Need to let loose a primal scream without collecting footnotes first? Have a sneer percolating in your system but not enough time/energy to make a whole post about it? Go forth and be mid: Welcome to the Stubsack, your first port of call for learning fresh Awful youāll near-instantly regret.
Any awful.systems sub may be subsneered in this subthread, techtakes or no.
If your sneer seems higher quality than you thought, feel free to cutānāpaste it into its own post ā thereās no quota for posting and the bar really isnāt that high.
The post Xitter web has spawned soo many āesotericā right wing freaks, but thereās no appropriate sneer-space for them. Iām talking redscare-ish, reality challenged āculture criticsā who write about everything but understand nothing. Iām talking about reply-guys who make the same 6 tweets about the same 3 subjects. Theyāre inescapable at this point, yet I donāt see them mocked (as much as they should be)
Like, there was one dude a while back who insisted that women couldnāt be surgeons because they didnāt believe in the moon or in stars? I think each and every one of these guys is uniquely fucked up and if I canāt escape them, I would love to sneer at them.
(Semi-obligatory thanks to @dgerard for starting this.)
so i figured out what their naloxone synthesis is, itās based on this paper https://sci-hub.se/10.1002/adsc.201300284 they say itās two step, itās not two step, itās 6 steps in two critical one-pot sequences. paper starts with oxymorphone and they start with oxycodone for some reason, thatās one step extra. that transformation requires handling BBr3 which is nasty but clean or NaSEt which is also nasty but safer, but also requires column chromatography for purification. it still can fail in a way that gives products of activity opposite than intended. requires hard to get and rather more on expensive side reagents like vinylmagnesium bromide and burgess reagent, both require strictly anhydrous conditions to work. vinylmagnesium bromide and even solvent used with it (THF) will destroy that shitty PLA lid. final purification in paper requires column chromatography as well. not to mention elephant in the room, that if counterfeit oxy pills are used that contain fentanyl instead it gets you either nothing or fentanyl
what is in paper
what they have shown
this synthesis is fucking garbled and itās only one of many steps
same with cabotegravir
theyāre also using advanced intermediates that could be very hard to source, because this kind of stuff is made internally in company only, particularly that pyridone on left
and thatās just naloxone. nothing particularly hard if you know what are you doing and have right starting materials. commercial synthesis is entirely different btw, and this is partially to make purifications easier and to use robust, high yielding chemistry using cheaper starting materials. they also want to make cabotegravir, mifepristone and fucking gene therapy, and diy hrt (they never cared about it before??) which was already a thing wayy before they got to it, it involved shipping steroids out of Ukraine iirc and it worked because no garage synthesis was involved at all. at least they admitted that making monoclonal antibodies is probably out of their reach, how merciful of them. and thatās just first 15min
it looks like theyāre desperately pivoting for attention left and right, i see there nothing but grift
when you have to consider what this arduino jar is even capable of, just taking a look at that naloxone synthesis makes it absolutely fucking useless. it canāt replace sep funnel, rotovap, chromatographic column; it canāt provide inert atmosphere, required in steps 3 and 5 of original paper, it canāt survive refluxing THF because lid will dissolve or melt and cave in, required in step 6 and whatever refluxing solvent is used in step giving oxymorphone from oxycodone, because they neglected to show it, and even if it did, thereās no condenser on top. it really is juicero of backyard chemistry
update: yeah nah what the fuck laminar flow fumehood is wildly out of reach of normal people, making sterile injectables in a garage is not a safe option for 99.99% of people
update 2: analytical techniques included: homemade raman, melting point measurement, dancesafe drug test suite. and fucking taste test, going all the way to 1890s best practices i see. none of these are good at detecting impurities, it will only be good to detect if chinese vendor sent you wrong stuff and itās only if it was pure
update 3: WEāRE MAKING HRT! looks inside: weāre buying APIs from India/China and compounding them in garage with zero real qc, also weāll solve HRT with garage gene therapy, promise, maybe, some years from now, donate in meantime
Thanks. The ending where he goes āhow would I deal with company patent lawyers? Well flips them offā is a bit annoying as well. I heard some make diy E makers and distributers were jailed already. So setting up some assistance system for that would be nice (esp after you made it worse by making it easier for the courts to call them terrorists, sure the term has degraded but law wise this has consequences. I really hope he at least got some trans people involved before he started this (and i also really hope im wrong about the risks here, as trans people should get all the meds they want)).
heās already easily covered under personal/research nonprofit use so he doesnāt have to care about any patents, itās even opposite, he can use all patents all he wants np as long as thereās no profits associated with it. he takes donations tho and idk if it qualifies. not that copyright is the biggest problem here
I read through this with my wife who actually did a whole course of organic chemistry, pre-med, etc. Her reaction to your criticisms was largely āof course you would have to do that and thatād be a pain in the ass but itās definitely doable.ā And I feel like thatās probably true but at the same time as a reasonably smart dude this is the first time Iāve heard the majority of these words.
It feels like theyāre reacting to the same tendency in tech culture that Iāve complained about before where specialized knowledge and domain expertise are treated like arcane revelations from beyond. Itās not that your average person is incapable of understanding or going through the relevant processes; Cs ,as the saying goes, get degrees and Iām sure many of the labs actually doing this work at scale are staffed largely by those C students. But itās also worth acknowledging that there is a level of investment in time and resources required to actually do it and this kind of āyou have nothing to lose but your pharmacological chainsā rhetoric is dramatically underselling how difficult those processes are and how bad the consequences can be if you screw it up. Anyone who wants to try should first read The Iliad, the Oedipus cycle, and at least one other epic-sized meditation on hubris. And the once youāve forged ahead read the relevant books on actually following the process for the love of God.
of course you can make it work but itās more expensive and harder than normal commercial synthesis. with such limited analytical methods you might not even be able to tell that something went wrong (melting points can be completely fucked up by traces of solvent, same with IR) naloxone is actually a nice example of how you can design synthesis in order to make your life easier, in terms of purification at least. one of commercial syntheses looks like this
anyway thatās what i found in one chinese patent (CN104230945A). they start from oxycodone, which they make from thebaine, which they donāt have to make because itās a natural product. thereās a very useful purification technique, column chromatography, that works like this: you take a tube, fill it with silicagel, then pour hexane through it, then put your compound on top of that silicagel column. silicagel is polar, and the more polar compound is, the stronger it is bound to it. so now in order to get your pure compound you wash this column with increasingly polar solvents, and this way you can recover various compounds in order from least polar to most. this allows you to get pure compounds most of the time
now, small changes in or near polar groups mean that polarity changes little. in particular, we can ignore for five minutes all these hydroxyls and just focus on amine because itās the most polar part and any changes at other groups make polarity change in the same way anyway. step 2 is von braun degradation, and it removes methyl and turns amine into amide. this amide is very likely to have much lower polarity than starting product and so it can be easily separated on column. here specifically, itās no longer basic so unreacted acetyloxycodone can be just washed away with acid extraction, which is good for both low tech and large scale. step 3 is hydrolysis, which gives us amine back, which again gives more polar product which means again that separation is easy. if some acetyloxycodone was left there, it would give very similar compound, just with that N-methyl left and separating it would be pretty hard. this here is especially important as N-methyl and N-allyl compounds have opposite effects
that weird synthesis with burgess reagent and everything else also allows for separation of these unreacted starting materials, but this requires column chromatography in the middle. if you skip it, maybe itāll turn out alright or maybe you just fucked up for the last time. maybe mCPBA was old, or maybe burgess reagent or THF was wet, or any variety of random bullshit that someone inexperienced would not even register. and this is only one point that brings us to point 2: that jarduino is really juicero of backyard chemistry. to begin, you need dry solvents, and this is something you should do yourself if you want it to be done right. this means you need to reflux THF with drying agent of your choice, then distill it away to clean dry bottle, fill it with argon, ideally add molecular sieves and tape it shut. then you have to reflux something, this requires all glass flask because that 3d-printed head will melt under these conditions. at some point you also need sep funnel and rotovap and column, and so on and so on and it turns out that you already have all glassware to do it all the normal way and jarduino isnāt even needed for anything. (also i donāt understand their choice of peristaltic pumps, as they already put everything in syringes, this means that you can just use syringe pumps and use normal medical long needles for piping of sorts. itās very chemically resistant as long as plungers arenāt rubber, which their demos had for some weird reason)
this is closer to the synthesis i thought they were using
if you swap oripavine for oxymorphone and cyclopropylmethyl bromide for allyl bromide, you should get naloxone, probably, in 2 steps. keeping cyclopropylmethyl bromide gets you naltrexone which also work itās from this paper https://cdnsciencepub.com/doi/10.1139/cjc-2014-0552
then there are all the sterility requirements, as they want to make injectables in garage. iām not pharmacist or biologist, but i expect it would be a bit harder to make it reliably and repeatably than what they make it look like. i take that your wife is a medical professional so if she weighed in on that, that would be nice
also, part of their advice is to just eyeball powder as a part of identification. this is a bad idea because how stuff looks like and behaves can change depending on humidity, traces of solvents if any, and ambient temperature, especially for low melting solids, and crystal habit can vary from batch to batch anyway and itās not a reliable indicator of anything