocarbon solvent, such as benzene. 55.2 g of o-chlorobenzonitrile is then added to the reaction mixture and stirred for three days. The reaction is then hydrolyzed by pouring it onto a mixture of crushed ice and ammonium chloride, containing some ammonium hydroxide. Extracion of the mixture with organic solvent gives o-chlorophenylcyclopentylketone, bp 96-97 C (0.3 mm Hg) (CAS# 6740-85-8).

Step 2: alpha-bromo (o-chlorophenyl)-cyclopentyl ketone

To 21.0 g of the above ketone is added 10.0 g of bromine in 80 ml of carbon tetrachloride dropwise at 0 deg. C. After all of the Br2 has been added, an orange suspension forms. This is washed with a dilute aqueous solution of sodium bisulfite and evaporated to give 1-bromocyclopentyl-(o-chlorophenyl)-ketone, bp 111-114 C (0.1 mm Hg). Yield is ~66%. This bromoketone is unstable and must be used immediately. Also attempts to distill it at 0.1 mm Hg lead to some decomposition, so it should be used without further purification.

The bromination may also be carried out with N-bromosuccinimide in somewhat higher yields (~77%).

Step 3: 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone-N-methylimine

29.0g of above bromoketone is dissolved in 50 ml of liquid methylamine freebase. Benzene may also be used as solvent. After one hour, the excess liquid methylamine is allowed to evaporate, although increasing the reaction time to 4-5 days may increase yield. The residue is then dissolved in pentane and filtered. The solvent is evaporated to yield 1-hydroxy-cyclopentyl-(o-chlorophenyl)-ketone N-methylimine, mp 62 C (yield ~84%).

Step 4: 2-Methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine)

The final step is a thermal rearrangement, and gives almost quantitative yield after 180 C for 30 min. An alternative to the use of decalin as solvent in this step is to use a pressure bomb.

2.0 g of the preceeding N-methylimine is dissolved in 15 ml of decalin and refluxed for 2.5 h. After evaporation of the solvent under reduced pressure, the residue is extracted with dilute hydrochloric acid, the solution treated with decolorizing charcoal, and the resulting acidic solution is made basic. The liberated product, 2-methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine), after recrystallization from pentane-ether, has a mp of 92-93C. The hydrochloride has a mp of 262-263 C.

As with PCE, the freebase is too caustic to be smoked, and must be converted into the HCl salt in order to be consumed in this manner.


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lucid_dream
post Sep 13, 2007, 05:16 PM
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And here's a supposedly more "user-friendly" ketamine synthesis:

1. o-chlorobenzoic acid.

Anthranilic acid 13,7g

HClconc. (d=1,19)

NaNO2 8g

CuCl 10g

13,7g anthranilic acid is stirred in a glass beaker in 40mls water, 28mls HCl and 20g ice. With constant stirring and cooling there's added 8g NaNO2 in 40mls water. Thus obtained clear solution of diazonium salt is very slowly added with stirring into a soln. of 10g CuCl in 25g HCl conc. A vigorous evolution of nitrogen is observed.

When the rxn ends, the ppt is filtered, washed with cold water and reprecipitated from aq. Na2CO3. The product represents fine crystals and melts at 140-141 C.

O-bromobenzoic acid can bee obtained in an analogous manner, substituting CuCl for CuBr.
2. o-chlorobenzonitrile.

Preparation A

(RCOO)2Zn + Pb(CNS)2 = 2RCN + ZnS + PbS + 2CO2

The best results are obtained when a zinc salt is employed instead of free acid. This rxn is unsuitable for amino-, nitro- and oxy- acids, but can bee used for bromo- and chlorobenzoic acids.

To a hot soln of 50g NaOH in 400mls water there's added 195g o-chlorobenzoic acid. Carefully neutralize with NH3 or NaHCO3 and add with heating 105g (~5% excess) ZnSO4 in 400mls water. The precipitated salt is dried for prolonged time at 200 C and mixed intimately with 205g Pb(SCN)2. The mixture is coffeeground and dried at 120-140 C for a prolonged time, then heated on open flame - the mixture melts and gases are evolved.

Distilled nitrile is treated with NH4OH, steam-distilled and salted out. Yield 137g (80%), mp=43-46 C, bp=232 C. The rxn usually takes place within 30-60 mins, but the duration of dryings makes the method quite time-consuming.

Preparation B.

This one doesn’t require a prolonged drying. Sulfaminic acid is dirt cheap and can bee acquired without causing any suspicion.

o-bromo-benzonitrile.

50g o-Br-benzamide and 35g (25g=theory) sulfaminic(sulfamic) acid is thoroughly mixed and heated in a Wurtz flask. At 250-255 C distillation begins, which is over at 285-295 C (takes approx. 1,5-2 hrs). The collected product is redistilled, yield 36g (80% of theory).

mp = 53-57o, bp = 251-253o

As I found recently, this can bee simplified yet more, by forming benzamides in situ from the corresponding acid and urea..but since this is a very good route to subst’d benzaldehydes from benzoic acids, I’ll post it later separately.

3.Cyclopentanone.

100g adipinic(adipic) acid and 10g Ba(OH)2 is intimately mixed and placed into a flask with a thermometer. The rxn is heated to 280 C, the mixture initially melts and then the distillation takes place, which lasts about 1-2 hrs. The hot distillate is saturated with NaCl, the upper layer is decanted and distilled, collecting the fraction boiling at 128-130 C. Dry with MgSO4.

Yield 51g (89% of theory).

Notes:

- Ca(OH)2 may bee substituted for Ba(OH)2 without much loss in the yield.

- if one is to use pre-made Ca or Ba adipinate, no temp control is necessary.

4. Aluminium isopropoxide.

Bp = 130-140°C at 7mmHg; mp = 118°C

Into a 250ml RBF equipped with an efficient reflux condenser there's added 6g Al foil, 70mls (51mls in theory) abs. IPA (commercial reagent grade IPA was used without any drying) and 0,1g HgSO4. The mixture is heated.

In the beginning of boiling 0,5mls CCl4 (CAREFUL! Extremely toxic!) and heating continued until H2 evolution starts, when it is stopped, sometimes even cooling's needed. After the rxn subsides, heating is continued until almost full dissolution of Al (5-7 hrs). The obtained solution is immediately used as is in the following preparation.
5. Cyclopentanol.

Into a 250ml RBF equipped with a 15cm Vigreux column and distilling condenser there's added 53mls (50g) cyclopentanone in 50mls IPA and the soln from the previous prep'n, which contains about 40g Al isopropoxide. The rxn is gently heated, which causes acetone with some water to distill off. The distillation is ended when the temp of the vapors rises to ~85 C.

The ppt inside the flask is carefully decomposed with 50% H2SO4 until acidic and saturated with NaCl. The upper layer is decanted and distilled, collecting the fraction boiling at 137-140 C. Drying with MgSO4.

Yield 47g (94%)
6. Cyclopentylbromide.

In a flask there’s mixed 47mls (45g) cyclopentanol and 60mls (90g) 48% aq. HBr. 10g NaSO4 is added. The rxn is left for 24hrs with vigorous stirring. After that it’s diluted with 200mls water and the lower organic phase is separated and washed with water twice. Distill, collecting the fraction between 137-138 C. Dryed with MgSO4.

Yield = 58g (74%)
7. Cyclopentyl magnesium bromide.

Into a 250mls three-necked flask equipped with a reflux condenser, addition funnel and inert gas inlet there’s placed 50mls THF (kept over KOH, prior to the rxn 150mls refluxed over 30g CaO for 6hrs and distilled). 9g of fine Mg turnings is added followed by some iodine crystals. The apparatus is flushed with argon and a gentle stream of gas is left flowing in. Magnetic stirring is commenced. The mixture instantly beecomes cloudy from MgI. From the addition funnel there’s dripped 55g (40mls) cyclopentyl bromide in 100mls THF so that the soln boils smoothly. The rxn is usually over in an hour, it is accompanied by precipitation of a white jelly-like mass, and at the bottom there maybee left some unreacted Mg as a dark-grey powder.

Usage of THF instead of ether is preferred since the rxn in it proceeds better and faster (THF is a more specific solvent for Grignards) , the yield is better as well. Beesides, THF can bee dried with CaO, while for ether,sodium metal is usually employed.

Notes on the possible usage of Zn-organics:

".. Nitriles are not bad as electrophiles, so it is possible that despite smaller reactivity of ZnR2 compounds, they would work equally well here - esp. if the rxn conditions are made harsher (gentle reflux instead of RT?).

What one CAN say for sure-is that the rxn with ZnR2 will go just fine if one is to use o-chlorobenzoyl chloride instead of benzonitrile. Haloanhydrides generally are the best species for coupling with metalloorganics.

Bis-dicyclopentyl zinc is conveniently made from the corresponding bromide, no need to make iodide here. And o-chlorobenzoyl chloride can bee easily prepared from o-chlorobenzoic acid (obtained in Step 1) and PCl5 or some such."

8. (O-chlorophenyl)-cyclopentylketone.

To the thus obtained Grignard soln there’s added 48g o-chlorobenzonitrile and the mixture is stirred for 3 days at RT. It is then poured into a mixture of ice/NH4Cl, with addition of some conc. aq. NH3 and left at ambient temp until all ice melts. The ketone partially floats, partially goes to the bottom. It’s extracted with benzene.

The yields fluctuate, but rarely drop beelow 55%.
9. alpha-bromo-(o-chlorophenyl)-cyclopentyl ketone.

40g ketone is dissolved in 70mls CCl4 and with cooling in snow it is added into a soln of 48g dioxane dibromide in 50mls dioxane, and stirred at RT for 30mins. Then 30mls water are added and the soln is washed with NaHCO3 aq. until neutral. This may lead to some preciptation of the bromoketone, which stays in CCl4. The solvent is removed, giving 47g (85%) of the bromoketone.
10. (1-hydroxy-cyclopentyl)-(o-chlorophenyl)-N-methylketimine.

45g of the above bromoketone is dissolved in 50mls benzene, add therein 50mls (17g(=23mls) is required for neutralization of HBr, but a 2x excess is used). The soln is then saturated with 5g methylamine, obtained by dripping a saturated soln of 15g MeNH2*HCl onto 10g NaOH, dried thru NaOH. The rxn is left for 1 day and the solvents are removed under aspirator vacuum, giving 30g (80%) of methylketimine.
11. Ketamine.

10g of methylketimine is dissolved in 100mls undecane and boiled at 195 C for 3-4hrs. Ketamine is extracted with 20% HCl. Acidic extract is basified and extracted with DCM. Solvent is removed giving the product as an oil that quickly crystallizes. It can bee purified by recrystallization from pentane/ether or hexane/ether.

The yields are close to quantitative.
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Flex
post Sep 13, 2007, 09:58 PM
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Just go to the vet an tell them your dog has back pain smile.gif
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lucid_dream
post Sep 14, 2007, 07:52 AM
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QUOTE(Flex @ Sep 13, 2007, 10:58 PM) *

Just go to the vet an tell them your dog has back pain smile.gif


since it's a controlled substance, the vet will not just hand over a sample of ketamine to you. I forgot to note above that, in Mexico, it's not a controlled substance and can be purchased from vets without problems. If you plan to visit Mexico for this purpose, make sure you speak Spanish as very few people speak English.
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M0142857
post Aug 18, 2015, 02:06 PM
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QUOTE(lucid_dream @ Sep 13, 2007, 05:13 PM) *


...The best yields are obtained if the ether solvent is distilled from the Grignard under vacuum and replaced with hydrocarbon solvent, such as benzene...


Benzene is not a good organic solvent as it is carcinogenic, therefore I would suggest to use diethyl ether instead. I understand that benzene is widely used solvent in the lab, however I suspect the persons utilising this method are probably not highly skilled chemists nor have a proper laboratory in order to carry out purification thechniques to a very high standard, hence my suggestion.
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winneriamawinine
post Dec 08, 2016, 08:26 PM
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QUOTE(M0142857 @ Aug 18, 2015, 02:06 PM) *

QUOTE(lucid_dream @ Sep 13, 2007, 05:13 PM) *


...The best yields are obtained if the ether solvent is distilled from the Grignard under vacuum and replaced with hydrocarbon solvent, such as benzene...


Benzene is not a good organic solvent as it is carcinogenic, therefore I would suggest to use diethyl ether instead. I understand that benzene is widely used solvent in the lab, however I suspect the persons utilising this method are probably not highly skilled chemists nor have a proper laboratory in order to carry out purification thechniques to a very high standard, hence my suggestion.



I can do another new route that never come up! Any one can help me? Should I apply for a patent?
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Asiandoggie
post Jun 20, 2017, 10:48 PM
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QUOTE(winneriamawinine @ Dec 08, 2016, 08:26 PM) *

QUOTE(M0142857 @ Aug 18, 2015, 02:06 PM) *

QUOTE(lucid_dream @ Sep 13, 2007, 05:13 PM) *


...The best yields are obtained if the ether solvent is distilled from the Grignard under vacuum and replaced with hydrocarbon solvent, such as benzene...


Benzene is not a good organic solvent as it is carcinogenic, therefore I would suggest to use diethyl ether instead. I understand that benzene is widely used solvent in the lab, however I suspect the persons utilising this method are probably not highly skilled chemists nor have a proper laboratory in order to carry out purification thechniques to a very high standard, hence my suggestion.



I can do another new route that never come up! Any one can help me? Should I apply for a patent?

Wanna find new ways to cook it up, contact me if possible. Got some very nice offer "for real" to pitch to you. My customer is eager to find someone that can cook.
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Danny Rock
post Sep 19, 2017, 11:35 PM
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sorry to my poor engish , anyone help me to get O-chlorophenyl)-cyclopentylketone, after i extract it with Benzene, then i was distilled the benzene, then i got few drop yellow oil and water, that is it i poured alot of ice ? or something wrong ?

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