Author Topic: Zealot: a complete synthesis of ketamine.  (Read 2092 times)

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Zealot: a complete synthesis of ketamine.
« on: September 11, 2002, 10:26:00 AM »
Ladies and gentlemen!

Let me proudly introduce to you another story from Zealot’s dream collection. The original source of the translation beelow is

Post 326212 (missing)

(zealot: "Ïîëíûé ñèíòåç êåòàìèíà", Russian HyperLab)
and the other Zealot’s posts in that thread.

While there’s 11 steps in the synthesis, its longitude is explained by the fact that all the precursors and even some reagents are made from scratch, employing user-friendly techniques and equipment (in fact, a need for vacuum is mentioned only once, and even that is for the removal of solvent); as well as only easy-to-get reactants.

Still the synth is obviously for the skilled only; for one thing, it involves making a Grignar. There is a potential possibility to use zincorganic comp’ds instead (discussed in detail beelow) – which is much cheaper and easier technically.

Also there is added an alternate preparation of o-clorobenzonitrile, found in

Post 352581 (missing)

(zealot: "Ïîáàëóþ â î÷åðåäíîé ðàç íàø íåæíûé ðîçàí÷èê...", Russian HyperLab)

With this said, let’s get to business.

A complete synthesis of ketamine.

by Zealot.

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 coolin there's added 8g NaNO2 in 40mls water. Thus obtained clear solution of diazonium salt is very slowly added w/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 w/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 w/NH3 or NaHCO3 and add w/heating 105g (~5% xcess) ZnSO4 in 400mls water. The pptated salt is dried for prolonged time at 200 C and mixed intimately with 205g Pb(SCN)2. The mixtr is coffeground and dried at 120-140 C for a prolonged time, then heated on open flame - the mixtr melts and gases are evolved.

Distilled nitrile is treated w/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 w/out causing any suspicion.


50g o-Br-benzamide and 35g (25g=theory) sulfaminic acid is thoroughly mixed abd 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 recntly, 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 acid and 10g Ba(OH)2 is intimately mixed and placed into a flask w/a thermometer. The rxn is heated to 280 C, the mixtr initially melts and then the distillation takes place, which lasts about 1-2 hrs. The hot distillate is saturated w/NaCl, the upper layer is decanted and distilled, collecting the fraction boiling at 128-130 C. Dry w/MgSO4.

Yield 51g (89% of theory).


- Ca(OH)2 may bee substituted for Ba(OH)2 w/out 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 w/an efficient RC there's added 6g Al foil, 70mls (51mls in theory) abs. IPA (commercial reagent grade IPA was used w/out any drying) and 0,1g HgSO4. The mixtr 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 cont'd 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 w/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 w/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 w/50% H2SO4 until acidic and saturated w/NaCl. The upper layer is decanted and distilled, collecting the fraction boiling at 137-140 C. Drying w/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 w/vigorous stirring. After that it’s diluted w/200mls water and the lower organic phase is separated and washed w/water twice. Distill, collecting the fraction between 137-138 C. Dryed w/MgSO4.

Yield = 58g (74%)


7. Cyclopentyl magnesium bromide.

Into a 250mls three-necked flask equipped w/a RC, 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 xtals. The apparatus is flushed w/argon and a gentle stream of gas is left flowing in. Magnetic stirring is commenced. The mixtr instantly beecomes cloudy w/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 solvt for Grignars) , the yield is better as well. Beesides, THF can bee dried w/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 Grignar soln there’s added 48g o-clorobenzonitrile and the mixtr is stirred for 3 days at RT. It is then poured into a mixtr of ice/NH4Cl, with addition of some conc. aq. NH3 and left at abmbient temp until all ice melts. The ketone partially floats, partially goes to the bottom. It’s xtracted w/benzene.

The yields fluctuate, but rarely drop beelow 55%.

9. alpha-bromo-(o-chlorophenyl)-cyclopentyl ketone.

40g ketone is dissolved in 70mls CCl4 and w/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 w/NaHCO3 aq. until neutral. This may lead to some pptation of the bromoketone, which stays in CCl4. The solvt 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 xcess is used). The soln is then saturated w/5g methylamine, obtained by dripping a sat’d soln of 15g MeNH2*HCl onto 10g NaOH, dried thru NaOH. The rxn is left for 1 day and the solvts 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 xtracted w/20% HCl. Acidic xtract is basified and xtracted w/DCM. Solvt is removed giving the product as an oil that quickly xtallizes. It can bee purified by rextallization from pentane/ether or hexane/ether.

The yields are close to quantitative.

Translated by


  • Guest
Hats off
« Reply #1 on: September 11, 2002, 10:34:00 AM »
Way to go Zealot! I'm no dissociative freak but you Russian bees really have a hard-working culture of your own.


  • Guest
Gawd what dedication!
« Reply #2 on: September 12, 2002, 11:05:00 PM »
Gawd what dedication!

For such a task one would have to be...dare I say it..a complete zealot!

Have a happy dissociation  8)

Mountain Boy


  • Guest
10 points
« Reply #3 on: October 06, 2002, 07:41:00 AM »
This was actually tested by a friend recently, minor modifications were made by him, in his eternal endeavour of perfection, it works as described by this man... This type of thinking allways reminds me of Cheapskates hard-to-forget-quaalude synth... outstanding work Zealot...

[pH]armacist - Never underestimate the power of retrosynthesis. Svenskar suger på fotboll!