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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: derekb.lowe@gmail.com Twitter: Dereklowe

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November 5, 2012

Caring About Yields?

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Posted by Derek

The discussion here last week about exaggerated reaction yields has gotten me thinking. I actually seem to go for long periods without ever calculating (or caring much) about the yields of my reactions.

That's largely because of the sort of medicinal chemistry work that I do - very early stage stuff, about as far back as you can get. For that work, I like to say that there are really only two yields: enough, and not enough. And if you can get product into a vial, or intermediate sufficient to make more needed analogs, then you have enough. I'd prefer that reactions work well, of course, but "well" is defined in my mind as much (or more) by how clean the product is than how much of it gets produced. A lower-yielding reaction whose product falls out ready to use seems nicer than a higher-yielding one that needs careful chromatography to get the red stuff out of it.

That's the opposite of the way I used to think when I was doing my grad school work, of course. Twenty-seven steps in a row will get you thinking very hard indeed about yields, especially later on in the synthesis. It occurs to you pretty quickly that if you take a 50% yield on something that took you two months to make, that you're pouring a month's effort into the red waste can. If you're going to take a nasty yield in a long sequence, it's much better to get it over with in step one. You'll see this effect at work in papers that just start off from a literature reference intermediate (the "readily available compound 3" syndrome), which can mean that compound 3 is a nasty prep which would besmirch the rest of the sequence were it included.

I'd certainly think differently were I in process chemistry, too, of course. And when I have to work downstream on a project, I do spare a thought for the ease of the chemistry, because that's closer to the point where my optimization colleagues will have to deal with what we produce. But back at the early stage, I have to admit, I really don't care all that much. The vast majority of the compounds that get made back there are not going to go anywhere, so whatever gets them made and tested quickly is a good thing. The elegant synthesis is the one that gets it out of the lab and down the hall, whatever the yield might be.

Comments (13) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Anonymous on November 5, 2012 10:06 AM writes...

Unfortunately when I was employed in med chem my experience was not the same. Reporting a low yield for a reaction at group meeting was consistently met with disapproving looks from both the group leader and the project leader. Thus, it became necessary to do at least some reaction optimization even at an early stage in the project in order to avoid getting slammed during performance reviews.

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2. B on November 5, 2012 10:17 AM writes...

@1: On the other hand, my situation is the complete reversal. We often like to say in the lab that we're studying chemical biology, not organic chemistry. If a reaction works and we get enough product to test, who cares about the yield? It's the biological data that counts!

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3. anon the II on November 5, 2012 10:47 AM writes...

If you're a real synthetic organic chemist, you should always care about yield and purity. Your situation may change what you do about it, but you should always care. As one of those old 50+ chemists described in Derek's other post, I luckily found a job doing what a friend of mine calls a geriatric postdoc at about 1/4 the pay I used to get. But I get to do some synthetic chemistry. And when I get a 17% yield, I may move on, but I write "damn, where did all that stuff go?" in my notebook. I have to care. It's just who I am.

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4. petros on November 5, 2012 10:56 AM writes...

But of course in the really old days it was necessary to get enough pure sample for microanalysis as well as biological testing.

And J Med Chem insisted on such data long after many companies had abandoned its routine use.

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5. Henry's cat on November 5, 2012 11:01 AM writes...

I concur with the opinion that yields really don't matter in discovery. BUT there is one massive reason to keep an eye on them and that is: publications. You have to keep on top of these things as you never know when your route is going to be included in a patent or paper, and we all know every published yield is genuine.

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6. CMCguy on November 5, 2012 11:10 AM writes...

I agree that making the compounds is the primary medchem mission and thus not caring about what the yields are is a reasonable approach (i.e. "enough" convention) however do have issues if are not routinely bothering to even calculate outcomes. What do you do if you ever go to write a paper or a patent? Sure you can always go back then provide yields then but seem would have been easy enough to record yields during the work for providing a first sense of the adequacy of the route. As you correctly note people who work to generate more materials to run assessments in larger models (often still medchemists) and then the process chemists care greatly about yields and even though will realize involve unoptimized or preparation mode the med chemistry route is the typical starting point in the development and is extremely frustrating when lack fundamental details to evaluate where to focus the subsequent efforts. Tangentially I am glad to see HPLC more widely available and in use as reduces the calling them "greater than 95% pure" compounds based on NMR and TLC subsequently surprising the analytical or process chemists the first time they look at by HPLC and achieve results of 60-75% for main compound with the added mission of sorting out which impurity might be responsible for the observed activity.

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7. LeeH on November 5, 2012 11:28 AM writes...

Enough for what? An in-vitro assay? A solubility assay? A tox study? Don't you think that your colleagues may want to know the availability of the compound?

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8. Torn on November 5, 2012 11:48 AM writes...

The problem with the "just enough" mentality is it eventually ends up affecting our productivity. How much of our time is spent re-synthesizing, scaling-up or adapting sub-optimal routes to other interesting analogs. It seems that at a certain point, spending resources on synthetic efficiency, either to a key building block, or on a novel synthetic pathway will pay-off beyond the "just enough" mantra, particularly in LO. But who will take the risk of optimizing chemistry over producing more analogs. We're always walking the tight rope on the "good enough line"!

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9. processchemist on November 5, 2012 1:21 PM writes...

@6

Most of the times that I've been involved in synthetic medicinal chemistry projects, for every compound a minimum 96% HPLC grade was requested. For a customer that was usually performing in vivo SAR on rats (and so the amount for every compound was 500 mg-1 g) their QC was testing for total ashes too.
Every time I've been involved in a Kg/multi Kg scale up of a drug candidate or of an advanced intermediate, the medchem route was only a distant memory.

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10. RM on November 5, 2012 2:49 PM writes...

Torn @8

On the other hand, needless fretting about yields also saps productivity. If you avoid a one-week 10% overall yield protocol in favor of a two-week 70% yield one, you're not doing yourself any favors if, like most compounds, it bombs in preliminary studies. Sure, the HTS guys will be glad to take the excess 60% yield off your hands, but you're not getting that extra week of effort back.

I think that's Derek's point - at his stage of the game it's the number of compounds tested and the speed of compounds tested that counts. Sure, planning for scale-up is fine, but at a 10% or less chance that any given compound will make it to the next stage, expending even a small extra effort for any given compound isn't worthwhile, even if it would mean you expend zero extra effort on the next stage. (e.g. 100*1 + 10*3 is less than 100*1.5 + 10*0 )

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11. squib on November 5, 2012 8:10 PM writes...

I think Derek is spot on here. Coming from a methodology group, one of the weirdest things for me in industry was realizing how little yields matter. If you only need 10 mg, or sometimes far less, to run an assay, who cares how you get there. Early SAR is all about getting the most number of useful compounds into assays. A lot of the time you're doing a library off of a common intermediate which would not be a good synthetic route for scale up anyways.

For intermediates that you might be making a good deal of variants from, yields still matter. However, for final compounds for early SAR, ease of purification is key. You're losing material every time you run something through a mass-triggered HPLC, so a 25% yield that can be easily separated is far better than a 75% yield that takes careful chromatography. That is something it would of been hard for me to admit while still doing academic research...

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12. DrSnowboard on November 6, 2012 3:20 AM writes...

I did a dull powerpoint once showing the costs for a short analogue synthesis and how, unless a reagent was almost prohibitively expensive, chemist time was the most important cost. 25mg would take a compound from primary assay to a simple PK dose in rat, and that chemists should aim for 100mg, so you can not care about losses, rather than fight for keeping 10mg. Peoples perception of waste was eye-opening.

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13. optimization colleague on November 6, 2012 7:38 AM writes...

The answer depends where you work. If you work in early Med Chem then yields are less important, provided you can make enough of the compound you want. If you work in lead optimisation it's in your interest to start working on more efficient routes and individual yeilds, as this might help your project to progress more quickly. As a process chemist working on a high volume, high cost compound, every 1% increase in yield will repay your whole salary for a year.

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