Sciencemadness Discussion Board

Easy Ketamine

flipper1590 - 28-8-2006 at 13:33

This was ones posted on the Hive I think. Seems pretty easy. But there is one problem. The Hydroxylimine.
Hydroxylamine can be made with nitromethane I think but what about hydroxylimine.

Does anybody know how to synthesize hydroxylimine???
Quote:

1: Certain weight of Hydroxylimine,assay 95% min, add in 1.5 times weight of Ethyl benzoate, heat to 40 50 c to dissolve Hydroxylimine basically.
2:Cool the solution to 20 C keep stirring and add in HCL vapor till ph 1.5 2.0.
3:Heat solution to 180 C hold on 30 min.
4:Cool the solution to 0 C hold on 2 h filter or centrifugate to separate liquid an dry component.
5:Dry the Compound at 80 C for 6 h now appears brown color
6:Add 10 times weight of water heat to 70 C add 5% weight of active carbon. stir 30 min
7:Filter three times to remove the carbon. The liquid should be yellowish
8:cool to 20 C add 10% NaOH solution till ph 8 9. Obtain freebase lye. The flake NaOH must be dissolved in Distilled water
9:centrifugate the lye at 20 C, dried by heating at about 60 C. Start from 50C and gradually up to 80 C for 24 h. It takes a long time drying due to low melting pointof Ketamine Freebase.

notice
1. heating to 180 C should be done in a porcelain enamel electrical heating reactor in 1 or 2 h
2. reactor size is 100 liters. Sizes of the batches should not be higher then 30 kgs
3.ethyl benzoate smells

yiels of Ketamine freebase is 80%

not_important - 28-8-2006 at 14:47

You are missing something in that prep. Look at the structure of ketamine, tell my where you are getting the cyclohexal ring?

The 'hydroxylimine' is not a simple inorganic like hydroxylamine, but the product of reacting hydroxylamine with a ketone - a cyclohexanone.

There's also a chlorine on the benzene rign that is missing in your prep; I don't think it is going to pop off the HCl on over to the aromatic under the given conditions.

This prep, like the Anarchists Cookbook and numerous ketone-peroxide procedures, appears to be an IQ test/Darwin Award pre-screening.

chemoleo - 28-8-2006 at 15:05

Well google says hydroxylimine is the precursor to ketamine. It is
1-Hydroxycycloamyl-(o-Chlorophenyl)-N-Methylimine Hydrochloride

From this, I am not sure why ethylbenzoate should be required at all...to get ketamine.
Its structure:

not_important - 28-8-2006 at 15:54

Solvent for the rearrangement imine is C=N, end up with C-N and the hydroxy going to C=O.

In short, the 'easy' method is easy because it starts with the immediate precursor of the desired product; a precursor which of course is OTC and found next to nutbutters on the shleves of fine grocery stores everywhere.

flipper1590 - 28-8-2006 at 15:57

Quote:
Originally posted by chemoleo
Well google says hydroxylimine is the precursor to ketamine. It is
1-Hydroxycycloamyl-(o-Chlorophenyl)-N-Methylimine Hydrochloride

From this, I am not sure why ethylbenzoate should be required at all...to get ketamine.
Its structure:



That's a bummer. I thought that Hydroxylimine is something much less complex.

Well I think that this is necessairy in that case
Quote:

Experimental

1. o-Chlorobenzoic acid

• Anthranilic acid 13,7g
• HCl (conc., 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(SCN)2 = 2 RCN + ZnS + PbS + 2 CO2
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-Bromobenzonitrile
50g o-Bromobenzamide 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 53-57°C, bp 251-253°C
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 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

Al(i-PrO)3 - 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 Na2SO4 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 cyclopentyl ketone

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 Na2CO3 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 triethylamine (17g/23mL 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.


## Zealot's from the russian Hive total synth from scratch##



[Edited on 29-8-2006 by flipper1590]

[Edited on 29-8-2006 by flipper1590]

Sandmeyer - 28-8-2006 at 16:01

Quote:
Originally posted by chemoleo


From this, I am not sure why ethylbenzoate should be required at all...to get ketamine.



The rearrangement requires some heat in order to proceed, the ethylbenzoate is a high b.p solvent. I wonder what the yield is for this step. I guess that by use of some non-nucleophilic base reaction could be done at lower temp, alt. PTC conditions.

Flipper, it's usually a good idea to look up the structural formulas of the compounds of interest. What is your point with the second post? Do some own research first.

[Edited on 29-8-2006 by Sandmeyer]

transformer - 18-1-2007 at 17:16

Another reason for using ethyl benzoate with this rearangement is the fact that it seems to do the same as acetone for the formed impurities, like acetone it disolves the nasty black tar that is formed during the reaction this tar which crashes out of the solution when using other high bp solvents like decalin for example, sticks to everything coating everything it touches with a fine black layer including glassware and this basically makes things really hard to extract the tar formation seems to be a little less at 160 celcius and a reaction time of 1.5 hour but then after filtration one needs to use more activated carbon and do 4 boils to obtain a white product.

[Edited on 19-1-2007 by samsung]

-TheMadMen- - 29-5-2009 at 08:28

Ketamine is a very easy chemical to synthesize, contrary to popular belief. Infact i'm surprised that more clandestine labs do not pop up everywhere, but i've never heard of one appearing anywhere. From reading this thread, all of these bullshit complex chemical precursors, ketamine needs none of those, just basic building blocks, infact, all relatively easy, i'll name one for instance, Cyclopentyl bromide, very easy to make from basic chemicals. I Have all of the chemicals i need to make ketamine, i might even do it oneday infact. But probably not, due to the fact that it's illegal.

Sandmeyer - 29-5-2009 at 12:12

Doing the thermal 1,2-shift is in ethylene glycol gives 75% yield according to a czech patent. IIRC other solvents rarely give more than 50%. It is extremely important to have a good yield in the last step for overall yield in a multistep process.

Preparation of 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride by thermal rearrangement of 1-hydroxycyclopentyl 2-(chlorophenyl) ketone methylimine-HCl.


Abstract

The title compd. (ketamine) (I) is prepd. by thermal rearrangement of 1-hydroxycyclopentyl 2-(chlorophenyl) ketone methylimine-HCl (II) in anhyd. ethylene glycol (III) at 185-190. III 2000 mL was added to II 2000 g, and the resulting soln. was stirred 50 min at 190 and cooled to give crude cryst. I 1500 g (75%).
Quote: Originally posted by -TheMadMen-  
. I Have all of the chemicals i need to make ketamine, i might even do it oneday infact. But probably not, due to the fact that it's illegal.


Good for you, now spare us some trolling... ;)

Attachment: CS236234B1.pdf (100kB)
This file has been downloaded 3790 times

[Edited on 29-5-2009 by Sandmeyer]

-TheMadMen- - 31-5-2009 at 07:22

Useless vitriol edited out.

If you want to post information about a simple ketamine synthesis, feel free. If you just want to say that you know a simpler way, without disclosing the chemistry, don't bother posting.

[Edited on 5-31-2009 by Polverone]

-TheMadMen- - 1-6-2009 at 05:36

More personal attacks removed

[Edited on 1-6-09 by The_Davster]

ScienceSquirrel - 1-6-2009 at 08:16

Making ketamine probably does not represent insuperable difficulties and it could be done by a home chemist with quite a bit of time available and a willingness to shop around for the reagents.
However it would be expensive and illegal and I would argue that ketamine is not that attractive a recreational drug.
Also it is quite a large scale animal tranquiliser so diversion from legitimate supplies or outright theft is more attractive for users or dealers.

-TheMadMen- - 11-6-2009 at 00:13

Yes you may indeed be correct ScienceSquirrel. As far as i am aware, most ketamine on the "street" is a diversion from licit pharmaceutical supply houses as you have mentioned. I Have never heard of any law enforcement reports documenting "clandestine" manufacture of the compound. But as you said, it would indeed not be an entirely impossible feat for the home chemist. Some shopping around would probably be required, there is no doubt about that, and there are some stages in the process which would probably require some fined tuned lab skills, since one of the intermediates is very unstable, it must be handled very carefully, that in itself may not be an easy feat to achieve, to avoid discomposure, before the final product is maintained.

I Would however, from a personal perspective, be quite fascinated with undertaking the synthesis one day, as i so blatantly said above, unfortunately. I Apologise for being such a loudmouth, it is unacceptable. Lesson learned, he he. As for undertaking the synthesis of ketamine all by myself however, i am not so sure that i want to do that, due to the legal factor, obviously. Such a pity indeed.

trinity - 22-12-2009 at 08:52

This Topic "easy ketamine" first provided by flipper1590 copied from Hive was too " Simple" and not realistic.

Doubt the purity of the "Ketamine Freebase-Final product", as it suggested when yellowish ketamine liquid made basic using NaOH , obtained "Freebase lye" ; I think the Ketamine freebase lye color formed would be GREENISH waxy participate. The method further suggested to "centrifugate the ketamine freebase ( i think Blue Color) lye at 20 C" and dried" and obtained Final Product was too SIMPLE, without mentioned purification.

Other purification method also not feesible , as suggested "extraction by DCM"; recrystallization using pentane/ ether", would be too costly if the orginal post was talking about KG quantity, not gram quantity.

ScienceSquirrel - 22-12-2009 at 09:24

I would argue that if you wanted to make something 'nice' you would be better off going for methylqualone. a comparable level of synthetic difficulty and reportedly quite pleasant.
PCP would be another possible target.
Both are illegally synthesised on a tonnage scale but they have no legitimate uses or sources unlike ketamine so diversion or theft is not an option. Some of this synthesis is done in totally clandestine labs but quite a bit is knocked out by the 'night shift' in legitimate plants!

meme - 6-1-2010 at 15:09

Too costly?

The industrial price of hydroxylimine is 1/20 the wholesale "street" cost of the product. Perhaps the process is too costly if done from total synthesis but that is not what is implied in the post by flipper.

entropy51 - 6-1-2010 at 17:28

I wonder why this forum attracts so many poor devils whose lives are so devoid of pleasure and bereft of happiness that they think being stupefied on ketamine improves their bleak existence?

It's a shame, really.

Barium - 6-1-2010 at 20:13

Entropy51, that I'm holier than thou-attitude doesen't get you any brownie points, really.

Vogelzang - 7-1-2010 at 11:57

Didn't entropy say he was a doctor? Back in 1981 when I told my doctor I had used amphetamines to help with studying, he told me he used to prescribe amphetamines for himself back when it was easier to get a presciption for them. He said he felt he could drive a truck better, but then said it was just the drug that made him believe that. Piracetam is a lot better for studying I think.

Sandmeyer - 7-1-2010 at 12:08

Quote: Originally posted by entropy51  
I wonder ...


I wonder how a troll managed to make nearly 800 posts in 5 months without being banned.

Nicodem - 7-1-2010 at 13:23

The original question has been answered, the rest looks just like unnecessary verbal masturbation.
No need to go any further.
Thread closed.