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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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December 12, 2013

Tiny Details, Not So Tiny

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Posted by Derek

Chemjobber has a good post on a set of papers from Pfizer's process chemists. They're preparing filibuvir, and a key step along the way is a Dieckmann cyclization. Well, no problem, say the folks who've never run one of these things - just hit the diester compound with some base, right?

But which base? The example in CJ's post is a good one to show how much variation you can get in these things. As it turned out, LiHMDS was the base of choice, much better than NaHMDS or KHMDS. Potassium t-butoxide was just awful. But the hexamethyldisilazide was even much better than LDA, and those two are normally pretty close. But there were even finer distinctions to be made: it turned out that the reaction was (reproducibly) slightly better or slightly worse with LiHMDS from different suppliers. The difference came down to two processes used to prepare the reagent - via n-BuLi or via lithium metal, and the Pfizer team still isn't sure what the difference is that's making all the difference (see the link for more details).

That's pure, 100-proof process chemistry for you, chasing down these details. It's a good thing for people who don't do that kind of work at all, though, to read some of these papers, because it'll give you an appreciation of variables that otherwise you might not think of at all. When you get down to it, a lot of our reactions are balancing on some fairly wobbly tightropes strung across the energy-surface landscape, and it doesn't take much of a push to send them sliding off in different directions. Choice of cation, of Lewis acid, of solvent, of temperature, order of addition - these and other factors can be thermodynamic and kinetic game-changers. We really don't know too many details about what happens in our reaction flasks.

And a brief med-chem note, for context: filibuvir, into which all this work was put, was dropped from development earlier this year. Sometimes you have to do all the work just to get to the point where you can drop these things - that's the business.

Comments (8) + TrackBacks (0) | Category: Chemical News | Infectious Diseases


1. old man on December 12, 2013 8:48 AM writes...

100 proof is only 50%. Are you trying to antagonize the process chemists in the group?

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2. Am I Lloyd peptide on December 12, 2013 9:22 AM writes...

Who said synthetic chemistry can be predictable? Fun stuff.

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3. nitrosonium on December 12, 2013 9:34 AM writes...

i often remind people that (seemingly) small changes can mean a world of difference in flask-derived outcomes. this is a thorough demonstration of that.

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4. Wheels17 on December 12, 2013 10:43 AM writes...

We used to use a carbon based antistatic coating that was extremely sensitive to materials sourcing. The vendor of the carbon prepared the material from a fraction of crude oil. They changed the source of the oil to a different field, and the whole system fell apart.

The system was also extremely sensitive to silicone. We chased problems down to a single valve packing in the distillation department, a contractor using silicone caulking on windows in the department, and worker's coats with silicone in the waterproofing.

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5. CMCguy on December 12, 2013 12:03 PM writes...

Often it seems for many process chemists chasing down the reaction details is the easy part as for Drugs you then have to consider GMP issues (Materials sources, Validation, Testing, Alignment to Reg submission), economic feasibility (which formerly was minimal factor but now of increased importance) and Time/Schedule factors (almost always limited development and keeping up supply on critical path).

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6. Yancey Ward on December 12, 2013 12:53 PM writes...

Well, the results with t-butoxide might be the result of a difference in reaction profile for the kinetic vs thermodynamic enolate. As for the difference in source for the HMDS, all I can think of is that the impurities change the nature of the aggregates present in both the reagents and in the reaction itself. Having prepared LiHMDS by both methods, I know the lithium metal route is somewhat messier in the by-products- some of which are polymeric in nature, but I don't really remember now what they are (and this is even assuming it was the lithium metal method that gave the lower yields).

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7. gippgig on December 13, 2013 3:22 AM writes...

I think I brought this up before, but is anyone systematically adding trace amounts of a wide variety of substances (i.e., metals) to common reactions to see how they affect yields, byproducts, etc.?

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8. anon on December 16, 2013 1:15 PM writes...

A research chemists gets a pure cpd after flash chromatography, in 30 % theoretical yield, and is satisfied that he's done a good job.

A development chemist gets a pure cpd in 95 % theoretical yield after crystallistation and worries about the remaining 5 % yield.

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