Discussion on possible ketamine analogs

[Manichi]

Hi all!  

I would like to open a discussion on possible ketamine analogs, notably this one:

(A) = 2-ethylamino-2-phenylcyclohexanone:

Molecule:

(A)=2-ethylamino-2-phenylcyclohexanone ("CCNC2(c1ccccc1)CCCCC2=O")

 

and this one

(B) = 2-methylamino-2-phenylcyclohexanone:

Molecule:

(B)=2-methylamino-2-phenylcyclohexanone ("CNC2(c1ccccc1)CCCCC2=O")

 

(A) is a ketamine analog without the 2-chloro and with an ethyl in place of the methyl on the amine. It is related to tiletamin too, as it is it with the thiophene replaced by a phenyl, also it is related to PCE as it is its 2-keto analog. The same compound with a 2-methyl in place of the 2-ethyl (compound (B)) look nice too, but is a bit less potent.

PCE:

Molecule:

PCE ("CCNC2(c1ccccc1)CCCCC2")



Tiletamine:

Molecule:

tiletamine ("CCNC2(c1cccs1)CCCCC2=O")



Ketamine:

Molecule:

ketamine ("CNC2(c1ccccc1Cl)CCCCC2=O")



in this patent:

Patent FR2973M

the activities of those compounds against PCP are claimed:

4+ = very good activity
3+ = good activity
2+ = weak activity
+-= thresold of effects


(A):

- on pigeons (birds) (dose mg/kg):

100: 4+  ;  50: 4+  ;  25: 4+  ;  12.5: 4+  ;  6.3: 3-4+  ;  3:  1+  ;  1.5: +-

- on apes (% relative on PCP):

potency: 60%
duration: 60%


(B):

- on pigeons (birds) (dose mg/kg):

100: 4+  ;  50: 4+  ;  25: 4+  ;  12.5: 2-3+  ;  6.3: 2+  ;  3: +-

- on apes (% relative on PCP):

potency: 30%
duration: 60%


Ketamine:

- on pigeons (birds) (dose mg/kg):

50: 4+  ;  25: 3+  ;  12.5: +-

- on apes (% relative on PCP):

potency: 20%
duration: 30%


As they were interested by the faster metabolized one, they considered ketamine would bee a good candidate to drug out the little dogs, but for we guinea pigs i think the non chlorinated analogs are way more interesting as to their potency and the avaiability of the precursors too. The ethyl analog A should be active at 15-20mg i guess, and the more easily avaiable methyl analog B should be at twice this dosage, around 35 mg.

The original JOC and JACS papers did the synthesis trough some sort of epoxide opening, i should reread it once more but it didnt look very easy. A more attractive route, in my opinion, is the one that is pictured in the

ketamine

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/pcp/ketamine.html#ketaminerxns) document at rhodium's.

The first step will have to bee a synthesis of the cyclopentyl-phenyl-ketone. To make it there are a few ways that i am aware of, most importantly:

-the addition of the cyclopentane-grignard on a (protected) imine or benzonitrile, with the need of synthetising the cyclopentyl-bromide, benzonitrile (from benzaldehyde + I2 + ammonia ala

Post 421248

(Vitus_Verdegast: "direct transformation of aldehydes into nitriles", Chemistry Discourse)) and subsequent grignard.

-the F/C reaction between benzene and cyclopentane-carboxylic-acyl chloride with a suitable catalyst. The need is the cyclopentane carboxylic acid which is somewhat expensive, SOCl2 or PCl3, benzene and catalyst.

Well, my sources are better for the second solution, so i will discuss on how to make the cyclopentane-carboxylic acid. The route to the cyclopentyl bromide is very nicely explained from cheap adipic acid by

Zealot's from scratch route

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/ketamine2.html)

I will check tomorrow this paper: Synthetic Communications (1990), 20(9), 1353-6. It describe a synthesis of the cyclopentanecarboxylic acid in 52% yield from cheap and non suspicious cyclohexene and potassium persulfate.    I really hope it turn out to bee a good synthesis, otherwise we are pretty fucked and must go through the bromide then grignard then carbonate it with CO2, a too much lengthy procedure for just a pre-precursor.

But once we have the cyclopentanecarboxylic acid, the chlorination step should bee a breeze with SOCl2, check that wonderful tiletamine patent:

Patent US5969159

. I wonder if graphite would work for our purpose with benzene as well than with thiophene!  Any one wanna argue on that point?

If those two steps work as good as they should, the second route to the cyclopentylphenyl-ketone is the way to go i guess.

Then after that is a bromination, largely detailed in the litterature, a imine synthesis with home made methylamine or better but harder to get ethylamine, then the thermal rearrangement.

All this could bee done in o-dichlorobenzene for a peacefull workup.

If the cyclohexene -> cyclopentane carboxylic acid synthesis work ok, and if the graphite can bee used as a F/C catalyst, those compounds are really straightforward to make, and this should bee a merry synthesis with easily aquirable chems for those interesting potent and legal dissociative compounds!      what bees do you think?  

Some final blurps:

-you can check those

serendipity's interesting ketamine references

(http://www.serendipity.li/dmt/ketref.html)

-Does anyone know why parke-davis did the chlorinated analog even it it is less potent? why ketamine? was that only because it was of shorter duration?? any one know why? also is really tiletamine of lower spaced out qualities like erowid's experiences tend to show? What are the differences between a ketamine trip and a PCP trip, except dose and duration? Anyone would like to share his experiences?

I hope this post will start some discussions on those dissociatives, and don't forget to check that tiletamine patent! It is the key!  

[josef_k]

Check out this patent:

Patent GB1066542

It tells you how to react benzene with cyclopentylcarboxylic acid and polyphosporic acid, to get phenylcyclopentylketone. That way you don't have to chlorinate the carboxylic acid.

[Manichi]

Thank you Josef_k, it is one more step toward OTCness!

I checked the reference I gave above (Synthetic Communications (1990), 20(9), 1353-6), and it works good!

Look all:

Oxidation of cyclohexene: Typical procedure.

A solution of cyclohexene (4.1g, 50 mmol) in 140 mL of acetonitrile was added to a solution of potassium peroxydisulphate (40.5g, 150 mmol) in 140 mL of water and copper sulphate (4g, 16 mmol). The resulting mixture was stirred at 80°C for 4h. The organic layer was separated and the aqueous layer was extracted twice with ether. The combined organic extracts were dried over sodium sulphate and concentrated to give the crude products. The crude products were separated with saturated sodium carbonate solution and ether. The sodium carbonate portion was acidified with dilute hydrochloric acid and extracted with ether, dried and evaporated to give the crude acid. The crude acid was distilled under vacuum to give cyclopentanecarboxylic acid, bp 130°C at 3mm; yield 2.96g (52%). The ether portion was dried and distilled under vacuum to give 1,2-cyclohexanediol cyclic sulphate, Bp 170°C at 3mm, yield: 2g (23%).

Considering the price of the cyclopentane carboxylic acid and the easiness of this synthesis, I find it handy, even for the big amounts of others chemicals used for such a small amount of cyclopentane carboxylic acid. The chemicals are fairly easy to aquire and cheap too.  

Also it may bee worth noting that the same reaction with 2 molar ratio of peroxydisulphate in 80% aqueous acetonitrile medium at 80°C gives 42% cyclopentanecarboxaldehyde and 25% of 1,2-cyclohexanediol cyclic sulphate.

Hehe it does look those compounds have clandestine potential!

[Vitus_Verdegast]

You've cleared the path to ketamine and analogs!  

If we have the cyclopentanecarboxylic acid, I suppose we can chlorinate it with the easily obtainable cyanuric chloride? If we have a way around SOCl₂ this synth is almost OTC  !!

That patent is so nice, F/C'ing with graphite, and multiple steps performed in the same solvent, what a wonderful find!  

I guess we have to find as much preparations for cyclopentanecarboxylic acid as possible. Oh yeah, price of absolutely non-suspicious cyclohexene around here: 20euro/L  


I found this one:

Synthetic methods and reactions.  31.  Oxidation of olefins with peroxouranium oxide (UO₄.4H2O).
Olah, George A.; Welch, John.   

Journal of Organic Chemistry  (1978),  43(14),  2830-2
CAN 89:59678, AN 1978:459678

Abstract

Cyclohexene, methyleneadamantane, and 2-methylenenorbornane were oxidized by UO₄ to give a cyclopentanecarboxylic acid-cyclopentanecarbinol mixt., adamantanone, and a bicyclo[3.2.1]octan-2-one-bicyclo[3.2.1]octan-3-one mixt.  A mixt. of Ph2CO and Ph2CMeOH was obtained from Ph2C:CH2.

[Manichi]

Yo, all!  

Here are some references about ketamine and related chemicals. There is a bunch of interesting patents that the library-deprived bee can check.

It appears clear when reading those patents that what i once thought was a not so easy synthesis can bee accomplished fairly easily (and ~OTC) finally.  

VV: no need to chlorinate it anymore, the polyphosphoric F/C patent posted above by joseph was recently completed by some other patent describing this route for tiletamine.    Also anhydrous methylamine is no more needed, as the 40% aqueous solution can bee used with great (if not greater) yields!    

I will describe the process more fully in another post...

Here are the refs i checked and found interesting:

[01]. JOC 1964 29 3146
[02]. JOC 1966 31( 2593
[03]. JOC 1966 31( 2601
[04]. JACS 1963 85 1464
[05]. JACS 1966 88 2769
[06]. JACS 1966 88 2803
[07]. JCS 1949 3156
[08]. Bull Soc Chim Fr 1955 784
[09]. Bull Soc Chim Fr 1958 522
[10]. Bull Soc Chim Fr 1961 516
[11]. Compt. Rend. Acad. Sci. 1953(C) 236 1978
[12]. Compt. Rend. Acad. Sci. 1953(C) 237 1720
[13]. Compt. Rend. Acad. Sci. 1954(C) 238 1425
[14].

Patent FR2973M

: The above mentioned french patent.
[15].

Patent US3254124

: One early patent of C. Stevens, check ex. 4 and 13.
[16].

Patent US3361817

: Preparation of N-alkoxy analogs, check the 'starting materials' section.
[17].

Patent US3522273

: Early tiletamine patent.
[18].

Patent US4845301

: Rearrangements + precursor to an analeptic amino ketone cited in [01].
[19].

Patent US5811464

: Our ketamine analog is also effective as a cure for herpes and HIV!    Check also the bad yield experimental. 
[20].

Patent US5969159

: The wonderful tiletamine patent cited above, one solvent, no isolation, AlCl3 or graphite as F/C catalyst.
[21].

Patent US6147226

: Follow-up of this tiletamine patent, polyphosphoric acid as a F/C catalyst.
[22].

Patent EP1333023

: Methods to detect ketamine and its metabolites, check the experimental.
[23].

Patent DD204081

: About the usage of aqueous amine solution for the ketimine formation.
[24].

Patent DD208610

: Experimental about epoxide formation with NaOMe, then hydrolise to the ketol.
[25].

Patent DD291751

: Very good bulk- and gram-scale ketamine preparation using aq. amine.

Enjoy!  

[Rhodium]

Here's a little gift from me - Reference #1-6 from

Post 466915

(Manichi: "Ketamine References Feeding", Novel Discourse)  

Epoxy Ethers. XX. Synthesis of Diamines, Morpholines, and Piperazines
Calvin L. Stevens, Morton E. Munk, Charles H. Chang, K. Grant Taylor, Alfred L. Schy

J. Org. Chem. 29, 3146-3151 (1964)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/pcp/ketamine.joc.29.3146.1964.pdf)

Aminoketone Rearrangements. II. The Rearrangement of Phenyl https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000465673-file_lwwo.gif" title="View this image">-Aminoketones
Calvin L. Stevens, Robert D. Elliott, Bradley L. Winch

J. Am. Chem. Soc. 85, 1464-1470 (1963)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/pcp/ketamine.jacs.85.1464.1963.pdf)

Amino Ketone Rearrangements. V. A Kinetic Analysis
Calvin L. Stevens, Harry T. Hanson, K. Grant Taylor

J. Am. Chem. Soc. 88, 2769-2774 (1966)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/pcp/ketamine.jacs.88.2769.1966.pdf)

Amino Ketone Rearrangements. VI. Synthesis of 2-Alkylamino-2-phenylcyclohexanones
Calvin L. Stevens, Arthur B. Ash, Andre Thuillier, J. H. Amin, Aldona Balys, William E. Dennis, James P. Dickerson, Ronald P. Glinski, Harry T. Hanson, Muriraj D. Pillai, John W. Stoddard

J. Org. Chem. 31, 2593-2601 (1966)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/pcp/ketamine.joc.31.2593.1966.pdf)

Amino Ketone Rearrangements. VII. Synthesis of 2-Methylamino-2-Substituted Phenylcyclohexanones
Calvin L. Stevens, Andre Thuillier, K. Grant Taylor, Francis A. Daniher, James P. Dickerson, Harry T. Hanson, Norman A. Nielsen, N. A. Tikotkar, Richard M. Weier

J. Org. Chem. 31, 2601-2607 (1966)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/pcp/ketamine.joc.31.2601.1966.pdf)

Radical and Thermal Rearrangement of https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000465673-file_lwwo.gif" title="View this image">,https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_docs/000465673-file_feqa.gif" title="View this image">-Epoxy Ketones
William Reusch, Calvin Keith Johnson, James A. Manner

J. Am. Chem. Soc. 88, 2803-2810 (1966)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/pcp/ketamine.jacs.88.2803.1966.pdf)

[k0dog]

I don't know the relavance of this comment but...

One of swims friends seem to have synthesisized the fluoro- analogue of ketamine (the chloro replaced by the fluoro).. meh here's the molecular pic...

Molecule:

CNC2(c1ccccc1F)CCCCC2=O ("CNC2(c1ccccc1F)CCCCC2=O")



He actually made his o-Fluoro benzonitrile cuz he could not find a good source... but not too sure how he did this.

Anyways Swim did have the oppurtunity to taste this in a secret experiement.... it was great... similar to ketamine.. but slightly more potent and definetly more dissociative then the chloro analogue. I suppose my views are a bit subjective too tho since I wanted it to be better than ketamine since swift worked so hard on it..

I would also think that this analogue would show certainly some psychoactive properties...

Molecule:

CCNC2(c1cccN1)CCCCC2=O ("CCNC2(c1cccN1)CCCCC2=O")



Also how practical would be the production of NorKetamine?

Molecule:

norketamine ("C2(c1ccccc1Cl)CCCCC2=O")



not too sure if it would be more potent but definetly is legal, and naturally created during consumption of ketamine via oral route (not sure the other routes tho).

P.s. I doubt the practicality for the production of norketamine simply because the route of ingestion would be hard and probably needs to be smoked... but maybe not... also I'm pretty sure that this would take form of a weirdish liquid...

[Rhodium]

I'm pretty sure that the analog lacking the amine function will be inactive.

Can you give us more information about the fluoro-ketamine? Dosage, duration, route of administration etc?

[k0dog]

I Did 1/3 a vial which is maybe... well a vial is 0.45g so... almost 150mg....  This was not measured as usual because I always do a bunch of ketamine, and I sorta expected the same action but more intense for a smaller pay load...

Anyways I did the Fluoro-ketamine at (around) 150mg, which is normally about 1/3 of what I do in a line.  It seems prolonged usuage adds to your tolerance quickly... don't try this at home kids... lol

Usually ketamine takes about 10 minutes to hit me when snorted, (which is the normal route that I take) but instead this took actions with a far shorter period.  Perhaps only 5 or 6 minutes and it was much quicker to the dissacoiative state.  I mean when I do a whole vial (450mg) I usually get holed, but it takes about 1/2 and hour for the complete holing to occure.

With the Fl-ketamine I seemed to get into that "prefered" state much quicker with a much quicker onset (as previously mentioned).

The duration would qualitatively be about the same time maybe a bit longer however it is hard to say since in the state I was in time is a bit warped.  It seemed like maybe 4 hours taht I was hoeld but from tjhe daylight and stuff I know taht to be wrong.  I would guestimate at maybe 1.75 hours..but take that as not guide (BTW that is from the initial dosage to complete come down).

Also I thought come down from ketamine was nice.  Fl-Ketamine is much quicker and less choppy (is taht possible) than the Cl-ketamine.  It is weird I thought that ketamine was the smoothest thing in the world.. but as once again I am provn wrong... hope you enjoyed... peace..

About the norketamine information below is posted a reference to show that ketamine is changed into norketamine when it is eaten. (which if you have ever done is slightly different than snorting or IMing it).
Whoops sorry I ment to have the molecdule look like this

Molecule:

norketamine (" NC2(c1ccccc1Cl)CCCCC2=O ")


anyways it says it is 25%-30% activity of normal ketamine..
which actually mean taht it is a horrible choice for anything to the nature of this post... anwyays here is the link.. it is a nice read anywyas.

http://www.pharmacology2000.com/General/Pharmacokinetics/kinobj4.htm

It has a short section of NorKetamine in the middle... but the majority of information is on ketamine.. =(

[ning]

How about a bayer-villagier oxidation of cyclohexanone, followed by esterification with ethanol and a base-catalyzed (PTC?) cyclization?
H2O2, AcOH?

Molecule:

one ("O=C1CCCCC1>>O=C1OCCCCC1")


hydrolysis, EtOH, H2SO4

Molecule:

two ("O=C(O)CCCCCO>>O=C(OCC)CCCCCOCC")


NaOH/K2CO3, PTC

Molecule:

three ("O=C(OCC)CCCCCOCC>>O=C(OCC)C2CCCC2")


As far as I know, this process is used to produce cyclopropylamine from butyrolactone. I'll look up more details later.