Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

On the design of complex drug candidate syntheses in the pharmaceutical industry

Nature Reviews Chemistry volume 1, Article number: 0016 (2017) Cite this article

Subjects

An Erratum to this article was published on 01 March 2017

Abstract

The overall goal of a process chemistry department within the pharmaceutical industry is to identify and develop a commercially viable approach to a drug candidate. However, the high chemical complexity of many modern pharmaceuticals presents a challenge to process scientists. Delivering disruptive, rather than incremental, change is critical to maximizing synthetic efficiency in complex settings. In this Review, we focus on the importance of synthetic strategy in delivering ‘disruptive innovation’ — innovation that delivers a step change in synthetic efficiency using new chemistry, displacing any prior synthetic route. We argue that achieving this goal requires visionary retrosynthetic strategy and is tightly linked to the discovery and development of new reactions and novel processes. Investing in high-risk innovation during the route design process can ultimately lead to safer, more robust and more efficient manufacturing processes capable of addressing the challenge of high molecular complexity. Routinely delivering such innovation in a time-bound environment requires organizational focus and can be enabled by the concepts of expansive ideation, strategy aggregation and strategy selection.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The two cultures of chemistry in drug discovery and development, and enablers of disruptive innovation.
Figure 2: Maximizing convergency and route optionality (case 1).
Figure 3: Developing novelty in a crowded arena (case 2).
Figure 4: Route development through expansive exploration of a strategy (case 3).
Figure 5: High-impact, low-probability disconnections (case 4).
Figure 6: Extreme material requirements driving the development of a concise, cost-effective route (case 5).
Figure 7: Mechanistically designed robustness for the implementation of new chemistry (case 6).
Figure 8: Efficiency driven by degeneracy in synthesis design (case 7).

Similar content being viewed by others

References

  1. Anderson, N. G. Practical Process Research and Development (Academic Press, 2000).

    Google Scholar 

  2. Li, J. & Eastgate, M. D. Current complexity: a tool for assessing the complexity or organic molecules. Org. Biomol. Chem. 13, 7164–7176 (2015).

    Article  CAS  Google Scholar 

  3. Chase, C. E. et al. Process development of Halaven®: synthesis of the C1–C13 fragment from d-(−)-gulono-1,4-lactone. Synlett 24, 323–326 (2013).

    Article  CAS  Google Scholar 

  4. Austad, B. C. et al. Process development of Halaven®: synthesis of the C14–C35 fragment via iterative Nozaki–Hiyama–Kishi reaction–Williamson ether cyclization. Synlett 24, 327–332 (2013).

    Article  CAS  Google Scholar 

  5. Austad, B. C. et al. Commercial manufacture of Halaven®: chemoselective transformation en route to structurally complex macrocyclic ketones. Synlett 24, 333–337 (2013).

    Article  CAS  Google Scholar 

  6. Stinson, S. C. Chemistry 2020: a myopic vision? Chem. Eng. News 75, 28 (1997).

    Google Scholar 

  7. Stinson, S. C. Counting on chiral drugs. Chem. Eng. News 76, 83–104 (1998).

    Article  Google Scholar 

  8. Mullin, R. Breaking down barriers. Chem. Eng. News 85, 11–17 (2007).

    Google Scholar 

  9. Christensen, C. M. The Innovator's Dilemma: When New Technologies Cause Great Firms to Fail (Harvard Business School Press, 1997).

    Google Scholar 

  10. Li, J., Simmons, E. M. & Eastgate, M. D. A data-driven strategy for predicting greenness scores, rationally comparing synthetic routes and benchmarking PMI outcomes for the synthesis of molecules in the pharmaceutical industry. Green Chem. 19, 127–139 (2017).

    Article  CAS  Google Scholar 

  11. Kola, I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3, 711–715 (2004).

    Article  CAS  Google Scholar 

  12. Fitzgerald, M. A. et al. Functionalization in the formation of a complex heterocycle: synthesis of the potent JAK2 inhibitor BMS-911543. J. Org. Chem. 80, 6001–6011 (2015).

    Article  CAS  Google Scholar 

  13. Chen, K., Eastgate, M. D., Zheng, B. & Li, J. The development of scalable and efficient methods for the preparation of dicyclopropylamine HCl salt. Org. Process Res. Dev. 15, 886–892 (2011).

    Article  CAS  Google Scholar 

  14. Mudryk, B., Zheng, B., Chen, K. & Eastgate, M. D. Development of a robust process for the preparation of high-quality dicyclopropylamine hydrochloride. Org. Process Res. Dev. 18, 520–527 (2014).

    Article  CAS  Google Scholar 

  15. Schmidt, M. A. & Eastgate, M. D. Regioselective synthesis of 1,4-disubstituted imidazoles. Org. Biomol. Chem. 10, 1079–1087 (2012).

    Article  CAS  Google Scholar 

  16. Beutner, G. L. et al. A method for heteroaromatic nitration demonstrating remarkable thermal stability. Org. Process Res. Dev. 18, 1812–1820 (2014).

    Article  CAS  Google Scholar 

  17. Gallagher, W. P., Deshpande, P. P., Li, J. & Katipally, K. Method for producing festinavir using 5-methyluridine as a starting material. WO patent 2014172264 (2014).

  18. Gallagher, W. P., Deshpande, P. P., Li, J., Katipally, K. & Sausker, J. A Claisen approach to 4′-Ed4T. Org. Lett. 17, 14–17 (2015).

    Article  CAS  Google Scholar 

  19. Ortiz, A. et al. Scalable synthesis of the potent HIV inhibitor BMS-986001 by non-enzymatic dynamic kinetic asymmetric transformation (DYKAT). Angew. Chem. Int. Ed. 54, 7185–7188 (2015).

    Article  CAS  Google Scholar 

  20. Benkovics, T., Ortiz, A., Guo, Z., Goswami, A. & Deshpande, P. Enantioselective preparation of (S)-5-oxo-5,6-dihydro-2H-pyran-2-yl benzoate. Org. Synth. 91, 293–306 (2014).

    Article  CAS  Google Scholar 

  21. Ji, Y. et al. Mechanistic insights into the vanadium-catalyzed Achmatowicz rearrangement of furfurol. J. Org. Chem. 80, 1696–1702 (2015).

    Article  CAS  Google Scholar 

  22. Chen, K., Risatti, C. & Eastgate, M. in Strategies and Tactics in Organic Synthesis Vol. 11 (ed. Harmata, M. ) 171–233 (Elsevier, 2015).

    Google Scholar 

  23. Wengryniuk, S. E. et al. Regioselective bromination of fused heterocyclic N-oxides. Org. Lett. 15, 792–795 (2013).

    Article  CAS  Google Scholar 

  24. Chen, K. et al. Synthesis of the 6-azaindole containing HIV-1 attachment inhibitor pro-drug, BMS-663068. J. Org. Chem. 79, 8757–8767 (2014).

    Article  CAS  Google Scholar 

  25. Tran, K. et al. Development of a diastereoselective phosphorylation of a complex nucleoside via dynamic kinetic resolution. J. Org. Chem. 80, 4994–5003 (2015).

    Article  CAS  Google Scholar 

  26. Uchiyama, M., Aso, Y., Noyori, R. & Hayakawa, Y. O-Selective phosphorylation of nucleosides without N-protection. J. Org. Chem. 58, 373–379 (1993).

    Article  CAS  Google Scholar 

  27. Chamberlain, S., Igo, D., Bis, J. & Sukumar, S. Crystalline solvates of nucleoside phosphoroamidates, their stereoselective preparation, novel intermediates thereof, and their use in the treatment of viral disease. WO patent 2013066991 (2013).

  28. Goldberg, S. L. et al. Preparation of β-hydroxy-α-amino acid using recombinant d-threonine aldolase. Org. Process Res. Dev. 19, 1308–1316 (2015).

    Article  CAS  Google Scholar 

  29. Schmidt, M. A. et al. Development of a two-step, enantioselective synthesis of an amino alcohol drug candidate. Org. Process Res. Dev. 19, 1317–1322 (2015).

    Article  CAS  Google Scholar 

  30. Bartolozzi, A. et al. Oxadiazole inhibitors of leukotriene production. WO patent 2012024150 (2012).

  31. Marek, Y. et al. All-carbon quaternary stereogenic centers in acyclic systems through the creation of several C–C Bonds per chemical step. J. Am. Chem. Soc. 136, 2682–2694 (2014).

    Article  CAS  Google Scholar 

  32. Zeng, X. et al. Remarkable enhancement of enantioselectivity in the asymmetric conjugate addition of dimethylzinc to (Z)-nitroalkenes with a catalytic [(MeCN)4Cu]PF6–Hoveyda Ligand complex. Angew. Chem. Int. Ed. 53, 12153–12157 (2014).

    Article  CAS  Google Scholar 

  33. Stymiest, J. L., Bagutski, V., French, R. M. & Aggarwal, V. K. Enantiodivergent conversion of chiral secondary alcohols into tertiary alcohols. Nature 456, 778–782 (2008).

    Article  CAS  Google Scholar 

  34. Bagutski, V., Ros, A. & Aggarwal, V. K. Improved method for the conversion of pinacolboronic esters into trifluoroborate salts: facile synthesis of chiral secondary and tertiary trifluoroborates. Tetrahedron 65, 9956–9960 (2009).

    Article  CAS  Google Scholar 

  35. Bagutski, V., French, R. M. & Aggarwal, V. K. Full chirality transfer in the conversion of secondary alcohols into tertiary boronic esters and alcohols using lithiation–borylation reactions. Angew. Chem. Int. Ed. 49, 5142–5145 (2010).

    Article  CAS  Google Scholar 

  36. Sonawane, R. P. et al. Enantioselective construction of quaternary stereogenic centers from tertiary boronic esters: methodology and applications. Angew. Chem. Int. Ed. 50, 3760–3763 (2011).

    Article  CAS  Google Scholar 

  37. Rangaishenvi, M. V., Singaram, B. & Brown, H. C. Chiral synthesis via organoboranes. 30. Facile synthesis, by the Matteson asymmetric homologation procedure, of α-methyl boronic acids not available from asymmetric hydroboration and their conversion into the corresponding aldehydes, ketones, carboxylic acids and amines of high enantiomeric purity. J. Org. Chem. 56, 3286–3294 (1991).

    Article  CAS  Google Scholar 

  38. Scott, H. K. & Aggarwal, V. K. Highly enantioselective synthesis of tertiary boronic esters and their stereospecific conversion to other functional groups and quaternary stereocentres. Chem. Eur. J. 17, 13124–13132 (2011).

    Article  CAS  Google Scholar 

  39. Senanayake, C. H. & Krishnamurthy, D. Asymmetric synthesis for process research. Curr. Opin. Drug Discov. Dev. 2, 590–605 (1999).

    CAS  Google Scholar 

  40. Farina, V., Reeves, J. T., Senanayake, C. H. & Song, J. J. Asymmetric synthesis of active pharmaceutical ingredients. Chem. Rev. 106, 2734–2793 (2006).

    Article  CAS  Google Scholar 

  41. Hoppe, D., Hintze, F. & Tebben, P. Chiral lithium-1-oxyalkanides by asymmetric seprotonation; enantioselective synthesis of 2-hydroalkanoic acids and secondary alkanols. Angew. Chem. Int. Ed. Engl. 29, 1422–1424 (1990).

    Article  Google Scholar 

  42. Hoppe, D. & Hense, T. Enantioselective synthesis with lithium/(−)-sparteine carbanion pairs. Angew. Chem. Int. Ed. Engl. 36, 2282–2316 (1997).

    Article  CAS  Google Scholar 

  43. Matteson, D. S., Soundararajan, R., Ho, O. C. & Gatzweiler, W. (Alkoxyalkyl)boronic ester intermediates for asymmetric synthesis. Organometallics 15, 152–163 (1996).

    Article  CAS  Google Scholar 

  44. Fandrick, K. R. et al. Addressing the configuration stability of lithiated secondary benzylic carbamates for the development of a noncryogenic stereospecific boronate rearrangement. Org. Lett. 16, 4360–4363 (2014).

    Article  CAS  Google Scholar 

  45. Fandrick, K. R. et al. Development of an asymmetric synthesis of a chiral quaternary FLAP inhibitor. J. Org. Chem. 80, 1651–1660 (2015).

    Article  CAS  Google Scholar 

  46. Fandrick, K. R., Gao, J. J., Mulder, J. A., Patel, N. D. & Zheng, X. Process for the preparation of carboxamidine compounds. WO Patent 2013119751 (2013).

  47. Munchhof, M. J. et al. Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened. ACS Med. Chem. Lett. 3, 106–111 (2012).

    Article  CAS  Google Scholar 

  48. Gillard, J. et al. Preparation of (2S,4R)-4-hydroxypipecolic acid and derivatives. J. Org. Chem. 61, 2226–2231 (1996).

    Article  CAS  Google Scholar 

  49. Peng, Z., Wong, J. W., Hansen, E. C., Puchlopek-Dermenci, A. L. A. & Clarke, H. J. Development of a concise, asymmetric synthesis of a smoothened receptor (SMO) inhibitor: enzymatic transamination of a 4-piperidinone with dynamic kinetic resolution. Org. Lett. 16, 860–863 (2014).

    Article  CAS  Google Scholar 

  50. Wiss, J., Fleury, C. & Onken, U. Safety improvement of chemical processes involving azides by online monitoring of the hydrazoic acid concentration. Org. Process Res. Dev. 10, 349–353 (2006). Azide processes and, in particular, the formation of hydrazoic acid are an important safety concern for large-scale synthesis.

    Article  CAS  Google Scholar 

  51. Wells, A. What is in a biocatalyst? Org. Process Res. Dev. 10, 678–681 (2006).

    Article  CAS  Google Scholar 

  52. Wells, A. S., Finch, G. L., Michels, P. C. & Wong, J. W. Use of enzymes in the manufacture of active pharmaceutical ingredients — a science and safety-based approach to ensure patient safety and drug quality. Org. Process Res. Dev. 16, 1968–1993 (2012).

    Article  Google Scholar 

  53. Wells, A. S. et al. Case studies illustrating a science and risk-based approach to ensuring drug quality when using enzymes in the manufacture of active pharmaceuticals ingredients for oral dosage form. Org. Process Res. Dev. 20, 594–601 (2016).

    Article  CAS  Google Scholar 

  54. Saville, C. K. et al. Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture. Science 329, 305–309 (2010). This paper offers a notable example of the use of a transaminase in the manufacture of sitagliptin.

    Article  Google Scholar 

  55. Bravo, F. et al. Development of a dynamic kinetic resolution for the isolation of an intermediate in the synthesis of casopitant mesylate: application of QbD principles in the definition of the parameter ranges, issues in the scale-up and mitigation strategies. Org. Process Res. Dev. 14, 1162–1168 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank all of the collaborators and researchers who have worked on these fascinating molecules during their development. M.D.E. and M.A.S. are especially grateful to P. Baran for insightful discussions and inspiration, along with S. Tummala, R. Waltermire, A. Ortiz and C. Guerrero for helpful discussions.

Author information

Authors and Affiliations

  1. Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, 08901, New Jersey, USA

    Martin D. Eastgate & Michael A. Schmidt

  2. Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, 06877, Connecticut, USA

    Keith R. Fandrick

Authors
  1. Martin D. Eastgate
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael A. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keith R. Fandrick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin D. Eastgate.

Ethics declarations

Competing interests

The authors declare no competing interests.

PowerPoint slides

Glossary

Ideation

Ensuring the robust and expansive evaluation of all key strategic bonds, developing a much fuller retrosynthetic analysis before entering the lab, and using the collective wisdom of multiple researchers to raise and address concerns.

Strategy aggregation

Taking the multiple synthetic proposals, or proposed disconnections, and collating them into clusters of aligned core disconnection strategies or reactivities, not focusing on any individual technology or precedent. Key experiments can rapidly be explored in the lab to assist in the triaging of strategies.

Strategy selection

Aligning the team on selecting a strategy, not an individual synthesis proposal. The selected strategy should have multiple related synthetic options (for example, shared reactivity patterns or common intermediates) such that high-risk disruptive approaches can be investigated, while data gained from the exploration can be applied to lower-risk proposals. Appropriate selection can also lead to a more effective staged approach to synthesis development, which is often crucial in aligning work to the risk of the drug progressing to market.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eastgate, M., Schmidt, M. & Fandrick, K. On the design of complex drug candidate syntheses in the pharmaceutical industry. Nat Rev Chem 1, 0016 (2017). https://doi.org/10.1038/s41570-017-0016

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/s41570-017-0016

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing