(Posting performance anxiety strikes again! Nearly an entire fucking month without a followup, for no reason at all! This level of pointless anxiety isn't normal, is it? Well time to get over this retarded fear and let this rip. Sorry if this lacks enough editing. I'm also donning an e-mail and tripcode in case I ever want to use this for cred on chemistry forums.)
>>19858>>19879Alright then. I researched several alternatives for steps in multiple routes and wrote down my findings and speculations. It's a OneNote notebook which, if exported to MHT file, weights in at over 223 MB, but it's an ungodly mess of disorganization, incorrect terminology and suppositions gleaned from reading hundreds upon hundreds of studies and chemistry forum threads without having the chemical education to serve as basis.
When it comes to the all-important amine function of so many drugs, I have come to the conclusion that the most amateur friendly method seems to be reducing nitros and imines to amines using metallic zinc in acidic media. It doesn't requiring getting small alkylamines, nor fiddling with them in either the gas state nor having to free it from its salt form, you just reduce the nitro to an amine using something as simple as just Zn dust in AcOH under air (tho it should be kept in mind this releases H2), then condense it with methanal or ethanal or whatever and apply the same recipe again to get an alkylated amine, maybe in a one-pot fashion, and maybe even in a single step (I'll talk about this a bit more near the end). This is because Zn-H+ seems to be quite selective for reduction of multiple nitrogen functions, but not unactivated aldehydes nor ketones, nor other common troublesome things like unsaturations, dearomatizations etc. Further, by controlling simple factors like temperature and acidity, it seems possible to fine-tune this electivity further. Other metals like iron and aluminum might be viable under various conditions, but based on all the studies I have seen, zinc seems to be the most well-behaved.
In particular, I'm currently interested in applying it to this ketamine precursor, as per
https://pubs.acs.org/doi/10.1021/acs.orglett.7b00040 and a couple of associated patents,
https://patents.google.com/patent/CN106478367B and
https://patents.google.com/patent/CN109232521A. As far as I can see, it's surprisingly straightforward, requiring pretty much just zinc dust and acetic acid. In the study, they use pure AcOH, tho in the patents, they seem to use the same recipe but dilute the AcOH with isopropanol. As far as my research goes, the waste product, Zn(OAc)2, is nearly insoluble in pure AcOH and presumably in isoproanol as well, greatly facilitating workup: once the reaction is done, just filter it to get rid of virtually all the Zn(OAc)2 plus unreacted Zn, leaving you with the norketamine acetate in pure or isopropanolic AcOH. They extract the norketamine into EtOAc using aqueous NaHCO3 (enough to neutralize acetates), tho presumably, one could prescind from EtOAc and simply make the norketamine crash out of solution then filter it out, tho obviously this would make for a less pure product.
This video shows this exact reaction, tho sadly not the workup, of a subtance almost identical to the one in the pic:
https://piped.video/watch?v=FROVCDzhbLs. Looking in the comments tho, he says he filtered and basified with aq. NaHCO3 as I as above. A couple of notes: he, like the study and patents above, used inert atmosphere, but apparently this isn't necessary judging by plenty of other examples; and the zinc doesn't need to be activated beforehand, tho at the cost of lower yield, as he comments under the video. Maybe pre-activating the zinc wouldn't be necessary, if a minuscule amount of HCl is added to the reaction, since apparently the higher acidity is all it takes to activate it?
In order to make this even more amateur-friendly, I wondered if simple vinegar could be used. After a lot of searching, I have found only one report of a similar reduction using zinc dust and vinegar, and it's applied to a benzylic imine rather than a benzylic nitro to reduce harmaline to tetrahydroharmine, as per pic 2:
https://www.dmt-nexus.me/forum/default.aspx?g=posts&t=29210 (related:
https://wiki.dmt-nexus.me/DMT-Nexus_Wiki:THH_Reduction). Still, given the reactivity profile of Zn-H+ reductions, I think that zinc dust and vinegar can affect the reation in pic 1. Apparently the formation of zinc oxide under these conditons is negligible. The one big difference from using pure or isopropanolic AcOH here is that the resulting Zn(OAc)2 is very water soluble, so you can't just filter it out. Still, this opens up a possibility of just neutralizing that Zn(OAc)2 using just NaHCO3, and the resulting ZnCO3 happens to be nearly insoluble in water. This is my chief question in this post for you. Picture the following. Apply the zinc dust and vinegar reduction to the nitro precursor of norketamine, then filter out the unreacted Zn, which should leave you with norketamine acetate and Zn(OAc)2 in aq. AcOH (assuming not all of the AcOH was consumed). Now, I assume that NaHCO3 would a) neutralize norketamine acetate, generating norketamine, NaOAc, CO2 and water, b) neutralize AcOH, generating NaOAc, CO2 and water, and c) undergo double displacement with Zn(OAc)2, yielding ZnCO3, NaOAc, CO2 and water. And here is where my lack of both chemistry education and practice comes in: can this double displacement reliably both get rid of the Zn(OAc)2 and make the ZnCO3 crash out? In a more abstract example, suppose that salts AB, CD and AD are all water-soluble but CB isn't; would simply mixing AB and CD in water make CB crash out?
The proposed route would be something like:
- reduce the nitro precursor of norketamine using zinc dust (activated or not) in vinegar under air
- filter out unreacted zinc dust
- add NaHCO3 to the solution (carefully since there's CO2 formation) to make ZnCO3 and norketamine freebase crash out, OR evaporate the solvents then dissolve the residue in just water so there's no AcOH to be neutralized and thus less CO2 formation
- it might be possible to make these two substances crash out separately, since ZnCO3 is insoluble in neutral water but soluble in dilute alkaline solution whereas norketamine, as is typical for alkaloids, should crash out at higher pH
- if it's not possible to make them crash out separately, filter out the cake consisted of these 2 substances then add them to neutral water or a lower alcohol; the norketamine freebase will dissolve but the ZnCO3 won't
- filter out the ZnCO3
- evaporate solvent to get norketamine freebase
Like I mentioned above, condensing norketamine with methanal (or some other small aldehyde or ketone) then applying the same protocol should work, and if one uses pure or isopropanlonic AcOH instead of vinegar, maybe the Zn(OAc)2 itself could be used as dehydrating agent for this condensation, so the two steps could be made one-pot. Going even further, I have found studies which do both things in one step simultaneously (tho in different substrates), by adding the aldehyde to the nitro before reducing it – tho results are debatable, in no small part because all but 2 of these studies are almost a century old and most are in Japanese, badly scanned and with worthless OCR, but I'll leave that to another post, in case there's interest.
How off-base (pun very intentional) am I?