Purely for it's simplicity:
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I developed pyrophenidone (effects identical to MDPV) at the same time but I noted that JUST an N-pyrrolidine produced a decent DRI so figured it was possible to optimise DRI OR NMDA properties. I never tried ring-modification if the above compound but as it is, it's a really interesting trip. I touched the tip of my fingers with the tips of my wife's fingers and at once we both lost the ability to feel where one of us ended and the other began.
A meta methoxy does not work. An ortho -Cl does work but the chemistry is more complex (hence the idiot French adding an ortho methoxy that turned out to be toxic. I would love to know if adding a p-Me to the beta aromatic would increase DRI although the NMDA/DRI balance is just about perfect as it is. Only if and ortho -Cl on the alpha carbon increases NMDA activity would I consider it.
I THINK someone added an ortho -F but I do not know if this was the best or merely the most convenient to make.
I also found what is without a doubt the simplest, safest, cheapest and highest yielding reductive amination so you can make isophenidine in 1 step.
US Patent Application WO2007124920A1 'Process for the preparation of [4(s,r)-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalen-1-ylidene]methylamine' Example 5.
Yield for isophenidine is 100% i.e. the product is pure enough to be used as is.
Why was this not a huge Hit? Well at the time the people in the lab had just bought 250L of piperidine so they figured out the (toxic) methoxyphenidine to use up the piperidine. Quite a few people spotted the 1,2-diphenylethylamine class of NMDA antagonist/DRI and newer and more complex compounds were marketed. In short, my own team buried it because they would have made a loss.
What it tells us is important. The QSAR is more like that of PCP than of ketamine. The N-isopropyl is the most potent monosubstituted PCP analogue. The meta methoxy derivative of isophenidine was not tested but m-methoxy & m-hydroxy derivatives PCP are considered to be very good (the latter also seems to display MOR activity). The m-hydroxy would also overlay the phenol of dextranophal & gives insights into optical activity.
BUT the key thing about isophenidine is that it is made from 2 VERY cheap precursors and the synthesis uses simple and cheap reagents. So maybe you might want to ring-substitute, but:
1,2-Diphenylethanone AKA Desoxybenzoin (CAS 207-193-2)
Isopropylamine Hydrochloride (CAS 15572-56-2)
I mean, 8A-PDHQ, MK-801 (dizocilpine), NEFA & N-methylhexahydrofluorenamine (PD-137889) all provide an decent training set to find the exact position of the N: relative to the aromatic and lanicemine shows possible modification of the beta aromatic, methoxyphenidine possible modification of the alpha aromatic. I take it we are looking for something with the appropriate NMDA antagonist : DRI ratio?
If one wishes to start with the simplest, isophenidine looks like a good prototype for quantum 3DQSAR calculations.