these people are full of shit. sofosbuvir contains single fluorine atom in such a place that its introduction requires either hydrogen fluoride (also as NEt3.3HF) or DAST (or other very friendly reagents like Xtalfluor-E) and even then, synthesis sucks balls as in has low-to-medium yield (15-50%) and requires extensive purification. you do not, under any circumstances, fuck around with hydrogen fluoride in your garage
I honestly feel really bad when I see fairly respected leftists and journalists celebrate Four Thieves as something that could make a big difference for folks who are paying way too much for medicine (which is all of us) and enable a mutual support network of hobby chemists saving lives.
and then I look at it and that’s not what I see at all — it’s just a fucking cosplay anarchist (complete with cheap camo pants) with the type of opsec that gets the people around them arrested and an understanding of chemistry that will get people killed. and that fucking sucks! the part of me that’s susceptible to a dream like this thinks a 3D printer for medicine (per the marketing) is a great idea!
every other part of me is horrified. 3D printers barely fucking work and that’s our reliability target for fucking organic chemistry, a branch of science where it’s so easy (and sometimes necessary for a synthesis, as you pointed out) to produce chemical byproducts that give you fucking horrifying cancer if you’re lucky? and then the fucker just forgets or doesn’t know about yield and purification? this fucker calls his output “street drugs” and expects you to fucking bareback them without an appropriate validation to make sure you haven’t synthesized fucking poison in your little tin-foil-and-tape reaction vessel? and he sure as fuck isn’t giving test catalysts out with the pills he keeps throwing into crowds
one thing I’ve noticed from this most recent article is they forked some MIT designs for their synthesis discovery software and their chemical reactor. I’m not a chemist, any chemistry knowledge above was gleaned from YouTube and probably isn’t correct (let me know if I was way off), so I wanna know — is there anything at all to that for any drug, or is the idea as a whole just fucking terrible? I’m leaning towards the latter, but like I mentioned, I’m susceptible to this kind of dream.
right, so let’s start with equipment. instead of using lab-scale techniques with lab-scale equipment, they instead decided to make an industrial-type reactor but tiny. so for a thing that stirs and heats your reaction mix they came up with arduino-powered jars that cost all in all $300-500. you know what does this job? a hotplate-magnetic stirrer combo with external thermometer that you can get on amazon for $70ish, with some associated glassware that still will be cheaper than $300 total, won’t leach plasticizers and that you can actually clean up thoroughly. if you’re looking for case of coder mindset where every problem can be solved with iot and 3dprinting, it’s there. that thing only really allows purification by extraction and crystallization, but this is straight up not enough for some cases. maybe they’re limiting their syntheses to cases where it is enough. sometimes you need to run distillation, if it’s something other than solvent this means vacuum pump ($2k ballpark) with dry ice trap (that has to be fused quartz and not normal glass) and dry ice. sometimes you need to run chromatographic column, that alone is easy if you know what you’re doing but it requires a lot of solvent that would be ideally recycled because there’s a lot of solvent involved (100x mass of compound to be purified is on lower end) (honeywell doesn’t want you to know this but recycled solvent is free you can do it in-house. i recycled 1500L). then you need equipment to evaporate that solvent (rotovap) and recycle it. like derek lowe said, it’s a lot of like trying to make your own aluminum foil
and then there’s entire waste management of it all, and there will be a lot of waste that you just can’t flush down the drain
another problem is that they expect anyone to be tied to this rube goldberg model reactor and don’t provide instructions in human readable form, but only as instructions for that contraption, and even that only through chatbot (??) if you can pull something let me know. (they have something better than machine generated free association right? as in, something they have tested. i don’t expect orgsyn.org level work where they repeat all procedures they publish, but at least something grounded in reality)
like you said there’s zero quality control and options for purification are extremely limited, this alone will get people killed. some of their testing was outsourced, and there are some ancient methods of determining what you’ve got based on things like melting point, but this is critically sensitive to fucking up due to not knowing what you’re doing. but this won’t tell you what it is, it only allows you to compare your result to someone’s else result to check if they match. i don’t know how likely in this case would be that fucking up synthesis will get patient killed, but in their previous one where they tried to cook naloxone there was a way to fuck up synthesis that would give compound with opposite activity to what was intended (oxymorphone).
regarding sofosbuvir. it’s fluorinated, which means they either
handled xtalfluor-type reagent and hydrogen fluoride-triethylamine complex in their garage, which will get people killed if they try to make it at home without necessary preparation like good fume hood and PPE and knowing what do to in case of accident, and requires teflon or poylethylene containers because this thing corrodes glass and expensive reagent disappears, or
bought fluorinated building block. due to quirk of stereochemistry in this case it’s easier to fluorinate that position after nucleobase is already installed, which means they just probably bought right half of sofosbuvir (as drawn on wikipedia) and tacked on the rest (which looks easy but still requires rather spicy chemicals). i don’t think their supply will be cheap then, but if it works then their stated goal of bypassing patent-based profit extractors could work if (load bearing if) nothing goes wrong along the way, but i have doubts as of how sustainable will this get, or
they’re just bluffing
e: by now i suspect they just ran with outputs from 2 without actually trying to make in their jarware. there’s also stereogenic centre on phosphorus which can, but doesn’t have to, make things significantly harder, but idk how actually important this is
and this is all forgetting about that sofosbuvir is used in combination therapy, where all the other drugs come from
the other drugs are also patented and just from looking at them it seems to me that these require a bit more specialized starting materials and a few steps that involve palladium couplings
synthesis-prediction software is an alleged thing that will sometimes work, i personally never did, but if you do use it, it’s critically important to know what you just have cooked because these outputs are predictions, not procedures. in this case point is moot because they just can replicate what is in patents, as patents describe something that already works, even if some details are missing
there are degrees to it. their abortion cards from what i understand just repurpose veterinarian misoprostol, which has similar if not the same requirements for purity and such and because it’s also used in humans, i won’t be surprised if it (as in, API) rolls off the same production line. but here, they don’t cook anything so there’s less room to fuck up. this is also not golden standard on how pharmaceutical abortion can be done now, but it’s available and it’s basically unregulated which i suspect was the entire point
single sane take from hn that is grayed out for some reason. something like quarter of discussion involves nootropics
This looks more like a libertarian nightmare than an anarchist dream. I couldn’t care less what you inject your body with, and will always support open science, but this is no solution to the USA’s disastrous healthcare system.
The real “right to repair your body” necessarily involves a socialized healthcare system, like in the rest of the West.
e: looked up their synthesis planner. for the easy example they mentioned (ivacaftor) 1/3 of the last step reactions are wrong, and these that aren’t require mildly to wildly spicy reagents (allergens, toxic or corrosive, that last bit is expected). first few candidates split entire molecule in two parts across amide bond (correctly) into amine and acid. acid is listed at $1/g amine is listed at $28/g, which are prices cited in 404media article actual link provided lists amine at $28 per 10mg. predicted synthesis of amine does not include the actual pathway that i found on reaxys (and one that would work in garage). ivacaftor is listed as commercially available at $86/g, but link provided only lists 10mg at $12. i take they just punched these compounds into their wrong prediction machine and ran with numbers it provided without checking
that’s not even synthesis planner like i’ve seen before that will provide you with suggested reaction conditions, any extra reagents and all that jazz, that still require careful supervision and good analysis of reaction mixture afterwards. no, here you have two bits that you can possibly stitch up to get something, fuck you, you won’t get anything better. figure out all the other bits, draw the rest of the fucking owl on your own
Deep dive into complex chemistry may be the most important thing in this thread. The bullshitters need more pushback like this, even though the effort involved means it can’t happen nearly as often as the bullshit. Thank you.
and their name would be a lot cuter if other fucking shitheads weren’t still to this day selling thieves’ oil (aka four thieves vinegar) as a cure-all to people with terminal illnesses
It’s interesting to me that they’re named after four thieves. Not sure if it’s a deliberate joke or just another manifestation of the anarchist herbalism tendency that seems to have developed in the last 20 or 30 years.
these people are full of shit. sofosbuvir contains single fluorine atom in such a place that its introduction requires either hydrogen fluoride (also as NEt3.3HF) or DAST (or other very friendly reagents like Xtalfluor-E) and even then, synthesis sucks balls as in has low-to-medium yield (15-50%) and requires extensive purification. you do not, under any circumstances, fuck around with hydrogen fluoride in your garage
relevant patent https://worldwide.espacenet.com/patent/search/family/051842422/publication/WO2016066283A1?q=pn%3DWO2016066283 first few pages for literature review, around 97-102 for procedures. these sub-50% yields are already heavily optimized
I honestly feel really bad when I see fairly respected leftists and journalists celebrate Four Thieves as something that could make a big difference for folks who are paying way too much for medicine (which is all of us) and enable a mutual support network of hobby chemists saving lives.
and then I look at it and that’s not what I see at all — it’s just a fucking cosplay anarchist (complete with cheap camo pants) with the type of opsec that gets the people around them arrested and an understanding of chemistry that will get people killed. and that fucking sucks! the part of me that’s susceptible to a dream like this thinks a 3D printer for medicine (per the marketing) is a great idea!
every other part of me is horrified. 3D printers barely fucking work and that’s our reliability target for fucking organic chemistry, a branch of science where it’s so easy (and sometimes necessary for a synthesis, as you pointed out) to produce chemical byproducts that give you fucking horrifying cancer if you’re lucky? and then the fucker just forgets or doesn’t know about yield and purification? this fucker calls his output “street drugs” and expects you to fucking bareback them without an appropriate validation to make sure you haven’t synthesized fucking poison in your little tin-foil-and-tape reaction vessel? and he sure as fuck isn’t giving test catalysts out with the pills he keeps throwing into crowds
one thing I’ve noticed from this most recent article is they forked some MIT designs for their synthesis discovery software and their chemical reactor. I’m not a chemist, any chemistry knowledge above was gleaned from YouTube and probably isn’t correct (let me know if I was way off), so I wanna know — is there anything at all to that for any drug, or is the idea as a whole just fucking terrible? I’m leaning towards the latter, but like I mentioned, I’m susceptible to this kind of dream.
right, so let’s start with equipment. instead of using lab-scale techniques with lab-scale equipment, they instead decided to make an industrial-type reactor but tiny. so for a thing that stirs and heats your reaction mix they came up with arduino-powered jars that cost all in all $300-500. you know what does this job? a hotplate-magnetic stirrer combo with external thermometer that you can get on amazon for $70ish, with some associated glassware that still will be cheaper than $300 total, won’t leach plasticizers and that you can actually clean up thoroughly. if you’re looking for case of coder mindset where every problem can be solved with iot and 3dprinting, it’s there. that thing only really allows purification by extraction and crystallization, but this is straight up not enough for some cases. maybe they’re limiting their syntheses to cases where it is enough. sometimes you need to run distillation, if it’s something other than solvent this means vacuum pump ($2k ballpark) with dry ice trap (that has to be fused quartz and not normal glass) and dry ice. sometimes you need to run chromatographic column, that alone is easy if you know what you’re doing but it requires a lot of solvent that would be ideally recycled because there’s a lot of solvent involved (100x mass of compound to be purified is on lower end) (honeywell doesn’t want you to know this but recycled solvent is free you can do it in-house. i recycled 1500L). then you need equipment to evaporate that solvent (rotovap) and recycle it. like derek lowe said, it’s a lot of like trying to make your own aluminum foil
and then there’s entire waste management of it all, and there will be a lot of waste that you just can’t flush down the drain
another problem is that they expect anyone to be tied to this rube goldberg model reactor and don’t provide instructions in human readable form, but only as instructions for that contraption, and even that only through chatbot (??) if you can pull something let me know. (they have something better than machine generated free association right? as in, something they have tested. i don’t expect orgsyn.org level work where they repeat all procedures they publish, but at least something grounded in reality)
like you said there’s zero quality control and options for purification are extremely limited, this alone will get people killed. some of their testing was outsourced, and there are some ancient methods of determining what you’ve got based on things like melting point, but this is critically sensitive to fucking up due to not knowing what you’re doing. but this won’t tell you what it is, it only allows you to compare your result to someone’s else result to check if they match. i don’t know how likely in this case would be that fucking up synthesis will get patient killed, but in their previous one where they tried to cook naloxone there was a way to fuck up synthesis that would give compound with opposite activity to what was intended (oxymorphone).
regarding sofosbuvir. it’s fluorinated, which means they either
e: by now i suspect they just ran with outputs from 2 without actually trying to make in their jarware. there’s also stereogenic centre on phosphorus which can, but doesn’t have to, make things significantly harder, but idk how actually important this is
and this is all forgetting about that sofosbuvir is used in combination therapy, where all the other drugs come from
the other drugs are also patented and just from looking at them it seems to me that these require a bit more specialized starting materials and a few steps that involve palladium couplings
synthesis-prediction software is an alleged thing that will sometimes work, i personally never did, but if you do use it, it’s critically important to know what you just have cooked because these outputs are predictions, not procedures. in this case point is moot because they just can replicate what is in patents, as patents describe something that already works, even if some details are missing
there are degrees to it. their abortion cards from what i understand just repurpose veterinarian misoprostol, which has similar if not the same requirements for purity and such and because it’s also used in humans, i won’t be surprised if it (as in, API) rolls off the same production line. but here, they don’t cook anything so there’s less room to fuck up. this is also not golden standard on how pharmaceutical abortion can be done now, but it’s available and it’s basically unregulated which i suspect was the entire point
single sane take from hn that is grayed out for some reason. something like quarter of discussion involves nootropics
e: looked up their synthesis planner. for the easy example they mentioned (ivacaftor) 1/3 of the last step reactions are wrong, and these that aren’t require mildly to wildly spicy reagents (allergens, toxic or corrosive, that last bit is expected). first few candidates split entire molecule in two parts across amide bond (correctly) into amine and acid. acid is listed at $1/g amine is listed at $28/g, which are prices cited in 404media article actual link provided lists amine at $28 per 10mg. predicted synthesis of amine does not include the actual pathway that i found on reaxys (and one that would work in garage). ivacaftor is listed as commercially available at $86/g, but link provided only lists 10mg at $12. i take they just punched these compounds into their wrong prediction machine and ran with numbers it provided without checking
that’s not even synthesis planner like i’ve seen before that will provide you with suggested reaction conditions, any extra reagents and all that jazz, that still require careful supervision and good analysis of reaction mixture afterwards. no, here you have two bits that you can possibly stitch up to get something, fuck you, you won’t get anything better. figure out all the other bits, draw the rest of the fucking owl on your own
Deep dive into complex chemistry may be the most important thing in this thread. The bullshitters need more pushback like this, even though the effort involved means it can’t happen nearly as often as the bullshit. Thank you.
if you want a deep dive, show me a procedure this thing is supposed to be using because i found nothing serious
also just noticed that their warrant canary does not include proof of date like news snippet and is not signed
and their name would be a lot cuter if other fucking shitheads weren’t still to this day selling thieves’ oil (aka four thieves vinegar) as a cure-all to people with terminal illnesses
It’s interesting to me that they’re named after four thieves. Not sure if it’s a deliberate joke or just another manifestation of the anarchist herbalism tendency that seems to have developed in the last 20 or 30 years.
Yes one of the !!fun!! chemicals.
Hello, Urist.
Here have a welcoming gift. *hands over !!«☼Rope Reed Left Sock☼»!!
of course it was on hn