Novel Reaction: Update

[Smyth]

I had another go at making the compound today. Basically this attempt was better than last time but still not great. After said reactions and workup I was left with 2.1g of a yellow oil. It corresponds to a 20% yield. I know all the tricks but I may have to develop a few of my own. I treated this oil with an equimolar amount of HBr 48% [1.3g] and 5ml acetone. Bright white crystals formed and after cooling these were filtered under vacuum. The crystals were then collected and added to a further 5ml acetone. After cooling/filtering the crystals were collected and weighed. 1.2g was obtained corresponding to a 12% yield. OK but the appearance of the crystals is promising and when I shake the sample tube I hear a pleasant rattling sound not unlike diamonds.

 

[joystick]

I didn't see the original post which I assume this post is the 'update' for, so would you mind telling me and everyone else just what exactly you synthesized? The most I could tell from your above post was that it was a hydrobromide salt, and the yield needed improvement.

You said, the mystery crystals have a "pleasant rattling sound not unlike diamonds." Are you talking about shards or what? I'm really kind of curious.

 

[Smyth]

Yes they are shards but the yield is a disappointment. I was planning on reducing the freebase with LAH but when my return lower than anticipated, I chose to skip on this step. This is the second time I have attempted this reaction after countless months planning. The target molecule that I am proposing to manufacture is basically the syn-hydroxymethyl derivative of the attached molecule as the hydrobromide. The trans isomers can be discarded. I am hopeful that if I can implement a modification, this might improve my yield. That is basically the barrier between making small amounts of a novel research chemical and the break through to commercially viable quantities.

 

[joystick]

Speaking of research chemicals, there is an exciting new nicotine analogue that is 200x stronger than morphine in relieving pain and is stimulatory in nature. It is a semi-synthetic derivative of a rare frog extract.

Chemically, it is a four membered (3 carbons, 1 nitrogen) ring--namely an azetidine ring-- with an oxygen attached at the #2 carbon (the carbon next to the cyclic nitrogen). The other end of the oxygen is attached to a pyridine ring with a chlorine ortho to the pyridine's nitrogen. The oxygen is attached para to the chlorine and meta to the pyridine nitrogen. Abbott pharmaceuticals is being very quote "tight lipped" about the early clinical pain trails that this true research chemical is undergoing and won't even say whether it is addictive, but I hope it is.

Notice that if you take any methamphetamine and connect via an imagined extra sigma bond between the N-methyl group and and the alpha-methyl group, then you will have a 2-substituted azetidine ring just like this new compound. Add two more carbons to the aliphatic ring and you'll get a phenidate type stimulant such as Ritalin (methylphenidate) or
2-benzylpiperidine, my unsynthesized idea of a good stimulant.

I can't help but wonder what taking a 2-substituted azetidine PEA would be like, what the 5-alkyl-2-chloropyridinyl ring system feels like (for example, plain is benzene is highly stimulating and benzodioxole is highly relaxing while 2,5-dimethoxyphenyl is a waste of time and money) or what it would be like to take a PEA with an oxygen connected to the aromatic ring instead of the usual methylene (-CH2-) subunit of the "ethyl" in phenylethylamine. 2-benzylazetidine looks like a good stimulant in my crystal ball as well.

But back to your project here, what do you mean by the syn-hydroxymethyl hydrobromide analogue of (I presume) methamphetamine? That sounds vaguelly like an isomer of ephedrine. Do you know the correct IUPAC name for your target compound? You said you were going to use LAH to reduce the freebase; by "freebase" in this case do you mean the 1-phenyl-2-nitro-1-propene intermediate or did you start with P2P/benzylmethylketone? No hydroxymethyl group will enter the lipophilic blood brain barrier that I know of. If you don't want to use LAH to reduce the nitropropene, then you could always first use NaBH4 to reduce the double bond followed by reduction of the nitro group to an amino group with HgCl2 and aluminium foil. Doing so obviates the need for the strict anhydrous conditions required by LAH. On a large scale, though, I guess you would be using a Parr hydrogenation apparatus, some H2 gas and either Raney Ni, Pt or Pd as the reduction catalyst.

Again, I am unclear what your target compound actually is.

BTW

What happened to the hive and rhodium's home page for the last two day? Does anyone know why they are down? If they are down permanently, can the bluelight moderators please, please create a Drug Synthesis / Chemistry forum?

Edit: error alert--ABT-594 has one more carbon (methylene unit) between its azetidine ring and the oxygen connecting to the chloropyridinyl aromatic ring system and thus is a 3C compound, not a 2C one like my beloved PEAs and AMPs.

 

[Smyth]

There is a file attached at the top of this thread. Sorry I cant just show you outright but my computer is weird like that.

Yeah ABT compounds are ok. Basically they are made from a 4 membered ring amino acid that would be analogous to proline. Just reduce the acid and then this is joined up to the pryridyl ring in a mitsunobu reaction. The para chloro is not necessarily imperative to activity but presumably rich drug companies like complicated affairs.

BTW they are not being totally tight lipped, you just have know where to look. These compounds cause a drop in body temperature as one of the side effects. What is exciting is that these compounds are even more systematic than opioids in their mode of action. Since acetyl choline is responsible for nerve impulses. These compounds are actually working on an electronic level, blocking Ca+ and Na+ channels that communicate pain messages.

 

[joystick]

Oh, I see.

I see the similarities with cocaine, and I like the 3,4-dichloro phenyl addition, but wouldn't 3,4-dichloro(meth)amphetamine be a better aliphatic group than a 4-phenyl substituted piperidine, which like Haldol, may actually block rewarding D2 receptor activity? What effect would inserting a -C(O)O- (ester) linkage between the piperidine ring and the phenyl ring have? Most importantly, what are the subjective effects of this, your new and strange research chemical? Is it any good? How much money does it cost?

 

[Smyth]

This is totally different to Haldol. Basically the syn pair of enantiomers are strongest at releasing dopamine. The trans pair of enantiomers will be good at releasing serotonin but not good at releasing dopamine. Both pairs of enatiomers release NET appreciably. Although the cis pair of enantiomers release serotonin, the emphasis is more toward dopamine with NET in the middle. The discrimination ratio is low which means that the user is expected to display drug seeking behaviour. Note: Only the syn pair of enantiomers is wanted - the trans isomers are discarded. A mixture of syn/trans isomers is thought to pose an unacceptable seizure risk. Dosage could be anywhere between say 3-10mg. Although hydroxy compound may be a little weaker it is considered that they will be safer and longer lasting.

Adding the ester between the phenyl group and the piperidine destroys activity.

Dichloromethamphetamine is an illegal analogue and would likely cause serotonin syndrome like toxicity even at low doses. Somebody should make it but I doubt the government would fund such a project.

The ester group and the 3 position basically modulates activity. If it is moved to the 4-position we get a compound whose activity at SERT stays roughly the same but activity at DAT drops considerably.

A compound which is bare at the 3 position is expected to contain all sorts of nasties, certainly not compatable with this ring substitution pattern. I believe that in the tropane series of compounds, analgous products are quite selective towards muscarinic recepetors.

 

[joystick]

Smyth, you have a very impressive array of knowlegde on this subject. I have some catching up to do in this field of knowledge, but I still don't see why 3,4-dichloroamphetamine must necessarily be so neurotoxic. After all, many pharmaceuticals share that particular structural feature with no apparent ill effects, such as Zoloft (3,4-dichlorophenyl residue) and Wellbutrin (3-chlorophenyl residue only), but I guess the amphetamine nature of the compound makes ingesting 3,4-dichloro(meth)amphetamine a risky proposition. Still, it probably wouldn't be any more toxic than para-chloroamphetamine would it? Who knows, I guess.

Also, do you know if ABT-594 is addictive/self-administered in animal models? As a nicotinic receptor agonist and potent releaser of catecholamine neurotransmitters, I can't imagine that it wouldn't be.

As for the necessity of the pyridyl 2-chloro atom, I think I just read in some study that while not absolutely necessary for nicotinic receptor activity, that particular halogen substitution greatly increased the analgesic properties of that class of compounds.

In my mind, 5-(2-methylaminoisopropyl)-2-chloropyridine should be considered for possible RC development. Using an alternate numbering scheme, this gives an amphetamine or methamphetamine analogue with an aromatic, cyclic N at the phenyl's 3 position (with its lone pair of electrons sticking out orthogonal to the cyclic pi bond system and in the same plane as the pyridine ring) and a chlorine at the (sometimes) highly psychoactive 4 position of the phenyl ring. This produces a substituted amphetamine of the 3,4-variety; in my experience, 3,4-substituted amps are superior to the 2,4,5-trisubstituted PEAs and AMPs that overpopulate the bulk of PiHKAL, even if their 2C analogues are not really active and they are of less potency than say, DOB. Potency should not be confused with quality.

Were the extra methylene unit of ABT-594 that I overlooked earlier to be removed by using an alternate synthesis, the similarities between ABT-594 and the amphetamine world might shine forth. Also, this oxygen between the aliphatic amine portion of these compounds and the aromatic ring system has piqued my interest as to what MDA or methamphetamine analogues would be like if their benzylic methylene units were replaced by an oxygen as with ABT-594. I have no idea (yet) how they would be synthesized, but I feel sure that it will be possible. In fact, I think one of those articles I just read stated that replacing that oxygen with a sulfur increased activity by some unbelievably high factor. I feel sure that MDMA has analgesic properties as well; I know mescaline does in rats anyway.

Anyway, I wanna get HIGH on some new nicotinic receptor agonists, especially those that also release NE and DA, the little darling chemical neurotransmitters of drug addicts the world over.

But, finally, and perhaps most pertinently to my interests here, have you yet had a chance to bioassay your new molecule or did you say the synthesis failed? The structure in your attachment reminds me of some kind of cocaine analogue; is this a correct statement?

 

[Smyth]

The only reason I dont want to try it is safety. This material is expected to be incredibly potent but that does not necessarily constitute a failure.

3,4-Dichloroamphetamine would probably be a great chemical infact, provided it is cut properly. It is however for somebody else to experiment with. My only concern is that it might be a little bit overkill. I guess it is not a great deal different from p-chloroamphetamine, just alot stronger. In any event it would be highly toxic. Hence it would have to be cut thoroughly prior to consumption.

I think that ABT-594 is very exciting because we have never seen anything quite like it before; it is not just another boring analogue. I heard it was pure chance that Abbot laboratories were working in this area at the same time that epibatidine was discovered.