Org Prep Daily

August 24, 2017

Breaking Bad in South Florida (5)

Filed under: Uncategorized — milkshake @ 6:45 pm

This is a work of fiction. Names, characters, businesses, places, events and incidents are either the products of the author’s imagination or used in a fictitious manner. If you find any resemblance to actual persons, living or dead, or actual events, deadly or lively, or actual molecules, carbons or heteroatoms, it is purely coincidental.

Part 5

(Here is Part 1, Part 2, Part 3, Part 4, Part 6)

Maybe I should make a little detour here and tell you about what our company was doing when not dabbling in the street drug manufacture – it is quite important to the story.

The main purpose of the company research was to formulate cancer chemotherapy agents into injectable therapeutic nanoparticles. We developed polymers composed of a random peptide sequence with lipophilic aminoacid residues and connected to a long polyethylene glycol chain. These polymers are bio-compatible and when dissolved in water they form pseudo-solutions composed of small fairly uniform micelle nanoparticles. They are acting like surfactant – with a greasy core and a halo of water-loving PEG chains projecting outside. When you have some lipophilic, poorly water-soluble drug that you want to formulate for intravenous infusion, you would dissolve it in organic solvent and add it to the micelles: the drug is going to partition itself into the micelle greasy core and after evaporating or dialyzing away the solvent you got an injectable formulation of a drug that is “solubilized” by being taken into the polymer nanoparticles.

Quite a few research groups developed this kind of system based on a polymeric excipient. A formulation like this is not stable and quickly unravels in the presence of plasma proteins. Our claim to fame and fortune was to include a metal-coordinating region in the polymer chain and finish the drug formulation by adding a small amount of Fe(III) salt: the added iron salt acted as crosslinker, it tied together the previously loose chains by metal atom coordination and we obtained stabilized micelles with the drug encapsulated inside. The nanoparticles could survive in the circulation and release their cargo gradually thus improving the drug residence time. The strength of used iron chelator is pH dependent and becomes weaker at lower pH and there is plenty of lactic acid in tumor sites. Tumors also have a voracious appetite for iron (with so many transferrin receptors on the surface of cancer cells) and their vasculature tends to be more leaky for the nanoparticles so there is an opportunity for improved delivery of a drug to the tumor sites with such iron-stabilized micelle drug formulation: The micelles make it to the tumor site, they preferentially fall apart there and the cancer cells get higher and more prolonged exposure to the chemo agent than they would get with a less elaborate formulation.

The controversial results with our technology came when I proposed and helped to develop an improved version of the polymer with stronger iron-binding properties. With the new polymers we saw the tumor mass discolored with iron that was part of the formulation, the tumor mass became visible on MRI and there were dense particles present in tumor cell vacuoles visible on electron microscopy. The company claimed that we can now observe the stabilized nanoparticles as they were making their way inside the tumor cells and releasing their drug cargo inside the cell.

There were few problems with this claim: 1. We had no proof that the high-contrast particles seen on EM and MRI were the original nanoparticles making their way inside the cell. A more likely explanation would be that cancer cells gorge on iron present in the formulation and they can protect themselves from the overload by stashing away the excess iron in vacuoles in a form of iron oxide particles that are highly visible and ferromagnetic. We did not try to look closely enough to be able to distinguish what were these particles. 2. There was no direct proof that our nanoparticles could survive their journey in the bloodstream and make it to the tumor site in one piece, as claimed by the company. We also couldn’t tell a micelle loaded with a drug from a micelle where the drug had already leaked out while it circulates in the bloodstream, and again we did not try to look very hard. 3. In fact, we had no way of distinguishing the free drug in circulation from the drug still loaded in the nanoparticle since any method used to analyze blood samples invariably destroyed the nanoparticles. You would “observe” a better drug residency times that way if you are combining together the concentration of free drug plus drug resting inside the nanoparticles and you cannot tell them apart.

I did not pay much attention to the biology, formulation or PK data analysis initially – I was interested mostly in making the polymers in high quality, trying to fix the numerous manufacturing problems. I hoped that after ten years in business the research director knew what he was doing. (He did: his plan was to sell the company at the first opportunity to the unsuspecting buyers.) But my biologist friend convinced me to look closer at the presented data and the story about the technology that our management was making and I noticed there was quite a bit of hand-waving that connected a perfectly sound research on how the drug was formulated with the results we were getting from the test animals implanted with xenografts and then treated with our formulations. We were blind as to the fate of the loaded micelles and their exact release mechanism, and the management probably should not have been making some of the claims in the absence of hard direct evidence.

My biologist friend was with the company for over 8 years, and he was clearly the most driven and most creative biologist we had, and the most skeptic one too. He would always run the controls on his controls, to make sure he wasn’t fooling himself – he came to believe that the entire subfield of therapeutic nanoparticles is polluted by sloppy science and irreproducible results. He blamed not only the difficulty of analyzing the nanoparticles in vivo but said it also originated from the wishful thinking, the socio-economics of postdoc academic labor and the relentless grantsmanship getting in the way of doing good science. He thought too many research groups were cherry-picking data to support their favorite notion without really asking the hard questions and this was the main reason why the nanoparticle field stagnated and so few approved drugs came out of it.

This biologist was always working on the periphery, on a sort of “woulnd’t it be nice also” kind of side-projects that were underfunded and received little chemistry support at our company. I was puzzled why the management did not have him on the clinical candidate formulation instead, with all his inventiveness and drive. The research director’s explained to me that my friend was “not a teamplayer”.

One of the side-projects that this biologist was doing was targeting: the idea of decorating the nanoparticle surface with ligands binding to receptors present on the surface of cancer cells. As our micelle was quite elaborate, fragile and not easy to follow in vivo, he developed a stand-in for a micelle, a toy model, a form of PEG-coated quantum dots of a similar size that can be easily studied in vivo because they are stable and highly fluorescent (you can even follow them in the circulation within a live animal if you use near-IR emitting Qdots.) He worked out all kinds of interesting details about the targeting problem and wanted to publish it. He also convinced himself that the micelle story the company was pushing was cartoonish and that the nanoparticles should not get inside the tumor cell if they looked anything like what the company was claiming.

When his targeting research project got cancelled in the summer of 2015 and my friend was finally put to work on the formulation with which we were going into clinic, he used some of his new analysis techniques and quantum dot-derived insights to have a more detailed look at our micelles. What he found was not encouraging: The drug was leaking from the “stabilized” micelle quite readily (on the timescale of minutes) once injected into a mouse, and the micelle itself was aggregating with blood plasma proteins. His work with cell cultures also supported a conclusion that the drug leaked from the micelles first and only then got inside the tumor cell, and not as a part of the intact nanoparticle. He did a FRET pair study with our nanoparticles – again, the leak out was rapid in undiluted plasma.

When my biology friend presented his data, there was a great deal of consternation among the chemists. The data indicated that there might be serious trouble ahead with our clinical candidate, and maybe even with the entire technology platform… In the meeting room after he finished we immediately started discussing fluorescent probes that would help us to clarify whether the problem was real and if it was, whether it was manageable with what we had, and if it was conceivable that the leakage problem was specific to the particular drug with which we were going into clinic (the drug did have a hydrolytic stability issue, the hydrolyzed ring-opened form was more polar and already known to leak out of the nanoparticles). Our research director cut the discussion short with saying that he was not surprised and that he suspected as much based on the animal data, and that he will carefully consider what will be the next step.

This was on Friday noon. Our research director then set up one-on-one lunch meeting with our biologist for the next Monday. This lunch meeting did not happen because our biologist found himself downsized already by 9:30 am that Monday morning. He received two months of severance for his eight years with the company – and he just had a newborn son and his ailing wife was at home with the kid. The research director also told him that his study the on quantum dot targeting wasn’t going to be published even though the company wasn’t interested in it anymore.

This happened to him after our management had been pooping on his work for years already and cancelling his projects every time he got some promising results, and now they were firing him for the work they asked him to do, in order to suppress his data. And he recently had to endure more than eighteen months of having our CEO for a neighbour – the CEO was using a lab located right behind his office desk, stinking up the place and cooking drugs like a maniac. The biologist wasn’t really given any other choice but to go after the company.


August 23, 2017

Breaking Bad in South Florida (4)

Filed under: Uncategorized — milkshake @ 6:28 pm

This is a work of fiction. Names, characters, businesses, places, events and incidents are either the products of the author’s imagination or used in a fictitious manner. If you find any resemblance to actual persons, living or dead, or actual events, deadly or lively, or actual molecules, carbons or heteroatoms, it is purely coincidental.

Part 4

(Here is Part 1, Part 2, Part 3 Part 5)

It is pretty certain that our CEO did manufacture some ecstasy before the fire in February 2014. Even as he was deleting his NMR files, he was careless with the temp files stored in the console and he occasionally also left his NMR sample tube in the magnet. My cranky senior chemistry colleague told me that he saw his spectra and that he even re-run NMRs on some of the samples he found after the CEO. Clearly, there was MDMA even if the purity wasn’t great, maybe 80-85%. We could only speculate how much the CEO managed to produce – but couple months before he was into the final stage already, with methylamine and Al foil reductive aminaton, and he was doing the preceding Wacker oxidation step with oxygen gas. (The research director bought an oxygen tank and regulator for our CEO so they weren’t using benzoquinone anymore.)

My own guess is that the duo – our CEO with the technician – probably wasted most of the precursor, the one kilo of methylenedioxy benzene that the CEO bought the summer before (and had to retrieve from the DEA), and they needed more. But even with all their bumbling attempts they would have produced at least something useful from it, to get our technician excited enough to try ordering the precursor through the university purchasing system. It is only my speculation. Either way, the university confiscated the new bottles and our CEO wasn’t going to buy the stuff again, not after these two very near busts.

When he moved back to his lab after the fire, for a while he was spending less time there, his previously feverish MDMA work slacked probably due to lack of starting material. He also had some problems with his back injury so running long experiments wasn’t easy for him physically. But he was still working in the lab and continued to be interested in drugs: One day I noticed two new unopened bottles from TCI – we rarely used this chemical supplier but our CEO somehow felt it was easier to order from them since they did not ask too many questions. (At least that is what he told to our technician who shared this great insight with my old cranky chemist colleague.) The new bottles contained m-methoxy phenylacetonitrile and bis(2-chlorethyl)methylamine hydrochloride, aka nitrogen mustard mechlorethamin.

I recognized that this stuff was a material intended for making ketobemidone or some other similar pethidine opioid analog. I went to the CEO and explained what could happen if he spilled even a tip of spatula of that water-soluble nitrogen mustard blister agent around the balances and left it there without cleaning up the spill – I asked him to never bring that shit into our main chemistry lab. And he did not; it stayed unopened until we departed from the company.

The next thing I remember, our CEO ordered materials for making synthetic tropane alkaloids, namely cocaine, and left it in shared storage cabinets in his lab. He got a big bottle of acetonedicarboxylic acid, and also 2,5-dimethoxytetrahydrofurane. But only the bottle of acetonedicarboxylic acid was opened: my senior chemistry colleague later told me that our CEO was fruitlessly trying to make monomethyl ester of acetonedicarboxylic acid and he did not manage to avoid its decarboxylation during workup and so he wasn’t getting anywhere. But he was still trying, more than half year after the very near bust by the police. At this point I just walked to our research director and gave him an ultimatum – I was leaving for Germany, to oversee a technology transfer to our GMP manufacturing partner and when I am back I want this private project to be over, clean and gone.

And it worked – I came back from the trip and the clandestine drug work had already ended. But just before my departure to Freiburg, the CEO came to me and said in a hurt voice that he was always my biggest supporter at the company and that I should think twice before crossing him… (Even after the two near busts, the ass-covering research director had to tell the CEO that it was me who was now forcing him to stop.) And so, by the end of November of 2014 the drug making at our little company finally came to close. Only the coverups and screwups kept piling on.

I have good memories of the first half of 2015. The clinical candidate we bought with the small virtual biotech had atrocious manufacturing problems but I did manage to come up with a reasonably scaleup-friendly alternative route and the management loved it. I was also scaling up intermediates for another clinical candidate project and was told that soon we should have money to do a GMP campaign and go to clinic.

Then all of sudden without warning, the management fired my friend – the best biologist at the company – and they did it because they disliked data he produced. His results flew in the face of the simplistic descriptions of our technology as advertised to the prospective investors and buyers, and the management wanted to suppress the findings. On Friday morning meeting, he presented his unfavorable data about our clinical candidate and by the next Monday morning he was already made redundant.

I don’t know if our management considered the one minor problem when firing the biologist and censoring his study: that his office and biology lab space was adjoining the satellite lab where our CEO was cooking drugs; my friend had a front-row view of what went on in there. He was going to use it now against the company. And his wife was a lawyer – before the maternity leave she used to be a partner at a major law firm suing insurance fraudsters on behalf of the insurance companies. It was gonna be awesome.




August 22, 2017

Breaking Bad in South Florida (3)

Filed under: Uncategorized — milkshake @ 4:47 am

This is a work of fiction. Names, characters, businesses, places, events and incidents are either the products of the author’s imagination or used in a fictitious manner. If you find any resemblance to actual persons, living or dead, or actual events, deadly or lively, or actual molecules, carbons or heteroatoms, it is purely coincidental.

Part 3

(here is the Part 1 Part 2, Part 4)

By the summer of 2013, our CEO switched to making methylenedioxybenzene (1,3-benzodioxole) by alkylating catechol with dichloromethane in DMSO. He was failing every time – the air oxidation of catechol in the presence of base at high temperatures proved challenging for his techniques. (I had to keep re-buying expensive 4L bottles of DMSO for my project that he was taking from our lab and consuming at the rate about one bottle per experiment… The CEO asked me why DMF did not work when he tried it to replace DMSO; he did not know DMF is unstable at reflux and even more so in the presence of K2CO3.) So I still had some reasons to hope that he would give up.

But our CEO grew tired of his attempts to prepare methylenedioxybenzene for his private MDMA project and he decided to buy the stuff from TCI. It alarmed me to see two half-liter bottles of methylenedioxybenzene suddenly in his lab – I informed my chemistry colleagues who freaked out too. This already got too far along the synthetic route to MDMA, and there was a chance he would manage to finish, maybe throw an Ecstasy-tasting party at his home, with the guests ending up in hospital. The purchase of a flagged precursor was a loud shout to the law enforcement to come and visit our company…

Little did we know that our CEO ordered these bottles of methylenedioxybenzene for delivery to his parents house, DEA intercepted the delivery and invited him to their Tactical Diversion Squad at the District Office, to kindly explain why he needed it. Our CEO put on his best act for the DEA agents (to this day, they are still pretty sore about it), describing them in detail his revolutionary drill bit boron doping hardening technology essential to his father’s business. Then he collected his confiscated kilo of precursor, brought it to our company and proceeded to brominate it.


He was getting close. Worse still, the expected management change – the IPO or takeover – wasn’t going to happen. Instead, it was our company that acquired another even smaller and more troubled virtual biotech that went belly up, apparently for their phase 1 clinical candidate completely unrelated to our company technology, in some kind of a complicated share exchange+debt deal, and our management stayed on to run the joint company. (I later learned that the people who brokered this deal and collected their finders fee actually helped to fleece us, by hiding serious problems. Our top management missed important things when performing the due diligence. But that’s another story.)

What really alarmed me was that our CEO bypassed the last remaining unpleasant step he struggled with, by obtaining a red-flagged precursor. The CEO also recruited the student technician working for my senior chemistry colleague, to help him watch over his reactions while the merger-related issues kept him away from the lab. And the technician was anything but a normal person: He was an Adderall-addled emo kid, a bullshitter and kiss-ass. He was also very interested in making drugs. (He never learned to read structural formulas but he loved to rant about random stuff like isoelectric point to impress girls). Now that it became management-sanctioned project run by our CEO, he was more than happy to help watching over distillations and with cutting aluminum foil for the amalgamated Al reductions. (Due to his obsessive behavior when on amphetamine, he was apparently very good at cutting Reynolds foil: in one sitting he could make drawers full of Al foil strips).

This was enough – how many times did I tell this dude not to involve himself in the clandestine project. I’d explain him what it was about – ten year sentences, snitching and paranoia – but he couldn’t resist the glamor of being Heisenberg, and he also hoped to earn extra cash from it. I went to my senior chemistry colleague to complain he should watch over what his technician guy has been doing for the CEO in the satellite lab. Unfortunately my cranky senior colleague really liked his technician, he took this as affront, went to the research director and told him I was oppressing his poor guy, and it was me who got berated and told to stay away. (It even ended up in my performance review)

By the end of year the enthusiasm of our technician somewhat faded, he hoped for loads of money for his extra foil-cutting work but was pretty disappointed when he got only a 1000 USD Christmas bonus check. He grumbled, “that he could go and tell things.” But he must have reconsidered since by February 2014 he was already back and ordering methylenedioxybenzene precursors himself, apparently through the university ordering system, and using his student ID – as if somehow that made the purchase less conspicuous. At which point the university police came looking for him – to interview him about the drug precursor. But they did not catch him because he just left due to family emergency: his father supposedly suffered a heart attack (although now I somewhat doubt it) and while he was away with his family, he received a message from the company and from the university to keep his mouth shut and never ever come back. (He later tried to blackmail the company by approaching the other two co-founders that were no longer with the company but they were not interested in his story, and the company management quickly put an end to it).

So this was already the second time we came very, very close to being busted, the university and the company management covered it up, not for the last time, and we did not learn about it until much later.


Just right at the same time, we also had a big fire in the main lab.

I used to believe it was an accident but now I see the timing as pretty suspicious. Apart from very nearly destroying the main lab (we had tanks with ethylene oxide, hundreds of liters of ether, heptane, THF etc, many gas tanks) the fire made it possible for our management to remove the precursors in the satellite lab in hurry. The flooding from sprinklers put the computers in the office out of commission – it erased the chemical inventory database and the ordering system was unavailable.

The drug investigation was done by the campus police in conjunction with the Department of research integrity and compliance presided over by the wife of our research director (he married the university vice-president). And the conclusion of the official inquiry was that a junior junkie student misused the satellite lab of our little company without the management knowledge. Perhaps he was ordering sketchy chemicals and making who-knows-what in the dead of the night but neither the company nor the university wanted to press the charges in order to avoid bad press.

And the fire itself was declared a poor housekeeping issue, not a safety violation. The university signed on this, our management vehemently lied to the police and all was good again.

We did not know about the circumstances of unhappy departure of our young student technician. We were instructed never to contact him so we figured that our student technician left on bad terms but the drug precursor investigation was kept from us, we were sent home immediately after the fire for the entire week while the flood and hazmat-related problems were handled. Apparently the drug investigation was done at the same time…

The week after we were already very busy: The fire disaster almost wiped us out, the official story was that an unsecured big beaker filled with ether placed into a common household fridge saturated the fridge with vapors and it exploded in the early morning hours when no-one was around. A big explosion that shook the building and pushed the drywalls by few inches, the door from the fridge flew across the the entire lab, bounced from the cement floor, narrowly missed our NMR magnet and broke the hurricane-proof window. Kilo bottles of diphosgene and butyllithium strewn across the room and got charred from fire (fortunately our 3kg inventory of diphosgene did not break), flood and soot was everywhere.

I have somewhat perversely happy memories of the fire aftermath. We were without a functioning lab for almost a month but the destroyed benches and fridge and cabinets got replaced at a record speed. It was an unpleasant work – every piece of glassware was soot covered (the main fire and smoke source were the safety blast shields stacked on top of the fridge that exploded – the shields were blast-proof but highly flammable), every single item had to be cleaned and moved to storage and then brought back – but I was impressed by the newfound friendliness and sense of solidarity among my colleagues and by the energetic actions of our management. Everyone was working hard to get the office and labs up and running. Our clothes were perhaps blackened with soot and the floor was still wet but it was harmonious time. Incidentally, the technician was gone & not missed, and the CEO drug lab was now used for temporary storage of all the stuff from the main lab while it was rebuilt and refurbished, so no more MDMA for the duration.

At the end of March 2014 we went happily back to our rebuilt lab, with a gleaming new oversized bench that gave us so much space for the instruments, and wider corridors that made the deliveries and rolling dewars of liquid nitrogen much easier. And our CEO returned back to his lab, now emptied of the stored things, and he started cooking again.


Breaking Bad In South Florida (2)

Filed under: Uncategorized — milkshake @ 1:02 am

This is a work of fiction. Names, characters, businesses, places, events and incidents are either the products of the author’s imagination or used in a fictitious manner. If you find any resemblance to actual persons, living or dead, or actual events, deadly or lively, or actual molecules, carbons or heteroatoms, it is purely coincidental.

Part 2

(Part1Part 3)

I repeatedly tried to intervene with our CEO, to talk him out of his MDMA scaleup project. At first, he promised that he would wrap it up soon and stop – but he didn’t. The next attempt at conversation, he would ya-ya-ya me, and the third time he just told me to buzz off and mind my own project. When I appealed to him that he was drawing attention and there were many rumors within our little company, his reaction was “the people who spread the rumors should really watch out”. Clearly, this wasn’t the door to push.

I also tried our research director, I would go and start by saying that there are problems with the stuff the CEO is doing, he stinks up the lab with methylamine all the time so people in the adjoining office are complaining and it is unpleasant to walk into that lab and look for the chemicals stored there… The research director interrupted me and said he would handle it himself. (I think he put a better waste container there for the CEO). Next, I brought up a large expensive piece of equipment that our CEO crushed by stuffing his flasks into my base bath – so I got instruction to set up a new base bath for the use of our CEO, the ruined custom piece went back to Chemglass for repairs and everyone carried on just as before. When our research director questioned why I am ordering so many large flasks, pumps, mechanical stirrers and other equipment, I explained that our CEO was taking them from our lab to his, trashing many of them so we had to replace – and this reliably silenced the otherwise stingy manager, he asked no more and had the stuff ordered…

My conclusion – and not only mine – was that the research director knew enough that he did not want to know more, quite aware whom he owed his #2 position at the biotech company, complete with oversized paycheck (triple of our average scientist salary) and all the prestige that goes with it. I think he became fond of his big house with a big indoor pool, flying first class everywhere, driving brand new Mercedes SUV and Lexus, ordering exotic scotch and vintage wines by the case (with company as the receiving address, it often arrived to our lab and sat there on a pile of boxes with the lab solvents and glassware). The research director was in his late thirties, a similar age as our CEO, and about to become very rich if the sale or IPO of the company came through. He wasn’t going to screw it up. And even if he was waiting for someone to come to him with a proof of illegality to stop our CEO, I was pretty sure he would go and sacrifice that poor schmuck to shield himself. (Tomas says you are cooking ecstasy – is that really true?)

I thought up a little ruse: The hood space in our labs was limited; all it would take was to fill the hood in the satellite lab. We could definitely use another chemist since we had more projects than people and I knew an excellent Swiss-American chemist who needed a job. So I talked to my chemistry colleagues, and to the research director and got his approval. All were impressed with the job candidate resume (a Pfizer and Scripps jobs, he worked for prof. Seebach at ETH) and I think they immediately caught on the real reason why I was doing this. They asked me to meet the candidate and set up his job interview. So I went to lunch with the guy, to find out when he could come to interview. Then I received a message that we needed to save money and the interview was to be postponed by few months. (When I tried again few months later, after yet another meeting with the job candidate, I was told the interview is cancelled outright because our CEO does not approve. They were jerking us around.)

Here I should probably explain why I did not run away from this company, with all the shenanigans and deceit around. I thought we were doing an excellent research and just our CEO got off the rails, and we could be a happy little company again – if only there was some way to make him stop or make him leave. The projects that I was working on were interesting and rewarding: not exactly high-level chemistry but the execution had to be immaculate. (10L Schlenk-like reactors with insane level of exclusion of moisture and oxygen). I learned new techniques used by organometallic chemists, and even devised some of my own that allowed us to accomplish this in a humid Florida summer without a glovebox. There were practical problems to solve on kilo scale, and once you found the right reaction conditions it was satisfying to see the progress. We basically inherited a technology that was in stage of a concept when I came aboard and it had so many difficult problems that the practical implementation was impossible but we fixed it and our new improved versions seemed so practical, the material quality was pristine and I had great enthusiasm about the company future… By the time this unfolded I already made key improvements to almost every aspect of our chemistry methodology, the managers kept flattering me how tremendous were my contributions, etc. It was the kind of process development projects I always wanted to do. And we had pretty good working conditions for a small company – while they did skimp on the office area the lab space and equipment was first rate. It was a great place to work until it wasn’t.


By the summer of 2013 the situation settled into new abnormal. Our CEO was puttering away in his lab trying to figure out the best way to cook MDMA. Meanwhile, the chemistry colleagues did not keep this secret – just as I hoped they couldn’t: my Canadian roommate-colleague and the student technician went drinking with biologists one evening and it took about two shots for them to start unloading. Other biology colleagues, long suffering in office next to our smelly CEO lab soon learned what went on there and came to me to ask for explanation. I mean, when you have a bare-chested CEO sprinting across the parking lot in his undies, people do take a notice. (The CEO had a large-scale reaction runaway, a splash of very irritant material on him and all over the wall. Since there was no safety shower he thought he would undress and run to his car and drive home. The reaction mix turned black on air so there was a light silhouette of him left on the darkening splashed wall that had to be re-pained. The unfortunate vacuum pumps nearby remained black for good).

It had unreal sitcom-like quality: while everyone in the company including the intern in the formulation lab was cracking the Walter White jokes, our CEO heroically pushed on. It is now clear that as far as our CEO was concerned, this was his company, he kept giving it cash injections from his family fortune so he did not think twice before turning it into his private chemistry club. In fact, the company existed as a vanity project and the cancer research we were doing was a vehicle for him, to be a biotech CEO and co-founder right out of the grad school, and to impress his older siblings and cousins. The promised success was taking too long to arrive and after 10 years he was getting bored, his failing attempts to sell the company or bring it public probably did not help his self-image. So he needed to become a badass chemist too, to impress himself and perhaps someone else too with his product…

For a short time, it looked like our CEO was finally about to change his project – he asked me about LAH workup, a reaction step that wasn’t on the MDMA route. Soon I found my missing bottle of oxalyl chloride in his hood next to a half kilo of indole and a big bottle of dimethylamine solution – so now he was also making tryptamine hallucinogens… Apparently our CEO was not pleased with the DMT chemistry very much, I remember him bringing a thick brown ooze, his crude product, to our lab to take the NMR, the stuff was giving off a revolting indolic smell. I think he stopped working on DMT because the material turned out too air and light sensitive for his mad skillz and he did not manage to purify it. It also smelled like a fossilized colostomy bag – it lingered on clothes.

After the DMT interlude, the next thing our CEO came up with was an alternative route to safrole and MDMA, starting from catechol. He bought a 5 kilo tub of catechol, 3 kilos of Mg turnings, NBS and bromine we already had kilos from an old project, and a 2.5 liter flask of allyl bromide. It looked like his updated plan was to turn 4-bromo-methylenedioxybenzene into Grignard, alkylate it with allyl bromide and use the produced safrole in the established MDMA route from Rhodium archive. He gathered precursors sufficient to produce kilos of MDMA. And it was a realistic plan.



August 21, 2017

Breaking Bad in South Florida (1)

Filed under: Uncategorized — milkshake @ 2:02 am

This is a work of fiction. Names, characters, businesses, places, events and incidents are either the products of the author’s imagination or used in a fictitious manner. If you find any resemblance to actual persons, living or dead, or actual events, deadly or lively, or actual molecules, carbons or heteroatoms, it is purely coincidental.

Part 1

(Here is Part 2, Part 3, Part 4, Part 5 , Part 6, Part 7 Part 8, Part 9, Part 10, Aftermath)

One day in January 2013, the CEO moved to our synthetic lab and started cooking Ecstasy.

The CEO told us he was pursuing a project unrelated to our company research – he said it was something for the business of his father (they lacked synthetic labs), a method of hardening finished steel drill bits by doping them with boron using volatile catechol-boronate complexes, a great trade secret that he invented himself and did not wish to discuss with anyone. The cover story was odd but our young CEO had a PhD in polymer chemistry and a tough guy attitude, dropping F-bombs at every opportunity, and it was his company – he was both the co-founder and a major shareholder. What puzzled me though was that he was setting up large-scale reactions, 2-liter flasks and more, and recrystallizing half kilo of p-benzoquinone in an oversized beaker. Benzoquinone has a strong, unusual odor and bright canary yellow color. The CEO asked me about the dark impurity in benzoquinone he was trying to remove (most likely quinhydrone.)

That he needed benzoquinone was curious; one can perform Diels-Alder with it, although most commonly it is used as oxidant in palladium-catalyzed alkene reactions, Wacker oxidation for example. Our CEO was running also reductions with amalgamated aluminum foil all the time – an obsolete method of reductive amination that is still popular with garage chemists. I did not make that connection initially and registered just the nuisance – our CEO was inept experimenter and inconsiderate one too, not used to cleaning after himself. He would stuff large flasks still dripping from oil bath into a 100L base bath which I used for cleaning our Schlenkware reactors dedicated to ultra-sensitive anionic polymerizations, and in there the aluminum leftovers curdled in contact with KOH + phosphate + detergent bath to form cement-like aluminum phosphate chunks that were hard to dislodge from the glassware and just few attempts of cleaning this mercury-contaminated crap with nitric acid convinced me to give up on washing his dishes. No-one else volunteered either.

Seeing the tension among the chemists, our research director arranged for refurbishing and equipping a satellite synthetic lab that we previously used only for storage, to serve our CEO private project. We went shopping to Lowe’s to get a storage cabinet and argon pipe fittings for the satellite lab and I noticed our research director wasn’t enthusiastic about the new lab at all – he was buying the cheapest plastic cabinet and shelving which really contrasted with his usual servile attitude towards anything CEO-related. I was curious but he did not want to talk about the “secret” project and said it was nobody’s business.

Soon our CEO moved his experiments to his own little lab but he was coming back to the main lab all the time, to run rotovaps and NMRs, to re-stock on the glassware he was trashing at a prodigious rate, and all the while asking innocent questions like “how can we best cleave off a methyl group from aryl methyl ether?” without explaining what he was trying to do. I replied it depends mostly on what is in the molecule since all known methods are harsh and incompatible with many functional groups. He wanted something like BBr3 or BCl3 but milder so I recommended him demethylation with AlCl3-Me3N.HCl 2:1 liquid complex. He promptly purchased the materials, made the complex and stored it in our fridge, then took it to his lab. A week later I asked him – how did it work? And the answer was vague. So I asked him what was in the rest of the molecule, that maybe it would explain the problem. He said he has been trying to demethylate eugenol. There was a little pause, a sharp intake of air, and then I asked him if he run Wacker oxidation on eugenol. And he said why, yes, and it worked! He was obviously pleased with himself so much. I asked him about the amalgamated aluminum – he nodded, yes, he tested the reductive amination, with methylamine and aluminum foil, it worked great too…

And so it finally became clear, mid March 2013, that our CEO was trying to develop a process for manufacturing MDMA from eugenol and that is why he obtained three 250mL bottles of it. MDMA is made from safrole, the shortest sequence is Wacker oxidation followed by reductive amination of the obtained ketone with methylamine. Safrole is a closely-watched precursor and our CEO was apparently using eugenol as a training material while he was dreaming about developing a method for converting eugenol to safrole. He was an inexperienced chemist and deluded one too so he did not realize that his imagined transformation of eugenol to safrole wasn’t trivial… At this point I just excused myself, walked back to our main chemistry lab and informed my labmate colleague, a cranky old hand, that our CEO went completely mad and aspired to run a street drug manufacturing operation from our biotech company.

That our company was now in the business of doing process development on MDMA, a category 1 controlled substance (for which we did not have the permits) and this was being done covertly by our CEO with his own hands came as rude shock to everyone in the chemistry lab. If somebody else tried to pull this stunt, we would be talking to the company management that very minute and have him arrested. But in this case, the whole two-man top management team of our little company was involved in it. The CEO was the co-founder and the main investor in the company and clearly the normal rules did not apply to him. The research director was the second co-founder, a former student-buddy of our CEO and he was always extremely protective of him and loyal to the hilt. It was the research director who convinced our CEO to start the company to begin with, right from the grad school. (They had two other classmates founding the company with them but when the relations soured the CEO paid the other two co-founders off.)

Our research director personally approved all company purchases of equipment and chemicals, and now he just set up a drug lab for our CEO. He also handled the HR agenda like hiring and firing. And he recently married a vice-president for research integrity and compliance at the university on which campus we rented the lab space in the research incubator building. We got to be careful.

Obviously we could have quit or reported this to the police or DEA and have the company raided. Or report it to the university anonymously. The problem with anonymous report is that it is hard to predict the outcome – It could still result in the police raid. It could be suppressed while the management gets a copy; pretty easy to determine who wrote it – and then it would be us, suppressed. More so, the wife of our research director was #3 or #4 official at a prominent university with enormous political clout, any complaint would be handled through the department she chaired. Every move looked bad for our future employability and the retaliation and cover up by the management was a very real possibility. We lived to see the massive coverup that followed, eleven months later.

What we decided back in the Spring 2013 was that first we should try to discourage the drug project continuation without doing anything drastic, and find out more about what was going on. It was clear at the moment the synthetic route our CEO has chosen was not realistic, and it won’t be necessary to sneak into his lab and pour tomato soup into his experiments – our CEO skill level was such that he would self-sabotage, and obviously we shouldn’t give him any help. (An average process chemist could optimize the route to MDMA and get the reproducibility fully tested on a hundred gram scale perhaps within three to six weeks, if he took it as a full time job and had the suitable precursors. But our CEO kept doing rookie mistakes in the lab and working only part time on a scheme that was poorly thought-out so there was still time, maybe couple months before he can get to the final product with his pace). If it was just his caprice after watching too many episodes of Breaking Bad, maybe he would tire of it and move to something else, to use his time in a more productive way –  for example, try to find more investors so that we can finally go to clinical trials with our cancer drug candidate.

Also, there was a good chance the company would soon operate under new management. At that time, our CEO and research director kept excitedly talking how they were in advanced talks with such and such investor group that would come and take over the company. They were also describing on the all hands meetings how they were right now going to take the company public by reverse merger into a shell company and got this big bank underwriting it…

(At the beginning I took all this talk about acquisitions and IPO seriously but the names kept changing and dates shifting. There were several waves of this excitement and nothing came through. The research director later told me they had been in talks with maybe couple dozens of companies, banks and big investors – they all pulled out at the last minute. I guess the due diligence can be a bitch.)

The senior chemistry colleague and I decided to warn a student technician in our lab (he freaked out but continued working for our company) – and I also talked to our Canadian chemistry colleague who joined us a short time later. And we would get more information and decide how to handle it quietly.

The reaction of the Canadian chemist was also interesting. He became very angry with me as I was explaining him the safrole chemistry on his second day in US (we just became roommates by renting a house together) – he finished a postdoc, he moved from Canada to US to be with his fiancé, he had trouble finding a decent job in a typical two body problem – and now this. He said he did not sign for this crap, yelled at me for getting him into trouble by telling him about it, he worried about his visa and his employability in US should this become a public scandal. But he soon came around and found humor in the insanity of our predicament.


March 5, 2016


Filed under: industry life — milkshake @ 5:35 pm


There is a darkly funny story behind this post

I guess you have seen this one before: “Experienced MS level chemist with a track record of research accomplishment is looking for a process development or biopolymer chemistry or medicinal chemistry position in the industry…”

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