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Baran on Total Synthesis

14 April 2018 - Philosophy

Almost written as a counter-essay to the Whitesides article on Organic Synthesis, Phil Baran has expressed his take on total synthesis in a recent JACS editorial. (DOI). The title suggests it is just another propaganda piece: "As Exciting as Ever and Here To Stay" but you cannot blame him. According to Baran, yes total synthesis helps students to prepare for a healthy career in pharma, and yes a new synthetic method is only worth something if applied in a total synthesis.

Baran is also not intimidated by artificial intelligence and process automation, he makes the bold prediction that "that our species will become capable of interplanetary colonization long before rooms of machines dramatically reduce the number of employable synthetic chemists or eliminate them all together". Baran reserves a sneer for bloggers and opinion writers who are all about AI and automation arriving tomorrow but the scientists who know better than that either are "too busy doing science (...) or simply dont have a platform". Also a special sneer for Lee Cronin, Baran articles tend to have "less headline grabbing potential than 3-D printing drugs".

Whitesides on total synthesis

14 April 2018 - Philosophy

George Whitesides has recently shared his thoughts on organic synthesis in an essay in The Israel Journal of Chemistry (DOI) In it he asks the big question about its future. Being a functional materials man Whitesides of course contrasts the aesthetics of complex biomolecule synthesis with the practical utility of molecules or materials that can actually do something (have a function). Curiously he introduces the concept of Organic Synthesis (with capitals) as a niche to be reserved for the complex construction of natural products in the tradition of the Woodward school. But did we not already have total synthesis for that? Whitesides does not mention it once and this is annoying because a formal definition of total synthesis is already hard to drag out of the specialists (they talk a lot about it but never explain what it is), a problem not solved by introducing an identical concept under a different name. But Whitesides is blunt about the future of Organic Synthesis: "almost any natural product can be synthesized, given enough time and effort" and industry is moving towards biopharmaceuticals anyway.

What else is there in the future? Of course many unsolved problems in chemistry are still out there, Whitesides mentions the origin of life problem but on the other hand the "Synthesis of commodity polymers is probably a solved problem". Any advice for the next generation of synthetic chemists? Chemists from India and China are just as good in organic synthesis as their counterparts from the more established countries making synthesis a global competition. All chemists will have to face the power of AI and continued process automation.

Two specific threats: according to Whitesides the development of complex drugs suffers from pressures on pharma prices. This argument seems me a bit odd as insanely high-priced drugs with powerless governments and insurers make up all the pharma headlines. Second threat: a fossil fuel phase-out is one thing but it deprives chemical industry of key specialty products.


With Derek Lowe providing the alert.

DIY chenodeoxycholic acid

06 April 2018 - Pharma

In a previous episode this blog has been reporting on a Dutch dispensing chemist who took it on himself the affordable production of a certain drug, otherwise only available from the pharmaceutical industry at highly inflated prices. This week in the news (link) a hospital doing something similar. This time the expensive drug is chenodeoxycholic acid (CDCA), the manufacturer is Leadiant, the disease is cerebrotendineous xanthomatosis (CTX) and the hospital the Academic Medical Center (AMC) in The Netherlands.

Forty years ago this drug just costed around 500 euro but recently the price has sky-rocketed to 200,000 euro per patient per year. The number of patients in this country is very small (50 and hence CDCA is an orphan drug), the disease causes excessive production of cholesterol in the body and CDCA is a natural bile acid able to dissolve this excess (It also used to be an effective treatment for gallstones). The hospital claims it will bring down the price of CDCA to just 20,000 euro per year per patient but the article is unclear about just how production will take place. Not a problem of course but we are just curious.

This website explains an average treatment requires three 250 mg pills a day per year. The total annual requirement is then 273 grams. Wikipedia explains the compound was first isolated from domestic goose (that explains the latin cheno prefix) but it is unlikely the hospital has taken this road (goose farming) as the start of a production line. A 1972 patent describes an organic synthesis from cholic acid in several steps (link) , basically removing the unwanted alcohol group from the steroid skeleton via the hydrazone and a Wolff-Kishner reduction. Cholic acid is industrially sourced from bovine bile. Other candidates are unlikely. There is the inevitable total synthesis route first explored in 1981 (doi) starting from an oil-based precursor (source). In ursodeoxycholic acid geese are replaced by bears (Ursos produce a different bile acid). This compound is an epimer but plenty of literature exists on cheno to urso conversion but not the other way round. Bear bile is much sought after in Chinese fake medicine (also known as traditional medicine) having given rise to the despicable bile bear industry.

Any other candidates? Interestingly, chemicals supplier Sigma Aldrich sells the compound for (97% pure) for just 416 euro per 25 grams (link), that would make a full treatment cost just 4500 euro. The only thing the AMC footage revealed was a worker filling up capsules, not exactly an organic chemistry laboratory. A repackaging scheme like this is plausible and would generate a profit of 15,000 euro.

August 2018 update: No, the AMC website explains the CDCA source is actually chicken bile from China (link). It also explains the Chinese production site is monitored by certified GMP inspectors. After arriving in the Netherlands the product is quarantined and then tested by certified Belgian laboratory. For adults, CDCA capsules only contain CDCA and nothing else.

August 2018 update: Leadiant has intervened by making a complaint to the Dutch Health Care Inspectorate (IGZ) (link). The IGZ did their own tests, found chemical impurities and has ordered AMC to stop manufacturing. To be continued?

26 August update: NRC story here, cheap out-of-patent CDCA medications have existed for many years for the treatment of galstones. Until Leadiant (through a subsidiary) first bought the rights to these medications and then removed them from the market. This opened the way for Leadiant to market their expensive version of CDCA for the treatment of CTX. To be continued?

26 November 2018 update: Hospital victory! Afore mentioned IGZ has now ruled that hospitals may in fact produce drugs if the price of the drug is unreasonable. (link) Additional rules: the raw materials should be safe and the hospitals are not allowed to advertise their products.