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Compounds With the Most Frustrating Syntheses

Smyth2 said:
3DQSAR have you checked this out yet?

commons.wikimedia.org

File:3,4-Diphenylpiperidine synthesis.svg - Wikimedia Commons

commons.wikimedia.org commons.wikimedia.org

Trans-3,4-Diphenylpiperidin-3-one is supposed to be a potent psychostimulant with antidepressant activity.

That's probably one of my favorite compounds to look at start working on (if I had a lab).
Click to expand...

It has to be said, that it one heck of a reference. A quick look at the history of the page told me a lot ;-) Can one of those phenyls be swapped for, say, a methyl?
 
I think 1-methyl-3-allyl-4-piperidone would result in a 3-propyl group which is optimal chain length for an alkyl group.

The strongest compound is 4-(3',4'-dichlorophenyl) group.

The plain phenyl compound was not actually invented by Hoechst but appears in the literature from many years earlier.

These are the background references (but you don't need to really know about that other than in a historical context):

[1] Gellert, E., Rudzats, R., Summons, R., Worth, B. (1971). "Diphenylpiperidines: Synthesis and properties of some methoxy-substituted 3,4-diphenylpiperidine derivatives". Australian Journal of Chemistry. 24 (4): 843. doi:10.1071/CH9710843.
[2] Koelsch, C. F. (November 1943). "A Synthesis of 3-Phenylpiperidines". Journal of the American Chemical Society. 65 (11): 2093–2095. doi:10.1021/ja01251a018.
[3] Koelsch, C. F., Raffauf, R. F. (November 1944). "The Configurations of Some 4,5-Diarylpiperidones 1". Journal of the American Chemical Society. 66 (11): 1857–1858. doi:10.1021/ja01239a013.
[4] Mortimer, P. (1968). "The preparation of 3,4-diphenylpyridine and some of its derivatives". Australian Journal of Chemistry. 21 (2): 467. doi:10.1071/CH9680467.
[5] Koelsch, C. F. (March 1943). "A Study of Some Michael Reactions". Journal of the American Chemical Society. 65 (3): 437–439. doi:10.1021/ja01243a037.
 
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Smyth2 said:
3DQSAR have you checked this out yet?

commons.wikimedia.org

File:3,4-Diphenylpiperidine synthesis.svg - Wikimedia Commons

commons.wikimedia.org commons.wikimedia.org

Trans-3,4-Diphenylpiperidin-3-one is supposed to be a potent psychostimulant with antidepressant activity.

That's probably one of my favorite compounds to look at start working on (if I had a lab).
Click to expand...

Didn't you mention these a while ago and I asked if it was a specific enantiomer that was used in the studies?

Experience has taught me that animal models of depression are poor and many compounds that appeared to be treatments for the condition turned out not to work in man or to have significant issues.

Nomifensine and then diclofensine were developed at antidepressants and those two newer compounds I mentioned are simply derivatives of that class. It was the sub-nM activity I found interesting and the fact that the p-ethynyl was pretty active.

So I would tend to test p-ethynyl amphetamine first to see where that goes.
 
The separate enantiomers were never resolved.

For the plain phenyl it might be that only one of the enantiomers is active like with nocaine.

But in the potentiating case of the 4-(3',4'-dichlorophenyl) ring compound I would expect all four isomers to be bioactive like with DMNPC.
 
I only ask because some compounds are resolved because as we know, nothing is totally non-toxic so resolving and using only the active is often the way to overcome a narrow TI.

Has that nocaine derivative turned up as an RC?
 
No because the synthesis starting from arecoline gives a mixture of by-products.

These are the newer methods but these are also challenging to make outside of a medical lab:

Czibula, László; Nemes, András; Sebök, Ferenc; Szántay, Csaba; Mák, Marianna (2004). "A Conven-ient Synthesis of (−)-Paroxetine". European Journal of Organic Chemistry. 2004 (15): 3336–3339. doi:10.1002/ejoc.200400067.

Yu, Marvin S; Lantos, Ivan; Peng, Zhi-Qiang; Yu, J; Cacchio, Thomas (2000). "Asymmetric synthesis of (−)-paroxetine using PLE hydrolysis". Tetrahedron Letters. 41 (30): 5647–5651. doi:10.1016/S0040-4039(00)00942-4.

Provencher BA, Eshleman AJ, Johnson RA, Shi X, Kryatova O, Nelson J, et al. (October 2018). "Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter". Journal of Medicinal Chemistry. 61 (20): 9121–9131. doi:10.1021/acs.jmedchem.8b00542. PMID 30240563.
 
Ah - whenever I see 'A Convenient Synthesis...' in the title of an academic paper, I always have a good slow look.


Actually, the first two steps don't make things look too good but from that point on it's quite efficient.

I note a LOT of people have worked on finding more optimal syntheses of paroxetine since obviously being a prescribed medication there is potentially a financial aspect to improving the syntheses.

If you want to find the most efficient synthesis, go through Google patents from the original route and looking at all the patents that cite that original OR one of those that improves on one of the improvements. It's like a tree with each patent one leaf.

In this case: US 3912743.

But I warn you, there are HUNDREDS of the damned things. I read a dozen and thought 'well, this isn't facile until you are making it in tonnes'.

Some may use more steps but you can bet your life that they are ALWAYS looking for the CHEAPEST synthesis.

There are labs whose business model is entirely in finding cheaper ways of making medicines.


I understand the ORIGINAL route yielded just 9.1% so lots to work on.

I have to hand it to you - that's one heck of a frustrating target.
 
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Like you say, Diclofensine and Nomifensine are both facile targets. This compound can be made from Nomifensine:

See the German patent for the compound codename in the table (can't be viewed from US patent).

DE3333994 idem Karl-Heinz Boltze, et al. US4564613 (1986 to TROPONWERKE & Co KG A CORP OF GERMANY GmbH, Troponwerke GmbH).

I was thinking the Liming Shao sibutramine analogue SNDRI compound looked not difficult relatively speaking and had decent Ki digits.
 
The picture is codenumber 3a in the German patent.

Actually the para-fluoro analog gives the highest potency (3b & 4).

This patent is definately a good find though.
 
Smyth2 said:
Like you say, Diclofensine and Nomifensine are both facile targets. This compound can be made from Nomifensine:
Click to expand...

My thinking is that the extensive QSAR study carried out on those more potent (but synthetically more complex) could be applied to the simpler nomifensine/dichlorfensine scaffold. After all, those later compounds were bases on the earlier compounds.

It seems at least some work has been undertaken.

pubchem.ncbi.nlm.nih.gov

2-methyl-4-(4-methylsulfanylphenyl)-3,4-dihydro-1H-isoquinoline

2-methyl-4-(4-methylsulfanylphenyl)-3,4-dihydro-1H-isoquinoline | C17H19NS | CID 21819578 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.
pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov

But if you are like me, you are going to be VERY concerned about that para -SCH3 as we all know the harm 4MTA wrought on punters who thought they had taken MDMA.

Franky, I would begin with para ethynyl amphetamine and/or para ethynyl methcathinone (likely the latter as these seem to have less MAOI activity - better safe than sorry).

I don't know why the p-ethynyls weren't explored. Shulgin tried it with the classic 2,5-dimethoxy and, well, it acts much as you would expect.

I'm just laying out what I think would be the logical progression in terms of resources expended to test the hypothesis. Go simple early.
 
The para-amino compound (Amifensine) was never prepared according to the pubchem database. However I did find this:
pubchem.ncbi.nlm.nih.gov

4-(1-Methyl-2,3,4,4a,5,9b-hexahydroindeno[1,2-b]pyridin-5-yl)aniline

4-(1-Methyl-2,3,4,4a,5,9b-hexahydroindeno[1,2-b]pyridin-5-yl)aniline | C19H22N2 | CID 21150864 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.
pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov
[1] Kunstmann, Rudolf; Gerhards, Hermann; Kruse, Hansjoerg; Leven, Margret; Paulus, Erich F.; Schacht, Ulrich; Schmitt, Karl; Witte, Peter U. (1987). "Resolution, absolute stereochemistry, and enantioselective activity of nomifensine and hexahydro-1H-indeno[1,2-b]pyridines". Journal of Medicinal Chemistry. 30 (5): 798–804. doi:10.1021/jm00388a009.
[2] Kunstmann, Rudolf; Lerch, Ulrich; Gerhards, Hermann; Leven, Margret; Schacht, Ulrich (1984). "2,3,4,4a,5,9b-Hexahydro-1H-indeno[1,2-b]pyridines: potential antidepressants". Journal of Medicinal Chemistry. 27 (4): 432–439. doi:10.1021/jm00370a004.
[3] Kunstmann, Rudolf; Fischer, Gabriele (1984). "Molecular analysis of hexahydro-1H-indeno[1,2-b]pyridines: potential antidepressants". Journal of Medicinal Chemistry. 27 (10): 1312–1316. doi:10.1021/jm00376a015.
[4] Kunstmann, R.; Paulus, E. F. (1985). "Vergleichende röntgenographische Untersuchungen an antidepressiv wirksamen optisch aktiven 8-Amino-Tetrahydroisochinolinen und Hexahydroindeno[1,2-b]-Pyridinen". Fresenius' Zeitschrift für Analytische Chemie. 321 (7): 639–640. doi:10.1007/BF00489618.
[5] Kunstmann, R.; Lerch, U.; Gerhards, H.; Leven, M.; Schacht, U. (1984). "ChemInform Abstract: 2,3,4,4A,5,9B-HEXAHYDRO-1H-INDENO(1,2-B)PYRIDINES: POTENTIAL ANTIDEPRESSANTS". Chemischer Informationsdienst. 15 (38). doi:10.1002/chin.198438220.
[6] Kunstmann, R.; Lerch, U.; Wagner, K. (1982). "ChemInform Abstract: NEW ROUTE TO INDENO(1,2-B)PYRIDINES". Chemischer Informationsdienst. 13(36). doi:10.1002/chin.198236180.
[7] Kunstmann, Rudolf; Lerch, Ulrich; Wagner, Konrad (1981). "Ein neuer zugang zu indeno[1,2-b]pyridinen". Journal of Heterocyclic Chemistry. 18 (7): 1437–1444. doi:10.1002/jhet.5570180731.
[8] Rudolf Kunstmann, Ulrich Lerch, Hermann Gerhards, US4118497 (1978 to Hoechst AG).

That compound is a bitch to prepare though. However it is worth pointing out the the SAR overlays with McN-5908 [105234-91-1], which is one the most potent psychostimulants ever discovered. The Hoechst compound of the 1980's has IC50's that are slightly less potent though.

I had the idea if one takes the para-amino tetrahydroisoquinone derivative (Amifensine) and converts it to an azido group (Azifensine), this would be an interesting molecule with drug like properties. A Sandmeyer reaction of the para-amino to a para-Iodo (Iodofensine) could also be attempted that was never seen before (only the other halogens).
 
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Aromatic amines are something to be wary of.

I'm sure you are aware that the body can form hepatotoxic and genotoxic metabolites.

I'm pretty sure nomifensine was removed from the market due to just such issues. It's a rare case in which the body will actually REDUCE which was a bit of a surprise when I first noted the fact.

I'm not saying any of those compounds are toxic, but I'm very conservative. That said, it's usually detected quite early via Ames test.

Still, that's some pretty thorough referencing.
 
It's worked out a number of times in the field of PABA -caine like local anesthetics. I won't got through an exhaustive list but the most regarded one is probably Dimethocaine.
 
The p-Cl homologue is the most active.

But here is the KEY thing I got wrong - the hydrochloride salt isn't very water-soluble so snorting it was extremely nasty. But later I discovered that the sulphate IS very soluble (more so than the phosphate) and works fine.

I'm sure I don't need to guide you through replacing that p-NH2 with a p-Cl.

But HINT - it's so cheap to make, your actually better of just making it rather than messing with azides.

With me, cost has always been one of the 3 drivers.

1-Safety
2-legalty
3-Activity

I would rather go to prison than harm someone, but I would rather not profit than to break the law. Wherever you are, cells are dull.
 
I Quit Selling Drugs Around Age 26 Maybe. I Am 48 Now. Why? Because I Noticed The People Going To Prison Were Almost All Dealers. After That, I Stuck With My Own Little Stash. The G6 People "Manufacturers" With Their Safrole To MDMA Route Wine Cellars Don't Get Busted Because They Are Too Rich, Powerful, And Intelligent.

Also, I Am More Than Happy To Leave These Experimental Lead Drug Inventions To The Practical Professional Organic Synthesis Teaching Assistant(s). For Bounce, Either NaCN (sodium cyanide) Or KCN (potassium cyanide) Is Required. If That Cyanide (-)CN Anion Can, It Will Bind Irreversibly To Hemoglobin, Leaving You Dead, So Keep The Cyanide Basic -OH. A Mineral Acid Such As Muriatic Acid (HCl liquid) Will Donate A Proton H+ To -CN, Which Can Lead To The Evolution Of Deadly H-CN(g), Hydrogen Cyanide Gas.

The Reduction Of MDMA With Methanol, MDP2P, And Excess Methylamine Is Not The Best Route (The Best One Would Be The Ammonium Formate Leuckart.) However, It Is Often Used.

However, To Put All This Into Perspective, It Appears That We're In An Abyss Right Now, And It Is Also Said That The Abyss Is, In Fact, Eternal.
 
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Smyth2 said:
Trepipram looks like quite a good hit.
Click to expand...

I'm uncertain what that is.

But it's worth remembering that only a small fraction of novel drugs that even make it to animal models (I've worked with Huntigdon Life Sciences so have reason to know) and only a fraction of those reach human trials and only a fraction of those ever become a medicine.

I've known MANY researchers who haven't brought a single new drug to market in their entire 40+ year career (these people often do not want to retire).

But that axiom 'go simple, early' has worke for me oh.... about 20 times. Roughly. I didn't keep count of every RC and certainy don't include things like metizolam because nobody could claim it took much thought to simply remove a methyl.

If you want something to reach market and you don't have billions to spend - there are still a VAST number of compounds that are known to be active, are simple to produce and are legal almost everywhere.

I think it was a group of French researchers who took amphetamine and added a methyl side-chain to the benzylic (beta in old money) carbon. It turned out they were almost as active as amphetamine if resolved. But even if not, it's so easy and cheap to make, even if you only resolve the amine, the stuff is still perfectly usable. Fastandbulbous noted that a benzylic methoxy did a fair imitation of phenmetrazine. I don't know about the synthesis of that one... dare I say L-PAC would be a good precursor?
 
Dopamine agonists have terrible side-effects. Vomiting is the most common and it's worth remembering that rodents have no vomit reflex.

Another example of why you can't look at an animal model and presume it will automatically work in man. If one only considers increased locomotion and reduced feeding, it looks great, but the side-effects are ones that would be hard to model. Headache, dizziness, hallucinations and confusion are sort of hard to spot in a rat.

What you want is something that releases dopamine or prevents it's reuptake.

I did point to a chemically simple example that WAS trialled in man. The chief problem WAS that it produced intense stimulation - a bug in the context it was used in, possibly a feature if one wishes to produce something akin to cocaine.
 
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