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Editorial pubs.acs.org/OPRD
BMS-663068: Another Quiet Victory for Chemistry
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of these wondrous achievements is practically shrouded in secrecy. In fact, most of the society equates chemistry with pollution and being part of a problem rather than celebrating the almost magical solutions it continually provides. One such example of the majesty of chemistry, this time in the development of a potential medicine (BMS-663068) to block the entry of HIV-1 virus into healthy cells, is outlined in this
f the many tabulated lists of humanity’s greatest accomplishments circulating on the Internet, few if any acknowledge the advent of modern medicine as a critical inflection point in the evolution of our species. Indeed, the dramatic relief of human suffering, from the alleviation of pain to cures for infectious disease, can be clearly traced to advances in this area. These days, the simple fact that chemical synthesis is at the heart
Figure 1. Selected medicinal chemistry efforts leading to the discovery of BMS-663068. Special Issue: From Invention to Commercial Process Definition: The Story of the HIV Attachment Inhibitor BMS-663068
© XXXX American Chemical Society
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Figure 2. BMS-663068: From the enabling route to commercial synthesis.
issue of OPR&D. The nine back-to-back publications contained herein are a veritable case study of the mission of modern pharmaceutical development to provide life-saving medicines to patients [Pub. 1, 10.1021/acs.oprd.7b00134; Pub. 2, 10.1021/ acs.oprd.7b00121; Pub. 3, 10.1021/acs.oprd.7b00115; Pub. 4, 10.1021/acs.oprd.7b00152; Pub. 5, 10.1021/acs.oprd.7b00132; Pub. 6, 10.1021/acs.oprd.7b00133; Pub. 7, 10.1021/acs.oprd.7b00191; Pub. 8, 10.1021/acs.oprd.7b00135; Pub. 9, 10.1021/acs.oprd.7b00138]. They represent the equivalent of hundreds of person-years’ effort by numerous process chemists from Bristol-Myers Squibb. One of us (P.S.B.) had the privilege of observing and participating in a very small way in this adventure starting in late 2005. Before diving into an overview of the innovation and accomplishments delineated in this issue, it is worth reflecting on the remarkable discoveries made by medicinal chemists
leading to the identification of BMS-663068. As illustrated in Figure 1, the story of this potential medicine spans two decades with the first lead emerging in the early 2000s (dates based on public disclosures in peer-reviewed journals).1−5 In addition to great insights into the biochemical mode of action,6,7 every aspect of the lead structures inspired the development of useful chemistry. For example, the departure from the initial indole-based lead structure to various azaindole isomers required the development of a rapid Bartoli-based method for azaindole construction.8 The Lewis-basic azaindole nitrogen could then be blocked in situ to allow for selective Friedel−Crafts reactions to take place.9 A new strategy was introduced so that the differentially acylated piperidine motif could be accessed in a programmable fashion.10,11 Finally, the 1,2-dicarbonyl function could be accessed through a unique oxidative approach capitalizing on the reactivity of α-amino nitriles.12,13 Several of the above B
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innovations can now be found in textbooks.14 The final medicinal chemistry route was relatively efficient and allowed for the flexible installation of all of the requisite subunits to enable extensive SAR investigations. While not depicted here, the route could also be adapted in a radiochemical sense to provide key intermediates for metabolic studies.15 A graphical overview of the chemistry covered in this issue is depicted in Figure 2. As a testament to the attractiveness of the discovery route to BMS-663068, the first scale-up routes were largely modeled from it. Thus, the first publication in this series [DOI: 10.1021/acs.oprd.7b00134] outlines the deft adaptation of the discovery route to deliver 100 kg of the pro-drug under extreme time constraints. The need for a commercial-scale synthesis then spurred departure from this initial approach after extensive route scouting, an alternative strategy to construct the azaindole core from simple pyrrole building blocks was disclosed in the second publication [DOI: 10.1021/ acs.oprd.7b00121].16 To overcome the scale dependence of the key Friedel−Crafts pyrrole acylation, rigorous mechanistic studies were undertaken, culminating in a scalable acylation− chlorination−amidation sequence depicted in the third publication [DOI: 10.1021/acs.oprd.7b00115]. The fourth publication [DOI: 10.1021/acs.oprd.7b00152] describes the construction of the azaindole core where robust Pictet−Spangler conditions and an efficient radical-based aromatization strategy were developed after assiduous experimentations. Regioselective installation of the C5 bromide was detailed in the fifth publication [DOI: 10.1021/acs.oprd.7b00132]the sequence was adroitly telescoped to circumvent the isolation of the intermediary N-oxide. It is in this context that our involvement extended beyond consulting visits and entered, into our own lab, the first publication of the BMS−Scripps collaboration.17 In the sixth publication [DOI: 10.1021/acs.oprd.7b00133], the oxalyl side chain was appended under phase transfer catalysis where gelling of the reaction mixture was averted; a subsequent one-pot amidation protocol was also developed that scales beyond 200 kg. The triazole motif was installed via an Ullmann-GoldbergBuchwald coupling which proceeded with exquisite regiochemical control as reported in the seventh publication [DOI: 10.1021/acs.oprd.7b00191]kinetic analysis performed by Blackmond and co-workers played an important role in this study. The conversion of the API to the lithium salt conferred favorable morphology. The eighth publication [DOI: 10.1021/ acs.oprd.7b00135] presented an efficient phosphonoxymethylation18 protocol that was enabled by a salt metathesis process; an N-6 alkylation byproduct was conveniently removed via an aqueous workup. The resulting penultimate intermediate was converted to BMS-663068 through deprotection and tris-salt formationthis final process, detailed in the ninth publication [DOI: 10.1021/acs.oprd.7b00138], eliminated the vexatious slurry-to-slurry transformation, furnishing BMS-663068 of consistent quality on pilot plant scales. While this incredible story is eye-opening and brimming with innovation, it is not a singularity within the realm of pharmaceutical development.19 Legions of talented and passionate chemists toil away over the span of decades with the mission of providing cures to patients in an efficient and environmentally friendly way. Their victories go mostly unnoticed by the society they humbly seek to serve, with the details of exciting conquests mostly deposited into the quiet storm of the patent literature. In this regard, the Bristol-Myers Squibb chemists should be applauded for scholarly summarizing this huge body of work into such an educational and coherent set of must-read publications.
This issue of OPR&D will undoubtedly serve as an inspiration to both current and aspiring practitioners of the art and science of drug development.
Ming Yan Phil S. Baran*
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Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Phil S. Baran: 0000-0001-9193-9053 Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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ACKNOWLEDGMENTS
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REFERENCES
BMS-663068 was part of a BMS−ViiV transaction, and development of the asset is now being progressed by ViiV Healthcare.
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(14) For example, see: Ishihara, Y.; Montero, A.; Baran, P. S. The Portable Chemist’s Consultant, version 2.7.1; Apple Publishing Group: New York, 2016. (15) Ekhato, I. V.; Rinehart, J. K. J. Labelled Compd. Radiopharm. 2011, 54, 289. (16) Chen, K.; Risatti, C.; Bultman, M.; Soumeillant, M.; Simpson, J.; Zheng, B.; Fanfair, D.; Mahoney, M.; Mudryk, B.; Fox, R. J.; Hsaio, Y.; Murugesan, S.; Conlon, D. A.; Buono, F. G.; Eastgate, M. D. J. Org. Chem. 2014, 79, 8757. (17) Wengryniuk, S. E.; Weickgenannt, A.; Reiher, C.; Strotman, N. A.; Chen, K.; Eastgate, M. D.; Baran, P. S. Org. Lett. 2013, 15, 792. (18) Zheng, B.; Fox, R. J.; Sugiyama, M.; Fritz, A.; Eastgate, M. D. Org. Process Res. Dev. 2014, 18, 636. (19) For examples, see: (a) Anderson, N. G. Practical Process Research & Development, 2nd ed.; Academic Press: San Diego, 2012. (b) Yasuda, N., Ed. The Art of Process Chemistry; Wiley-VCH: Weinheim, 2011. (c) Nafissi, M., Ragan, J. A., DeVries, K. M., Eds. From Bench to Pilot Plant: Process Research in the Pharmaceutical Industry; ACS Symposium Series 817; American Chemical Society: Washington, DC, 2003. (d) Gadamasetti, K. G., Ed. Process Chemistry in the Pharmaceutical Industry; Marcel Dekker: New York, 1999.
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