https://www.science.org/content/blog-post/not-such-better-living-through-chemistry Advertisement * * news * careers * commentary * Journals * Covid-19 Science Science * * * Log in * Become A Member [science] science [sciadv] science advances [sciimmunol] science immunology [scirobotics] science robotics [signaling] science signaling [stm] science translational medicine [spj-cover] science partner journals Quick Search anywhere Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Quick Search in Journals Enter Search Term[ ] Searching: Anywhere AnywhereScienceScience AdvancesScience ImmunologyScience Robotics Science SignalingScience Translational Medicine Advanced Search Search Trending Terms: * covid-19 * climate * monkeypox * abortion * perovskite Log In Become A Member Quick Search anywhere Enter Search Term[ ] science.org * Custom publishing * collections * videos * podcasts * blogs * visualizations * prizes and awards * authors & reviewers * librarians * advertisers * about * help * * * * * * AAAS Logo * Terms of Service * Privacy Policy * Accessibility * Commentary Home * Opinion * Analysis * Blogs GET OUR E-ALERTS HomeCommentaryBlogsIn the PipelineNot-Such-Better-Living Through Chemistry Back To In the Pipeline * In the Pipeline * Chemical News Not-Such-Better-Living Through Chemistry * 6 Jan 2023 * By Derek Lowe * 2 min read * Comments Share: * Twitter * Linked In * Facebook * Reddit * Wechat * Email There's an area where synthetic organic chemistry has been steadily growing in importance over the years, one where improvements in process chemistry (route optimization, supply chain management, waste streams, economies of scale) have evolved greatly in response to broader economic factors, the regulatory environment, and to customer demand. This entire sector has become more streamlined and profitable, and continues to open new markets using modern manufacturing and distribution methods. I'm talking, of course, about illegal drugs. And in particular, I mean the ones brought to us by synthetic chemistry, like methamphetamine and fentanyl (to pick two extremely prominent examples). This is a strange inverted world, one that has its own unique challenges but which also shares many of the same issues that you find in legitimate pharma manufacturing. And it's one where synthetic chemistry expertise has never been more valuable. For most of human history, consciousness-altering drugs (whether used for recreation, religious ceremonies, or just good ol' addictive abuse) have been natural products derived from plants, fungi, and a few other sources. The human race didn't know enough chemistry to do it any other way. In fact, the quest to learn more about these substances has been one of the things driving progress in organic chemistry over the centuries. There are a lot of important natural product medicines that aren't in this category, of course (salicylic acid, quinine, digitalis, doxorubicin, penicillin and more), but Serturner's isolation of morphine from poppies was the first time that the principle active substance from a medicinal plant had ever been purified and characterized, and it is an indisputable milestone in medicinal chemistry. This is how it went for much of the 20th century as well. If you wanted morphine, you had to isolate it from poppy plants. If you wanted cocaine, well, it was time to grind up coca leaves and start extracting. Some newer drugs of abuse were semisynthetic analogs from these - heroin, famously, was first produced in the 1870s by the acetylation of morphine, but you were still going back to a natural product, of course. Back when I was a teaching assistant in grad school, I used to draw a "molecule of the week" on the board in my lab sections and have the students guess what it was. One week, I put up the cocaine structure, and by then folks were learning enough organic chemistry to wonder if they could make some. "Let's switch from chemistry to economics", I told them. "If this were easy to make in the lab, why would you go to South America to do business with a bunch of machine-gun-toting machete-waving crime lords?" And so it remained. There is still no commercially viable synthetic route to cocaine or to morphine - you will be growing plants, extracting, and purifying. If you aren't able to do that where you live, you will be dealing with the people who can do it where they live, and good luck to you. The first break in this time-honored business model was the amphetamine drugs. Ephedra plants had long been known in China for their stimulant properties and other effects, and the active ephedrine was isolated in the 1880s by Nagayoshi, who later produced methamphetamine from it as he investigated the chemistry in this area. Separately, Edeleanu synthesized the parent amphetamine at around the same time (1887), but he made it from scratch, not from a natural product precursor, and that's the starting point of our modern situation. Weirdly, neither of these compounds was recognized as having any particular medicinal effect until the 1920s, but over the next few decades they becames very popular (and very profitable) indeed. Illegally manufactured methamphetamine really started becoming noticeable in the US and other countries as the 1950s went on, and became very prominent in the 1960s. Before then, there was frankly plenty of legal supply; amphetamine and methamphetamine were popular pharmaceuticals and (like everything else back then) were relatively lightly regulated, with plenty of off-label use and diverted supplies. The clandestine production was a reaction to increasing regulatory and legal restrictions in the industrialized world, and in the US I believe it was motorcycle gangs that often moved into this lucrative business opportunity. In California, the Hell's Angels were particularly known for their ability to supply the drug, and they have by no means abandoned this tradition. There are at least six major routes to the synthesis of methamphetamine, but I do not propose to review their comparative advantages in detail here. Those have in any case changed over time. I believe that the Hell's Angels for many years used the reductive amination of phenylpropanone (P2P) with methylamine, with both these chemicals coming from a wide array of sources. Methylamine, for example, was sourced by means ranging from stealing tanks of the pure reagent all the way down to reducing nitromethane (model airplane fuel) or by reacting formaldehyde and ammonium chloride. It is likely that these reactions were conducted with less attention to safety and to waste disposal than most trained organic chemists would recommend. As supplies of the various precursors tightened up, routes changed, and each of these in turn came under regulatory and legal pressure. Many of these depended on reducing the benzylic alcohol off of commercial pseudoephedrine, and thus the restrictions on its sale. To this end, a number of deeply alarming procedures were carried out in barns, basements, and garages around the world. One of these used red phosphorus and hydrogen iodide, and if that doesn't sound like enough fun in an unventilated shed, a variation used phosphorous acid and produced phosphine gas as a by-product. Birch reduction was also a popular method, and this ranged from The Real Thing, condensing liquid ammonia and adding pieces of sodium metal if you had the materials and the equipment, down to the "shake-and-bake" variation. This was done in a sealed and periodically hand-vented plastic soda bottle with lithium foil from batteries, alkali from drain cleaner, ammonium nitrate fertilizer, in a mixed solvent of water and something like lantern fuel, kerosene, or cold-weather starter fluid from the auto parts store. My fellow organic chemists will already have noted several things that could go drastically wrong with this procedure, e.g. a hot piece of lithium metal melting through the plastic container and thereupon igniting a jet of the solvent under pressure. As noted in that last link, "the method does not scale". But honestly, in most cases it didn't have to, since this one was often the choice of people who couldn't get their hands on large amounts of pseudephedrine to start with. And anyway, that era is past. Since about fifteen or twenty years ago, most of the methamphetamine on the market has been produced on larger scale, and this has driven out the smaller producers (and the more squirrely synthetic routes). And there has been some real process innovation going on. Methamphetamine has a chiral center, so you can produce the pure (D) isomer, the pure (L), the exact 50/50 racemic mixture, or anything in between. (L) methamphetamine is a pretty good decongestant, but it is otherwise unenjoyable and has no market as a drug of abuse. The classic P2P reductive amination will of course give you the racemate; there's nothing chiral about the synthesis at all. At the other end of the scale, reduction of pseudoephedrine starts with a pure chiral material, and you get only (D) methamphetamine as a product. But starting in the mid-2000s, samples of the drug began to show up that were in between these extremes, which is chemically very interesting. The chiral center in methamphetamine is not labile; it does not scramble (racemize) on its own. So a nonracemic mixture of enantiomers strongly implies that someone has figured it a chiral synthesis or purification that is biasing things toward one isomer, but just not all the way. That last link is a very interesting look at this phenomenon and is well worth reading. What happened was the advent of a procedure well known to synthetic chemists: chiral resolution. That's the separation of a racemic mixture by using some other chiral reagent to pull one of the two components out in some fashion. Since methamphetamine is (as the name tells you) a basic amine, forming a salt with a chiral acid is a classic resolution technique. The two different salts will have different solubilities and different crystal behaviors; you can often find some combination that lets you selectively crystallize out the combination you want, and treating that with another base regenerates the amine. Depending on how well it works, you can get pure enantiomers or mixtures that are enhanced in the desired product - which is just what the DEA and other agencies were finding. And around that time, they began to find supplies of tartaric acid when illegal meth labs were seized. There you have it: that's a chiral acid, found in fruits and produced by large-scale fermentation, and it's been used for resolution of amines since the 1800s. But there's more: resolution methods will leave you with a big pile of the unwanted isomer, and if you can't come up with a use for it, you are throwing away exactly half of your synthetic output in the absolute best case. I mentioned that the methamphetamine chiral center doesn't racemize on its own - but what if you used a chemical route to take the unwanted (L) compound and turn it back into the 50/ 50 racemate? Then you could resolve that again with tartaric acid, and gradually use up all the unwanted isomer, converting it each time around to more of the desired one. This sort of thing is done wherever feasible in pharmaceutical production - ideally you'd want a synthesis that only makes your desired enantiomer, but this is the next best thing. And that's what some nameless organic chemists (probably in northern Europe) have managed in this case. More recent lab seizures have featured free-radical reagents such as AIBN and various thiols, which tells us that the unwanted (L) methamphetamine is being racemized through a free-radical route. As this report from the European Monitoring Center for Drugs and Drug Addiction puts it, ". . .combining the expertise of Mexican and Dutch drug producers and applying techniques from the pharmaceutical industry has maximised production efficiency". Unfortunately. Moving from natural products to simpler synthetic compounds changes everything - the supply chains, the economics, the locations of production (and the distribution afterwards) and more. The plant makes the compound the way it always has, and if you're getting it that way it means that it's making it better than you can do it. But a human-designed synthetic process can always be human-redesigned. It happens constantly in the drug industry - the production of such a common drug as ibuprofen changed completely in the early 1990s, for example (a story for another time). For an illegal drug, that means that law enforcement will always be a step or two behind as new methods come on line. And it means that stopping the supply of such a drug will be difficult-to-impossible as well. . . About the author Derek Lowe Derek Lowe email Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. --------------------------------------------------------------------- Comments Please enable JavaScript to view the comments powered by Disqus. IN THE PIPELINE Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog, all content is Derek's own, and he does not in any way speak for his employer. Advertisement YOU MAY ALSO LIKE 27 Dec 2022By * Derek Lowe Acid Personalities 11 May 2022By * Derek Lowe Paxlovid, Personally 15 Jul 2022By * Derek Lowe Fainting From Fentanyl Exposure? 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