chempig
Harmless
Posts: 1
Registered: 18-8-2019
Member Is Offline
|
|
Revisiting ketamine synthesis (from a serious synthetic perspective)
New to the forum, but I have seen a number of posts on here regarding proposed synthetic methods for making ketamine that have piqued my intellectual
curiosity.
It is interesting to me that every discussion I have seen here has suggested the possibility of brominating o-chlorophenyl cyclopentyl ketone
(6740-85-8) with Br2, with the occasional suggestion of N-bromosuccinimide (NBS). However, I have yet to see any mention of using copper (II) bromide
in ethyl acetate to perform the alpha-bromination. I'm curious to hear your thoughts on why the latter does not seem to receive attention.
In the following step, I am fascinated by the widely propagated experimental description for the next step that says, "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." (reference: https://www.erowid.org/archive/rhodium/chemistry/ketamine2.h... and appearing many other places as well.)
I have a hard time deciphering what the author could have meant by this. What is being neutralized here? The HBr generated by the bromination should
have already been neutralized by the bicarb wash in the preceding step.
More importantly, what is being described for the addition of methylamine? I understand that the author is suggesting to make methylamine in situ, but
the description here seems vague, at best. Is the author suggesting to suspend the methylammonium chloride in benzene and then add this to NaOH to
liberate methylamine? I have a hard time understanding what saturated solution the author is referring, or what they mean by "dry thru NaOH." I can't
imagine they are suggesting to run the reaction for the course of a day while still on NaOH pellets, are they? While I'm sure the solubility of NaOH
in benzene is sparing at best, I would imagine hydroxide could lead to deleterious reactivity. Am I misunderstanding this whole prep?
Lastly, it is intriguing to see the breadth of solvents suggested here and elsewhere for the final pinacol-type rearrangement. I would have thought
that the primary requirement here is simply a solvent that is high boiling enough to facilitate the thermal rearrangement. And yet, reported yields
range drastically depending on the chosen solvent from less than 50% to near quantitative conversion. I wonder if anyone has thoughts into the role of
solvent or the fate of this transformation? Is poor yield due to incomplete conversion, or are there competitive decomposition pathways that arise
under certain reaction conditions?
I know that asymmetric syntheses of ketamine have started to receive a lot more attention in recent chemical literature due to the newly approved
application of the S-enantiomer for depression treatment, but it's interesting that little improvement of the racemic mixture synthesis has been
explored since the original Stevens patent from the 1960s. Hoping to stir up some interesting and insightful discussion for those who are fascinated
by synthetic organic methodology!
|
|
|
draculic acid69
International Hazard
Posts: 1371
Registered: 2-8-2018
Member Is Offline
|
|
I'm guessing that the price of copper bromide is the reason.and second just because someone hasn't posted that they've done it doesn't mean that it
hasn't been done.
|
|
|
Cactuar
Harmless
Posts: 32
Registered: 25-7-2014
Location: Denmark
Member Is Offline
Mood: No Mood
|
|
Quote: Originally posted by chempig  | | I have a hard time deciphering what the author could have meant by this. What is being neutralized here? The HBr generated by the bromination should
have already been neutralized by the bicarb wash in the preceding step. |
The HBr formed from the Sn2-reaction with methylamine.
| Quote: Originally posted by chempig | | More importantly, what is being described for the addition of methylamine? I understand that the author is suggesting to make methylamine in situ, but
the description here seems vague, at best. Is the author suggesting to suspend the methylammonium chloride in benzene and then add this to NaOH to
liberate methylamine? I have a hard time understanding what saturated solution the author is referring, or what they mean by "dry thru NaOH." I can't
imagine they are suggesting to run the reaction for the course of a day while still on NaOH pellets, are they? While I'm sure the solubility of NaOH
in benzene is sparing at best, I would imagine hydroxide could lead to deleterious reactivity. Am I misunderstanding this whole prep?
|
I don't think it's very vague. A saturated solution of aqueos MeNH2 HCl is dripped onto solid NaOH, the liberated gas is dried through additional NaOH
and the dried gas allowed to saturate the reaction solution.
|
|
|
|
![[*]](images/xpblue/default_icon.gif){kind=icon}
