Wednesday, November 11, 2015

Process Wednesday: the number of Suzukis done on process scale is less than I thought

From Organic Process Research and Development, a review by Elder and Teasdale [1]  on the difficultly in avoiding potentially genotoxic/reactive intermediates in later-stage syntheses. The authors reviewed the last decade of OPRD papers and found the following:
...The review covered 302 publications from this journal covering a 10-year period (2001−2010). The review data are provided in Tables S-1 to S-10 in the Supporting Information. (CJ's note: PDF) There was only one synthetic route (i.e., for netilmicin, published in 2002) that avoided the need to employ reactive intermediates during the entire synthesis....  
On the basis of this survey, we can conclude that the average number of steps required to synthesize each API was 5.9 and that the average number of reactive intermediates per synthetic route was 4.1. 
...In the second half of the decade (2006−2010; Figure 4), whilst these two classes of reactive intermediate (acid halide and alkyl halide) remained prevalent, they were joined by aromatic amines and Michael acceptors as the predominant classes. Aromatic amines (along with the related aromatic nitro precursors) have attained popularity because of the desire to introduce late-stage coupling reactions (e.g., Suzuki, Heck, etc.) into chemical schemes as part of green chemistry initiatives. Similarly, activated alkenes (or Michael acceptors) can readily undergo addition reactions with nucleophiles, one of the most attractive methods for the formation of C−C bonds, using mild reaction conditions. These findings are somewhat at odds with an earlier survey of good manufacturing practise (GMP) bulk reactions run in a research facility between 1985 and 2002, which showed that Michael addition reactions remained constant at about 7% of the total over that time period. However, this may be a vagary of the chemistries studied....
I am somewhat surprised at the relatively small number of boronic acids - I wonder if that number will either rise or fall for the 2010-2015 period? I wonder what future reactive intermediates will be seen?

1. Elder, D.P.; Teasdale, A. "Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?" Org. Process Res. Dev., Article ASAP DOI: 10.1021/op500346q


  1. aromatic amines and Michael acceptors are not all created equal. Only electron rich anilines are a problem (N-hydroxylation, quinone formation), electron deficient anilines, especially when substituted in para position are pretty innocuous - as various aminopyridines and aminopyrimidines attest. p-aminosalicylic acid was used as a tuberculostatic drug in doses in excess of 15 grams daily. Acrylates are bad but cinnamic acids, their amides etc are too lazy to act as a good Michael acceptor. There are sound reasons for avoiding nitro groups but there is a whole slew of old drugs (and even one new one) that have nitroaromatic part and they are safe.

  2. I've noticed that, at the scales usually used in academia, that the boron reagents used to prepare the boronic acid starting materials are usually rather pricey. By what factor does their price decrease, when used commercially?

  3. I've historically worked a couple of programs which use Suzuki couplings in key parts, although I've seen some process chemists try to stick those earlier in the synthesis (pre-GMP steps) in order to keep the residual Pd low throughout the GMP steps - scavenging resins aren't cheap. Additionally, I've anecdotally found that we can lower our catalyst charge if we're earlier in the synthesis, and with Pd(II) being the price it is that can make a difference in overall manufacturing costs.

    As for price, I've worked on two programs with late-stage Suzuki couplings, one with a small arylboronic acid which was by far the cheapest part of the compound, and one with a pinacolborane, made from (Bpin)2. The second program was for a semi-commodity API, so COG limited (it was for a new target to an currently-treated indication, and we were told our new pill had to be cost-competitive with the existing therapies), and that step didn't break the bank (I think we had to keep the API costs to <$25/pill, so <$70/g all-in.)

  4. There is also a report in OPRD discussing the mutagenicity of boronic acids, which may be a bit worrying for everyone?
    Hansen, M. M., Jolly, R. A., & Linder, R. J. (2015). Boronic Acids and Derivatives—Probing the Structure–Activity Relationships for Mutagenicity. Organic Process Research & Development,

  5. Good point - I know that boronic acids usually are hits in DEREK/Leadscope/SARAH software, and that it's been an expectation that any specific boron-containing compound we're using in GMP routes gets eventually put through an Ames or other tox test.

  6. I feel like Suzuki reactions are typically done more on the med chem side of things than the process side since it allows for simple SAR studies

  7. Interesting to see an aminoglycoside as the only one without reactive intermediates. Those antibiotics are a synthetic nightmare with 7-10 polar groups and 12-18 chiral centres each. Though the production of netilmicin is just the addition of an ethyl group to sisomicin, which might be why the reaction is comparatively mild. More complex aminoglycoside synthesis are still almost a no-go, we're limited to biological production or modification of biological ones.