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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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August 6, 2007

Here, Fix This, Would You?

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Posted by Derek

As I mentioned the other day, drug companies manage the shift from med-chem to process in a lot of different ways. (For those outside the industry, the medicinal chemists are focused on making relatively small amounts of a lot of different compounds, while the process labs concentrate on making large amounts of a few). Some places allow the med-chem labs to use whatever wild chemistry they can think up, on the theory that if a compound is really interesting the process labs will find a way to make it on scale. Others strongly discourage some kinds of chemistry (particularly nasty solvents and reagents), since real problems can occur if a lead compound comes from that sort of background.

I incline more to the latter. Perhaps it's just a dislike of leaving messes for other people to clean up. But I'm not as pure as I might sound, because I have done some ugly reactions (mercury, organoazides, etc) in my med-chem analoging, and these were real possibilities for trouble if the compounds had ever taken off (they didn't). In these cases, the unappealing reactions were by far the fastest way into the compounds I wanted, and I figured that I'd take a quick look and see if they were any good. (The same reasoning, I'm sure, had led to most of nightmares that process groups find themselves in).

Other things being equal, though, I'd rather approach my drug analogs using something that isn't demonstrably foul. I suppose that's as good a middle ground as any - try not to use hideous reagents, but if they're the quick way into a series, go ahead - but be mindful of the tradeoff you're making. If you go the next step, where the ugly stuff is (as far as you can tell) the only way into a series, then you're taking a real risk and should only do it with a reasonable expectation that it'll be worth it. It's very hard to have reasonable expectations of that kind in medicinal chemistry, though - which is why this sort of thing shouldn't become a habit.

The comments that came in to my recent post on this topic were all over the place - I wouldn't mind seeing an informal head count of how various departments feel on this issue. If we get a decent sample, I'll post on the results.

Comments (19) + TrackBacks (0) | Category: Drug Development


1. such.ire on August 6, 2007 11:42 PM writes...

I was always under the impression that finding a good clinical candidate always tended to be the limiting step in finding a drug, rather than the process-chem step. Is that so, or is it just a misconception? If it's true, then wouldn't it be best not to make the hardest step even harder by semi-arbitrarily limiting the pool of possibilities? Or is the reason that since there are too many possibilities and not good ways to limit it, that you simply choose a convenient way to concentrate on only one part of the chemical space?

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2. milkshake on August 7, 2007 12:02 AM writes...

If one wanted to be perfectly process-friendly, he would have to avoid chromatography and dichloromethane, and -78C among other things. But there is no time to optimize in medchem if 95% of all stuff ends up discarded.

However, using obviously unpleasant chemistry feels "inelegant" to most chemists, it is just like putting extra chiral centers in the molecule. There has to be a good rational for doing it. One usually starts with the simplier things, the chemistry that offers least resistance.

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3. MTK on August 7, 2007 6:55 AM writes...

Speaking as a process chemist, a nice clean, easily scalable route from med chem is a plus, but really should not be the job of the med chemist, IMO. Don't get me wrong, we like to bitch about the crappy med chem route, but only to make us look better later. Sort of like the fighter pilot who will always claim that the guy he shot down was the greatest pilot ever to push a throttle.

As for things such as chromatography, low temp chemistry, and so forth. My advice to a med chemist is don't even worry about it. Just do it. Most process groups can handle all of that, or at least outsource those steps which it can't do. To give you an idea, we've done 20 kg chiral chromatographies, sodium azide reactions on 50 kg scale, tBuLi reactions on 10 kg scale. If the compound goes anywhere your route is going to trashed anyway, so don't bother trying to fix it. Whatever time you spend getting rid of those items would be better spent getting the PK, bioavailability, and all those other things right. I truly believe that the med chemist has one of the most difficult jobs in pharma research. No sense making it even more difficult by adding the responsibilities of the process chemist.

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4. Buddha on August 7, 2007 8:07 AM writes...

I concur with MTK. I believe as a medicinal chemist if you are worried about what the process chemist is going to think about your route, your focus is in the wrong place. Make targets that are going to add value to the project as quickly as possible. If that means a Stille coupling, so be it. Trust your process group. Can you imagine hearing "Yeah, he got the recommendation candidate but he used a Stille coupling. What a hack!"

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5. Clark Kent on August 7, 2007 8:27 AM writes...

"But there is no time to optimize in medchem if 95% of all stuff ends up discarded."

All the projects I worked on made 1-10K compounds before canidate selection, So its more like >99.9% get discarded.

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6. pc on August 7, 2007 10:24 AM writes...

"If you go the next step, where the ugly stuff is (as far as you can tell) the only way into a series, then you're taking a real risk and should only do it with a reasonable expectation that it'll be worth it."

This probably is an extreme on the scale. My guess is most med chem falls in between. Well if this does occur and one feels strongly about his/her candidates, why not sit down and chatt with the process folks and see what they can come up with. This is probably a good time to initiate such communications.

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7. weirdo on August 7, 2007 10:36 AM writes...

I think how a research group approaches this topic has a lot more to do with how good the process group is, as opposed to how fast the medchem group is.

If I worked at Merck, I'd use any old nasty reagent I could lay my hands on. The Merck process guys are legendary, there are a lot of them, and they can fix anything.

It's a sliding scale after that, all the way down to "Let's see how good our overseas CRO's can make this." At this end of the scale, you better not have anything but pour and roar reactions in your scheme, or it won't matter how promising your candidate is. Trust your process guys? Only if I know where they are, and can speak their language.

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8. SynChem on August 7, 2007 10:44 AM writes...

Completely agree with MTK. Medicinal chemists shouldn't hesitate to use the technologies and methodologies that our process colleagues would avoid.

Having said that, I'd be a bit leery if my medchem colleagues a couple of hoods down tried to use mercury reagents or hexamethylditin. I think it puts everyone's health in jeopardy, which is why I have the habit of leaving my shoes outside of the house. In grad school, I worked with Thallium salt and hexamethylditin a lot. Don't ever want to deal with those things again.

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9. milkshake on August 7, 2007 3:03 PM writes...

Last week I did a Dieckmann condensation on t-Bu acetoacetate dianion and I replaced HMPA-THF that the procedure called for with TMEDA-THF; On a 10g scale I was making favaor to myself (rather then trying to help a process chemist).

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10. AR on August 7, 2007 3:31 PM writes...

I have a question that is a bit out of the topic, but again is related to work with toxic stuff.
I am trying to reduce this azide in the last step of the synthesis of a molecule that contains acid and base sensitive protecting groups (also sensitive to hydrogenation). So far I have tried trimethylphosphine/H2O, mercaptoethanol and Na2S in pyridine/H2O they are all very slow (azide in a secondary carbon) and the yields are only about 30%.
I found this procedure that uses H2S in pyridine and the authors claim a quantitave conversion to the amine; since my synthesis is on the multigram scale I am a little bit concern with using that stuff. Has anyone worked with this gas before on a medium to large scale, and if so do you have any tips, experiences or recommendations. Any advice will be appreciate. Thanks.

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11. milkshake on August 7, 2007 4:25 PM writes...

I am suprised Me3P was slow in your case because this phosphine adds to trityl azide at room temperature in THF to produce Ph3C-N(-)N=N-PMe3(+) which upon addition of a carbonyl compound splits N2 and forms trityl ketimine. Trityl azide is pretty hindered and unreactive, with decomp temperature well above 200C.

If your molecule has no esters or other reactive carbonyls that can get eaten by borohydride, your can try 2M LiBH4 in THF with added catalytic amount of elementary selenium (5 mol%), it dissolves to form a yellowish solution and the in-situ formed lithium selenide is a powerful reducing agent. You have to do it under Ar because Li-selenide is very air sensitive. If the reduction is lazy at RT, you can heat up to 50C.

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12. WC on August 7, 2007 4:33 PM writes...

I've mostly worked for small companies that don't have extensive process chemistry capabilities. As a result, we've had to do some of the preliminary process work when we get to the compound(s) we think will be produced on a larger scale (>100g) and then outsource our work. I've found the outsourcing to be hit or miss. Some places are fantastic and others not so fantastic. Having internal talented process chemistry would make life easier.

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13. Polymer Bound on August 7, 2007 7:16 PM writes...

My company has a fantastic process group, so I'm of the "whatever it takes to make the compound quickly" mindset. As leading compounds are profiled, you usually are given the opportunity to scale them a couple of times which allows some attempts at optimization and nastiness circumvention. Most of my first syntheses don't use anything even remotely process like. I use a lot of solid resins and sealed tube microwave chemistry that would need to be re-worked... something I often end up doing for a re-synthesis.

Besides toxicity and handling issues, all kinds of other issues come into play in process research like cost, exotherms, reliability, ability to crystallize intermediates. There's a reason those folks walk with a swagger. If your compound gets to the manufacturing stage, most likely there will be nothing left of the med chem route. You do have to feel really bad for the folks responsible for first delivery though.

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14. Petros on August 8, 2007 2:28 AM writes...

The process guys can't always sort things out.

In working on a candidate that made it to phase II an initial shortage of process resources (in the Wonder Drug Factory's home) meant that our small research group had to deliver kg quantities of drug for initial tox.

We provided a synthesis of a chiral compound on that scale and with a process that avoided chromatography. However, the process guys never managed out to sort out two capricious steps that meant the cost of goods became a serious issue.

The first was generation of an ldehyde, prone to polymerisation, via a Rosenmund reduction, and the subsequent Wittig reaction where yields were consistently modest.

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15. milkshake on August 8, 2007 2:55 AM writes...

In early 90s we had a pretty potent and safe tripeptide Xa factor inhibitor that was orally available and could have replaced coumarins. But the Marion Merell process group was rather disfunctional (they got a new bos and we got their ex-boss to be our new site-director, he turned out as a agressive braggard + scheming imbecile, I wonder if he was responsible for the mess in the process group at Marion). So their process group never managed to produce L-para-cyanophenyl alanine in kilo quantities even though the synthesis and enzymatic resolution was quite straightforward 3 step task; always there was some snag about capacity, broken reactors and key personell leaving. As the company was going through yet another merger with Hoechst, there was re-evaluation of projects and clinical candidates - and our compound was deemed hard to make and not sufficiently block-buster like.

Sometimes good projects die for completely non-scientific reasons.

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16. Philiocrates on August 8, 2007 12:10 PM writes...

In our company, we (Process R&D) engage early with Med Chem and find that early interactions can benefit both parties. I agree that its Med Chems role to find the best candidate come what may, but if it can be done with scaleable chemistry then it helps us and speeds up time to the first 3-5 Kg for 28 day tox and Phase I. Our input can also save time for Med Chem in suggesting suitable chemistry for multigram syntheses of intermediates to a series. If HMPA, tin and similar are present then at least we get early warning and can assign resource early to address these issues.

I'm all in favour of Med Chem and Process early collaboration.

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17. Ed Vawtrer on August 8, 2007 1:54 PM writes...

Speaking as another process chemst of 15 years, I appreciate it when med chem folks at least are aware of these issues. I personally believe in early collaboration and having process chemists attend drug discovery group meetings. I was involved in a project at BMS about 12 years ago than went very well primarily because I had attended that discovery groups meetings for the previous year or so and so was aware of the many things tried that didn't work that never seem to get written up in tech transfer documents. We saved approx 6-10 months of work on the initial development becuase of this arrangement. This was one of the primary reasons back then BMS had proces development on the same site as many of the drug discovery groups.

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18. CMC guy on August 9, 2007 10:26 AM writes...

The thread of comments above bring out many good points and highlights out a common distinction between typical Big Pharm vs Biotech type operations. Most (though not all) large companies tend toward "throw over the wall" interactions in med chem/process chem as is implied in the title subject. Smaller companies tend to have more overlap if they even have real process groups at all (rather than med chemist charged with making large quantities). Early interactions are a benefit to both and can lead to faster discovery and development although each group must perform its own mission. Choices not just in chemical options but identification of possible problem starting material analogs (i.e. no real source beyond catalog) or different physiochemical properties (crystal vs. amorphous) saves headaches when can be applied to help select between lead compounds of similar activity.
Med chem focus is on biological results and getting to a candidate that is best regardless of the possible warts. Expediency is the norm and using "exotic" reagents and conditions often chosen although sometime things seem to follow "academic fads" when old/simpler reagents do the exact transformations. Process people deal with the demands of the chemistry along with multiple different requirements such as safety, costs, analytical and regulatory. Its fun to be part of the rivalry and its nice when cooperation leads to mutual stimulation but success drugs requires each group to do good work.

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19. anon on August 22, 2007 2:19 AM writes...

Someone said to me that a med chem gets 40 % yield after flash chromatography and thinks that he has done a good job; a process chemist gets a 95 % yield after recrystalisation and thinks that he has done a poor job because of his 5 % loss in yield.

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