Org Prep Daily

August 23, 2017

Breaking Bad in South Florida (4)

Filed under: procedures — 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)

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.

 

USF4

 

June 10, 2015

The power of blunder – based optimization

Filed under: industry life, procedures — milkshake @ 8:46 pm

I have been trying to optimize a difficult reaction; I thought a presence of zinc chloride might help so I gave this a try and there was an improvement: The results were getting better, week after week.

Some time later – by now with improved product purity and filtrability – I begun to wonder if the zinc chloride effect was real, or maybe something else was going on, so I finally got around to run a control. And sure enough, the reaction worked even better without zinc chloride. So, after many tries with quantities of reagents and additives, I arrived at optimized procedure which looked almost exactly like the one that I started with, except few minor details – the little changes that were incidentally co-introduced because of the ZnCl2 addition – few small changes that make a difference… I would have never tried these changes without it. And I would have given up if I had run the control experiments earlier and found out it does nothing.

It is delightful to read methodology papers, the observations and explanations arranged neatly, flowing like a good detective story, with a chain of clear logical reasoning based on the experimental evidence. But I suspect it is mostly fictional (There is no good place in a process paper to explain that after very slow reagent addition because of a clogged valve that no-one cared to inspect before the pilot run, the impurity profile improved and the troublesome sideproduct from the second step no longer buggers up the recrystallization). I worry that reading published accounts of process research can give the management a very unrealistic impression what a normal project should look like.

May 22, 2014

A kilo-scale hydrogenation reactor?

Filed under: procedures — milkshake @ 8:22 pm

I have been running some hydrogenations of our polymers on kilo scale, at atmospheric pressure under balloons, and it is a bit of a chore. It would be nice to have something akin to a beer keg-sized Parr shaker and run the hydrogenation under few bars of H2, to reduce the catalyst loading and shorten the reaction time.

I wanted to ask the readers from process groups if they worked with a low-pressure batch stirred hydrogenation reactor that they liked and could recommend – for us to buy. Specifically,  we would need a hydrogenator that can accommodate 8-10 liters of a reaction mixture that has tendency to initially foam under reduced pressure (this means that the total available volume should be about 15-20 liters). Maximum operating pressure 3 bar would be enough, no heating or cooling is required and the typical solvent is water. I am not really interested in flow hydrogenation systems because they would be unsuitable to our particular case. A glass vessel or at least a glass window on the top would be nice to have, because of the foaming problem during evacuation.  Thank you for your suggestions!

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September 24, 2013

O-selective acetylation of tyrosine

Filed under: procedures — milkshake @ 7:30 pm

1. HTyr(Ac)OH.MsOH:

Methanesulfonic acid 80mL (1.2 mol) solution in acetic acid 0.5L was added to L-tyrosine 181.2g (1.0 mol, Aldrich 97%+) in a 5L 29/42 joint flask and the mixture was stirred vigorously without cooling until complete tyrosine dissolution (about 2 hours). The flask was placed in +10C water bath and the mixture was stirred till the internal temperature was about 15C. Neat acetanhydride 105mL (1.1 mol) was added dropwise over a 30 min period with a vigorous stirring and cooling on cold water bath, then continued at 15-20C for additional 90 min, at which time a voluminous precipitate solidified the reaction mixture. Peroxide-free THF 1L was added to the crystalline mass, the mixture was mashed up with a large spatula to break the lumps and then stirred vigorously for 20 min. The precipitate was collected by filtration, washed thoroughly with THF, the product was dried by suction under N2 blanket and then in vacuo until only a faint smell of AcOH remained with the product (10 Torr, 1 day). Y=259.8g of white solid (84% th)
1H(d6-DMSO, 400MHz): 8.28(br s, 3H), 7.29(app d, 8.6Hz, 2H), 7.10(app d, 8.6Hz, 2H), 4.20(br t, 6.4Hz, 1H), 3.10(br d, 6.4Hz, 2H), 2.33(s, 3H), 2.26(s, 3H)

2. HTyr(Ac)OH:

The O-acetyl tyrosine mesylate salt from the first step was dissolved in D.I. water 0.5L in a 4L large beaker, a solution of triethylamine 118mL (0.84 mol; 1 eq.) in ethanol 0.5L was added rapidly with stirring, the crystallized mixture was combined with additional ethanol 1L and agitated with a large spatula, then stirred for 30 min and finally placed into a refrigerator (+ 4C) overnight. The precipitated product was collected by filtration, rinsed thoroughly with chilled 200-proof ethanol (0.5L, +4C) and then with few small portions of ambient ethanol (4x20mL), dried by suction under N2 blanket and then thoroughly dried in vacuo. Y=168.4g (79.5% overall) of a white fluffy solid.
1H(D2O 0.7mL/10mg, 400MHz): 7.36(app d, 8.4Hz, 2H), 7.14(app d, 8.4Hz, 2H), 4.79(s, 3H; HOD), 3.98(dd, 8.0Hz, 5.5Hz, 1H), 3.29(dd-ABX, 14.7Hz, 5.3Hz, 1H), 3.14(dd-ABX, 14.7Hz, 7.8Hz, 1H), 2.34(s, 3H)

Note:  Effective stirring and cooling during the Ac2O addition is important for achieving good results. Using a cheap grade of tyrosine (a yellowish muddy powder, with some impurities detectable on NMR in aromatic region) is tolerable – and MsOH from an old bottle that was already a bit dark worked fine in this procedure – but the used THF should be aldehyde+peroxide free.

September 4, 2013

nitrilotriacetic acid anhydride

Filed under: procedures — milkshake @ 1:48 pm

NTA

30 mL of acetanhydride (317 mmol) was added to a slurry of nitrilotriacetic acid N(CH2CO2H)3 50.0g (261.5 mmol) in DMF 100mL. N-methylimidazole 0.21mL (1 mol%) was added and the mixture was stirred and heated on a 60 C oil bath for 6 hours under Ar – the mixture gradually became homogenous. Neat allyl bromide 0.5mL (2.2 mol%) was then added and the heating was continued for additional 30 min, to inactivate the catalyst. The flask was finally equipped with a shortpath distillation adapter and the mixture was concentrated by vacuum distillation from a 60 C oil bath (1 to 0.1 Torr; the receiving flask was chilled with liquid nitrogen). With most volatiles removed and the distillation residue solidifying, the distillation was terminated and the distillation flask was cooled to ambient temperature under Ar. The residue was dissolved in acetone 300mL (15 min stirring at ambient temperature. Fisher histology grade acetone was used straight from the can). The obtained cloudy solution was diluted with 1,2-dichloroethane 200mL and filtered through a fine-porosity Buchner funnel. The filtrates were slowly concentrated on rotovap from an ambient water bath down to about 150mL total volume. The precipitated crude product (35g) was collected by filtration, washed with dichloroethane and dried in vacuo. The crude product was dissolved in acetone 250mL, the solution was diluted with dichloroethane 250mL and then slowly concentrated on rotovap from ambient water bath, down to about 200mL total volume. The precipitated purified product was collected by filtration, rinsed with dichloroethane and dried in vacuo. Y=31.81g (70% theory) of a light-pink colored crystalline solid that gradually turns white on storage.

1H(d6-acetone, 400 MHz): 3.920(s, 4H), 3.620(s, 2H); 13C(d6-acetone, 100 MHz): 171.18, 165.51(2C), 54.79, 52.54(2C)

Note: The crude product from reaction mixture evaporation residue contains another anhydride species, up to 15% by NMR (similar spectra but shifted downfield), which “disappears” during the workup. It is probably a dimeric bis-anhydride because it gets hydrolyzed by traces of moisture during the workup whereas the desired product is reasonably stable in non-dried acetone (in the absence of N-methylimidazole). The starting material N(CH2CO2H)3 is insoluble in acetone, so it is removed by filtration

May 24, 2013

Oil pump desanguination – brilliant!

Filed under: procedures — milkshake @ 3:38 pm

I just had the fastest and most enjoyable pump oil change of my career, thanks to a colleague. We use large Welsh DuoSeal belt-driven pumps installed in metal cabinets under the hoods and these beasts are rugged, dependable – but so heavy: They take over 3 liters of oil to fill and the whole damned thing weights about 50 kilos. The oil drain valve is inconveniently located right near the bottom so the pump cannot be easily drained inside the cabinet. The normal oil change procedure requires disconnecting the vacuum hose and dragging the pump out. I would prop the pump on an empty solvent barrel, put oil collection bucket beneath the drain valve and keep draining, tilting, flushing, draining, filling, cursing. Lifting the pump requires two pairs of hands, the oil drips everywhere, and given the large and awkward shape of the (very heavy) re-filled pump that has to be finally coaxed back in and over the cabinet lip, the vacuum hose reattached and the inadvertent vacuum leaks fixed, it is a pretty unpopular job – a job that keeps getting postponed for as long as is possible, while pumps are left sloshing with tired crud that has the look and smell of burnt molasses. But not much longer!

Prodded by his injured back and by desperation, my colleague conceived a brilliant apparatus –  he took a large (4L) Erlenmeyer filtration flask closed with a stopper with a tube through it. To the tube he attached a cheap vinyl transparent tubing (like you would use for water in reflux condensers) and connected it to the oil drain valve at the bottom of the pump so that he can aspirate the spent oil by vacuum. Turns out, if the oil is warm (from a pump that has been run, so it is less viscous), it can by sucked out through the drain valve into the Erlenmeyer filtration flask under house vacuum in few minutes. After one fill with flushing oil, 2 min pump run and another suction-assisted drain and final re-fill, the entire oil changing operation can be completed in less than 15 minutes. No mess, no need to take the pump out, no need to disconnect the vacuum hose from the pump.

Our biologists of course claimed credit for the pump oil change idea, for having used this kind of setup previously when sucking off liquor from cells in multi-well plates. But I am afraid the true origin of this oil change breakthrough is rather more disturbing. You see, my colleague is leaving for medical school in few weeks and in preparation, he has already taken the anatomy labs. As I was sucking out gallon of alarmingly dark rotten muck from my pump with his gadget, he calmly observed that the really good, top-of-the-line embalming machines can aspirate blood while at the same time pumping formaldehyde solution back into the empty veins: The happy operator just needs to correctly insert the inlet and outlet tubes into the still body, turn on the flush routine and wait until the aspirate finally starts coming out clear…

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