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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

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. To contact Derek email him directly: Twitter: Dereklowe

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July 22, 2007

A Farewell to Tin

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Posted by Derek

I was browsing through the posts at Totally Synthetic, which is now my substitute for looking at total synthesis papers in the primary literature, and came across this question:

"However, this brings me to a point of consideration - why are Stille coupling (reactions) more common in academic publications, and Suzuki more so in an industrial/commercial context?"

(For the non-chemists in the audience, these two reactions are ways to skin what is basically the same cat - forming carbon-carbon bonds on a particular class of starting materials). And this is one of those questions with a one-word answer, and in this case you can pick your word. Either "tin" or "toxic" would work just fine. The Suzuki uses boronic acids or esters, which are generally water-soluble and nonpoisonous. The Stille reaction, although it has a reputation for working on small scale in finicky, highly functionalized molecules, uses organotin compounds. These are highly nasty, and very difficult to completely remove from your final compound. If your final compound is going to be something that people are going to put in their mouths, which is our dearest hope in the drug labs, you're just not going to use tin.

And I don't mean that you'll tend to avoid it, or only use it when other things don't work as well. You just won't touch it. I'm not aware of a single pharmaceutical process which uses an organotin reagent, and I'm not holding my breath for one to appear, either. There are a lot of other reagents in this category: things that you basically have to edit out of your repetoire.

Obvious farewells are made to things like nickel carbonyl, which a lot of people in academia don't want to use, either. But in drug research, a lot of people decide to ditch their old grad-school favorites like HMPA, a solvent that can make some reactions work when little else can. But if your compound can only be made using HMPA, is it going to be a drug? Highly, highly unlikely.

Naturally, one way around this difficulty is to assume that the process chemists are going to fix this little problem later on if your compound goes ahead. But your compound isn't going to go ahead, chief. Something nearly as good as your candidate has surely been made in the course of the project, something that doesn't use HMPA. It'll win. You're honestly better off trying something else in the first place and not wasting your time. And the same, exactly the same, goes for the Stille reaction. Enjoy it in the universities, folks. If you go on to industry, you won't be seeing it again.

Update: Check the comments - there are some well-informed disagreements!

Comments (9) + TrackBacks (0) | Category: Drug Development | Life in the Drug Labs


1. milkshake on July 23, 2007 1:09 AM writes...

In initial medchem work, the reaction don't have to be efficient or use non-problematic reagents - you can live with 30% yield, especially if it happens in the last step. Medicinal chemists are like engineers - they try to be as little inventive as possible, they just put things together with whatever methodology is available and look for the simplest solution (of a problem of finding a good drug candidate). Non-problematic chemistry that uses commercial building blocks is going to be favored. Coming up with ides is easy, trying them out is hard - Very often, one could think of ten times as many analogs than one has time and energy to make. One has to prioritize.

Using nasty reagents with a cumulative toxicity is allowable at the early stage - but why bother if you can just as well go in another direction? Many times the medchem projects takes the path of the least resistance.

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2. LNT on July 23, 2007 9:15 AM writes...

I disagree completely Derek -- In my corner of the "wonder drug factory" world, Stille couplings are still very common. In particular, we just cannot obtain the boronates of complex heterocycles. If you want to attach a substituted imidazole onto an aryl iodide core, I would challenge you to find some Suzuki conditions that will work. In our hands, we have to use Stille couplings to get the reaction to work. We have a compound in late stage development that contains a benzofuran. We initially attached it via a Stille coupling. We never found Suzuki chemistry that gave acceptable yields. In the end, the process team ended up attaching an acetylene and doing a cyclization via a phenol to form the benzofuran ring.

There's always ways around Stille couplings -- but at the medchem stage of the process it really isn't worth trying to figure them out.

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3. Anonymous BMS Researcher on July 23, 2007 10:02 AM writes...

Nickel carbonyl is used in Gordon Dickson's classic SF novel The Spirit of Dorsai to poison an occupying army. What makes it such a searing plot point is some of the defenders themselves deliberately die along with the occupying army in order to prevent them getting suspicious until it is too late.

[PS: despite the timestamp I'm not typing this on work time nor am I using a BMS connection. I happen to be home with a nasty cold today. After taking medicine and checking email and a couple blogs, I'm gonna crawl back into bed.]

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4. skyywise on July 23, 2007 10:59 AM writes...

A marginally relevant joke.

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5. fat old man on July 23, 2007 6:07 PM writes...

Derek, I am a big fan of yours, but I too must disagree. At least where I am, project managers pick new drug candidates graduating from Discovery solely on biology parameters. They figure it's up to the process chemist (who used to be me) to fix the chemistry. I have seen a Sn coupling go as far as a Phase 1 batch before it was fixed with an ethylene coupling under pressure. Although there are some minimum scaleup paramters that are supposed to be met, the reality is that process development management does not like to reject Discovery's promising progeny.

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6. Harold on July 24, 2007 8:51 AM writes...

While we initially prepared prostaglandins from iodovinyl beta chain starting materials via lithiation, transmetallation to copper reagents, ending with conjugate additions to cyclopentenone, those iodovinyls were indeed nasty to deal with. When we switched to tributyltinvinyls, it was a walk in the park and two compounds ended in development using such tin reagents. Rioprostil made it to phase III and Butaprost to phase II before they died for reasons unconnected to any toxicity of the tin.

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7. waiting4data on July 24, 2007 10:48 AM writes...

It would be very embarrassing to a medicinal chemist if the excellent inhibition observed in a cellular assay were due to cell tox caused by minor tin (or nickel, etc) impurities instead of actual inhibition caused by the target compound.

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8. Jose on July 24, 2007 11:29 AM writes...

There are some great scavenger resins (Polymer Labs and others) that mop up excess metal (Sn, Ru, Pd, etc.) like a charm. Well worth the trouble.

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9. totally process on August 1, 2007 8:46 AM writes...

First, I agree with your comment about totally synthetic: a very valuable and useful blog that I read often. I also enjoy reading this blog; however, I must disagree with the entire last paragraph of this entry. I have been doing process chemistry for 15 years and I cringe when I hear these things. Med-chemists should focus on potency, PK, et..things that will actually make a better compound! You should also make it any possible way that you can (without hurting anybody). May the best molecule win!... and when it does, we will be happy to provide the resources and find a way to make the bulk. I have never seen a good molecule die or even slow down due to synthesis problems. I have scaled some nasty things in my time, including Stille reactions (I have run columns with HMPA, methylene chloride!) and although these things cannot be tolerated long term, the chance that the molecule will die for other reasons (>85%)requires us to march forward. So please, don't throw out your HMPA, tin or other very useful reagents. These things are around because they work, and you should us them! Drug discovery is hard enough without adding any additional barriers to the hard working Med-chemists. Good luck!

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