Sciencemadness Discussion Board

Revisiting ketamine synthesis (from a serious synthetic perspective)

chempig - 18-8-2019 at 18:30

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 - 18-8-2019 at 23:11

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 - 21-8-2019 at 00:16

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.