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The beginnings of Syntex


Expensive and complicated cortisone synthesis
Carl Djerassi Scientist
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So returning to cortisone in 1948, why is it that cortisone was so much more difficult? Because cortisone and here is the structure of cortisone and that’s rather easy to see because you can see I, I emphasised in black the really distinguished thing. First of all, this part here in black is exactly the same thing that you have in progesterone or testosterone. That’s very easy to synthesise from cholesterone. That is a common feature. But cortisone, the adrenal hormone is something else, has an oxygen atom at a position called position 11. That’s unprecedented because no other steroids have that. So that’s in a very inaccessible position and then is a side chain here. In progesterone it is just a simple one. In testosterone it was only OH. You see in cortisone it’s much more complicated. I just don’t even have to tell you what that is, but you can see it is more complicated. So the problem in a synthesis of cortisone that people faced was A, to generate this – but that was less difficult, not easy but less difficult – but how to introduce an oxygen here in a place where there isn’t any oxygen in cholesterol? Something like that. What Sarrett did, that was the first partial synthesis of cortisone, is to convert a bile acid and this is called the oxalic acid though it makes no difference. A bile acid and you see the difference there. It has a long acid side chain but people know how to remove it because cholesterol also has a long side chain, except it doesn’t have this. So one already knew how to do that, but it had an oxygen. The natural occurring one in position 12. What he had to learn is how to move it from there to there, and you can’t just pick it up and put it there. This is again any number of steps. So he did develop a synthesis of cortisone from the bile acid, which took 40 different chemical steps, and that was at that stage the longest partial synthesis in chemistry. Who developed that? Lewis Sarett, a young- And Ed Merck. And Merck actually manufactured the first few grams, grams of cortisone from bile acid by what was at that time the most complex industrial organic synthesis that had ever been carried out. And in fact even to this day is one of the most complicated, but at that time it was unprecedentaly complicated and they accomplished that. The yields were infinitesimal because if you have, if you get an 80% yield in a given chemical transformation that’s a very good yield, and 90% is just superb. But just think about it. If you have a two-step synthesis and you get a 90% yield in each case the overall is only 81%. And if you do a three-step synthesis it’s only 72%, and if it’s a four-step synthesis only 56%. You do that 40 times and even if you have a 90% yield you’re getting to a fraction of a percent final product. So this is damn expensive, damn complicated. So everyone’s grandmother wanted to work with this, and I wanted it to. And I was, you know, an organic chemist and I was sophisticated and I was ambitious, and I was not permitted to do this at Ciba because that- They of course worked on this very hard. That was being done in Basel and some of the real competitors were- There were two groups at Harvard. Woodward, the most famous organic chemist, the American organic chemist of the last century. A man named Louis Fieser who was professor of organic chemistry and wrote the most important textbook in steroid chemistry. A man who among other things had worked during the war on very important anti-malarial’s as well as discovered napalm. So you can see the range is sort of like Fritz Haber in Germany doing both. You know, first poison gases and also nitrogen fixations. You see always black and white issues in, in chemistry and every one of the pharmaceutical companies. So everyone was working on this here and I couldn’t.

Austrian-American Carl Djerassi (1923-2015) was best known for his work on the synthesis of the steroid cortisone and then of a progesterone derivative that was the basis of the first contraceptive pill. He wrote a number of books, plays and poems, in the process inventing a new genre, 'science-in-fiction', illustrated by the novel 'Cantor's Dilemma' which explores ethics in science.

Listeners: Tamara Tracz

Tamara Tracz is a writer and filmmaker based in London.

Tags: Ciba, Basel, Lewis Sarett, Ed Merck, Louis Fieser, Fritz Haber

Duration: 4 minutes, 32 seconds

Date story recorded: September 2005

Date story went live: 24 January 2008