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!