Welcome aboard, krest17
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Note 1: Thread hijackers and comment-section bandits, watch out: Now there is two of us [2]
Note 2: Formally, Note 2 serves to remind you about the importance of Note 1 – but in reality it ribs CBC
I have been doing some asymmetric hydrogenations recently. The pieces that I was making were carboxylic acids and since the highest optical purity that I could get from my system was about 90%ee and the product couldn’t be enriched by a simple recrystallization, I needed to make a salt - preferably with some optically pure amine – to bring the material up to 98-99% ee. I got quite lucky with chloramphenicol base: the salt enrichment in a single recrystallization proceeded with high recovery.
I also tried few other chiral amines, norephedrine worked but it was not very efficient (with the salt being too soluble). And norephedrine is rather expensive and it is on the controlled precursor list – its delivery got halted for nearly a week by the bureaucracy and eventually we had to fax a statement to the supplier, declaring that we are not making a dope.
This got me to realize that unlike with the chiral pool of acids, there is only a limited choice of inexpensive optically pure amines that one can buy both enantiomers of (a typical problem with many alkaloids and other natural-product derived amines). Chloramphenicol is a generic antibiotic made by old-fashioned racemic synthesis and resolution hence both enantiomers are available. And not every amine is likely to provide a nice crystalline salt; what probably makes chloramphenicol base effective is the combination of para-subst nitrophenyl group and the two hydroxy groups that contribute to ordered interactions in the crystal structure.
Chloramphenicol base has been used as a resolving agent in industry: Roussel Uclaf, the company that commercionalized a large-scale production of chloramphenicol many years ago, is using the base as a resolving agent for racemic trans chrysantemic acid – a precursor for making synthetic pyrethroid insecticides such as Deltamethrin. The resolution takes place very early in the sequence. Given that pyrethroids are made on ton scale, the availability of the optically pure amine needs to be pretty good.
The actual resolution of racemic chloramphenicol base is noteworthy: Chloramphenicol base is among the rare (1-2%) compounds that crystallize as a conglomerate of optically pure crystals. This means that it can be resolved by selective crystallization based on seeding with one and then the other enantiomer. In reality the process is somewhat tricky – one has to work under carefully controlled conditions and use a massive quantity of the enantiomerically-pure seeding material to have a fast growth, and stop the crystallization very early to ensure that the other enantiomer keeps in the super-saturated solution. But this sort of process is doable in a chemical plant and “resolving stuff with nothing” helps to produce the optically pure material cheaply .
The recent post at Terra Sigliata brought up memories of my first thesis project in Prague. I got involved with ’independent cancer researchers’ and one of them became my thesis adviser. He was a very kind old man and he let me do anything in their lab I wanted to – but eventually I moved out of there because doing synthetic chemistry in a poorly equipped biology lab was difficult. I managed to re-synthesize some of their substances - the compounds turned out to be active in antiproliferative assay done at another institute but we could not really test them extensively anymore and my adviser retired and that was the end of the project.
It was an interesting experience. The sad part of it was that our colleague who actually started the work and made most contributions before retiring used to be a reputable virologist - he pioneered interferon production method using human fibroblast cultures. Later he got interested in analysing a ’natural cancer cure’ from a quack that seemed to have positive results. So this virologist began looking for the active principle and was doing animal testing on the extracts - a legitimate research program – but his chemistry and also the animal work done in a very limited setting was not up to the task. The lab absolutely lacked the resources needed for natural product research and synthesis. He had nobody to test it so he brough mouse cages into the lab… He tried to push forward on non-existent budget and without the necessary expertise, simply by improvising and calling favors on his friends to gain the testing and instrument access unofficially. With this strange research project going on for years, his confrontational style also won him no admiration within the management and the neighboring groups at his institute. He was never forced to stop but he got himself isolated in his little lab before reaching the retirement age.
He identified something interesting - a class of naturally-occurring substances related to synthetic cytotoxic ether-phospholipid analogs of PAF (that were independently developed for chemotherapy). His natural ether phospholipids seemed to work on some cancer lines and were well-tolerated by normal fibroblasts. They also showed a promise in xenograft mice tumor models. Since these phospholipid substances are naturally-occuring in humans (under conditions like ischemia), the hope was that perhaps they could be less toxic than the synthetic alkylphospholipids.
As he and his few colleagues were getting increasingly anxious about the project progress and its lack of support, they decided to campaign in the media. They were also giving out their naturally-derived quack remedy to cancer patients; they genuinely thought they were doing favor to these patients… and they antagonised the medical community. That made them even more exasperated and resentful.
I had nothing to do with this patient compassionate ”treatment”, I only re-synthesized some substances in a pure form and got them independently tested; the compounds were active in a cancer cell culture but their poor solubility was a major complication:
Here is the synthesis I did for the project - it turned out to be a fairly straightforward scheme although it took some effort to figure out. (There was a bit more to it; I was also isolating these substances from a natural phospholipid mixture and characterizing them by chemical derivatization).
This project story from 20 years ago shows that people promoting the “natural cancer remedies” may even have careful scientific approach at the beginnig but as they continue they get carried away by wishful thinking to the point of delusion. They start as researchers but derail as quacks. When you are working on biologically active natural substances and you have great hopes for the medicinal potential of your project you have to be very conservative about the way you interpret and present your results. You can’t skip the preclinical research stage even when your compounds are “natural and non-toxic”. You need to look for any artifact argument against your promising results - if there is a discrepancy in your numbers you have to understand it (could the results be possibly influenced by the purity/instability/solubility of your compounds, the way you make the stock solution, grow the cells or inject the mice?). Claiming that your critics from the medical community are hindering you because they surely are in confederacy with pharma companies is the quickest method of earning yourself a crackpot reputation.
Also, please don’t take a thesis adviser who works on a fringe project even if you are excited about the research - it was somewhat difficult for me to find a job immediately after finishing my thesis; my adviser and his colleague were well-meaning but they could not help me and when they retired our work came to nothing.
Methamphetamine illicit production is a serious problem not to be made light of in these times when getting hold of precursors is growing more difficult. We prepare ourselves for the start of promising TV series this Sunday by comparing the merits of four popular methods [1, 2]:
1. Heating pseudoephedrine with red P and iodine. This is a dirty method that needs glassware and some practice. The reflux produces a nasty phosphine smell, in the absence of fume hood the cook would want to use a mask. This is the actual method featured in “Breaking Bad”.
2. Pseudoephedrine treatment with Li metal and anhydrous condensed ammonia mixture in ether. Anhydrous ammonia is a common fertilizer that could be pilfered from outdoor storage tanks. This used to be a hillbilly favorite method – the cooks stir the mix in a bucket while throwing in the Li chunks. This is feasible only in open country as the escaping NH3 stinks up the whole area. The method is quick, the average batch size tends to be smaller. The complicating factor is a benzene ring over-reduction. The agricultural liq NH3 is nowadays frequently denatured with inorganic salt additives to ruin its usefulness in meth production.
3. Hydrogenation of chloromethamphetamine hydrochloride solution over palladium. The chloro intermediate is obtained by mixing the hydrochloride salt of ephedrine or pseudoephedrine with thionyl chloride. This is a clean and high-throughput method favored by Mexican cartels. It is best performed in pressure hydrogenators – which makes it less available to most home cooks. (It may turn home-friendly should hydrogen-powered cars become common).
4. Reductive amination of phenyl acetone in the presence of methyl amine. This method, popularized by the Hells Angels cooks, produces a racemic crank product that has only half potency of the pseudoephedrine-derived meth. With advent of ephedrine/ pseudoephedrine –based method the old phenylacetone route fell into disuse. Variation of the reductive amination method is still commonly employed in the production of Ectasy.
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I grew up in a communist country and I remember the moment when the enormously popular codein headache pills became prescription-only (just as the enterprising chemists figured how to convert it into a fairly potent street version of hydrocodone). Meanwhile ephedrine remained plentiful, being manufactured in town Roztoky for the entire Eastern Bloc. The meth problem in Prague was getting serious – one bottle of cheap decongestant drops contained enough material to produce several doses of meth. But I never got close to the dope-related issues when I was growing up – I was reading books and articles about it once the censors allowed the information about such antisocial decadent problem to be revealed.
Soon after arriving in US, I was asked by the Maricopa County attorney office to volunteer for 20 hours of a community service (because of some very fast highway driving). I noticed that most of my fellow food bank coworkers happened to be paroled men serving out the rest of their sentences on drug-related convictions. To pass the time, sometimes they would make a coment about quality and availability of “stuff” one to another as we were unwrapping boxes of a cheap infant formula – but this had an unreal movie-like quality for me, soon I completed the service and left their parallel universe behind.
Only when I moved to the Bay Area I got face-to-face with the problem. My next-door neighbor in the checkered San Mateo neighborhood was a terminal-stage meth user. A former construction worker, he has lost his job and he was clearly unable to contain himself. He would alternate the dope with heavy drinking (probably to quell the clenched jaw and jittery edginess of the meth high). He was completely manic and very, very angry about injustices that happened to him – he would scream obscenities all alone and he carried long arguments all by himself in his apartment. Sometimes at night I would hear the screaming coming from outside – I would look out and there he was, running back and forth wearing only his shoes and undies – I guess he had a hyperthermia episode so he did some bare-chested shouting along the train-tracks next to our tenement. I remember he also brought a boyfriend over to his place once and they were having a vicious argument next morning and he stood there punching the other guy in the face, right there in the hallway as I was leaving for work. One night the police came over, broke through the window of his apartment and took him away. Unfortunately my neighbor soon posted bail and returned, mad as hell and convinced that I ratted him out (I sure complained to the landlord repeatedly but not to the police – in reality it was his failure to appear in court on a preceding possession charge that got him re-arrested that night). Yet he was sure that I was somehow responsible for his troubles, and he wrote “SNITCH ASSHOLE” on my car and he also threw some eggs at my door – at that point I did call the police and then promptly moved out; my meth-head neighbor was almost 7 feet tall and must have been quite muscular before his habit got better of him.
At that time (six years ago) there was plenty of folks with a growing meth problem in the Bay Area: The dope was cheap, provided a long-lasting high and acted as a great add-on for the active party lifestyle (with Viagra compensating for the most annoying side-effect). One could keep at it for quite some time and feel empowered by it, before washing off broken.
Note 1: The manufacture-related information discussed here is available to any unmotivated reader
Note 2: Pseudoephedrine has been phased out in OTC medications, ether is becoming permit-only, red phosphorus and iodine are flagged and so is hydroiodic acid, methyl amine, thionyl chloride, acetic anhydride, phenyl acetone and benzyl chloride. Home possession of hydrogenation equipment is illegal in US. The mandated sentences for meth production and conspiracy to manufacture are harsh; and the unauthorized possession of a sep funnel together with a tubing and aqueous HCl suffices as a proof of intent to manufacture in many jurisdictions.
Note 3: For sordid paranoia-rich bust stories, the reader is encouraged to look up what happened to Hobart Huson aka Strike and to Leonard Pickard + Clyde Apperson
So is Kinase Pro - Atompusher - Totally Synthetic- Heterocyclic Chemistry – Organometallic Current – Totally Medicinal – Jungfreundlich
Today I settled all family business.
Just don’t tell me you’re innocent.
Come on - you think I’d make my sister a widow? I’m Godfather to your son. Admit what you did.
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Credit: Robin Alciatore playing Beethoven Sonata No. 14 in C sharp minor Op. 27 No. 2 I. Adagio Sostenuto
Turns out Paulie Boy is stil alive. No way we can get to him now. Roth has played this one beautifully.
I got a C grade from the radiochemistry labs once and it troubled me a great deal: I wanted no C on my transcript. The overbearing fellow in charge of the labs was throwing tantrums because of some weakly-labeled sulfur spilled on my bench. (A soft emitter less active than plain KCl, I argued – but the bossman would have none of it)
And I fought hard and requested extra weeks in that basement lab: I would redo everything, on those noisy detectors.
Thus I earned the second C from the radiochemistry dude - proving his point that I was an exemplary failure.
I prayed for this man’s suffering. A swimming accident - fast comes the boat with two cruel propellers…
Now I see only a disappointed man, trying to discipline kids. The years in a basement lab with obsolete instruments
