Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19

Allais, Christophe; Bernhardson, David; Brown, Adam R.; Chinigo, Gary M.; Desrosiers, Jean‐Nicolas; DiRico, Kenneth J.; Hotham, Ian; Jones, Brian P.; Kulkarni, Samir A.; Lewis, Chad A.; Lira, Ricardo; Loach, Richard P.; Morse, Peter D.; Mousseau, James J.; Perry, Matthew A.; Peng, Zhihui; Place, David W.; Rane, Anil; Samp, Lacey; Singer, Robert A.; Wang, Zheng; Weisenburger, Gerald A.; Yayla, Hatice G.; Zanghi, Joseph M.

doi:10.1021/acs.oprd.2c00375

Cited by 15 publications

(12 citation statements)

References 40 publications

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“…The overall process used for these initial campaigns is depicted in Scheme . Building on internal experience from the development of a similar amidation reaction used in the synthesis of lufotrelvir, the western fragment 5 was coupled with eastern fragment 6 using EDCI and 2-hydroxypyridine- N -oxide (HOPO) in methyl ethyl ketone (MEK). The reaction mixture was quenched with acidic brine and charged with MTBE to facilitate the separation of the liquid phases.…”

Section: Initial Campaigns and Screening Of Steps 3 Andmentioning

confidence: 99%

Synthesis of Nirmatrelvir: Design and Optimization of an Efficient Telescoped Amidation–Dehydration Sequence

Algera,

Baldwin,

Bowles

et al. 2023

Org. Process Res. Dev.

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Development of a scalable route for the synthesis of nirmatrelvir, the novel SARS-CoV-2 3C-like protease inhibitor discovered in 2020 by Pfizer scientists, was initiated shortly thereafter to supply material for the first clinical studies. This route was optimized for commercial manufacture of nirmatrelvir in high yield and acceptable quality with consideration of efficiency and sustainability. Herein, we report the evolution of final steps (3−5) used to synthesize nirmatrelvir (steps 3−5), from the manufacture of the initial regulatory lot to the design and implementation of the final commercial process.

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Section: Initial Campaigns and Screening Of Steps 3 Andmentioning

confidence: 99%

Synthesis of Nirmatrelvir: Design and Optimization of an Efficient Telescoped Amidation–Dehydration Sequence

Algera,

Baldwin,

Bowles

et al. 2023

Org. Process Res. Dev.

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“…Chiral aminolactam 5.5 is a fragment that was known in the literature and common to previous drug candidates. The recent report of the scaled synthesis of lufotrelvir provided process optimization details, as shown in Scheme . First, careful control of temperature in the diastereoselective alkylation of glutamic acid derivative 5.11 using LiHMDS as base provided nitrile 5.12 in >99:1 d.r.…”

Section: Anti-infective/antibiotic Drugsmentioning

confidence: 99%

“…The recent report of the scaled synthesis of lufotrelvir provided process optimization details, as shown in Scheme 8. 63 First, careful control of temperature in the diastereoselective alkylation of glutamic acid derivative 5.11 using LiHMDS as base provided nitrile 5.12 in >99:1 d.r. Due to poor crystallinity, intermediate 5.12 was telescoped forward to a reduction using either hydrogenation with Raney nickel or cobalt and sodium borohydride to access amine 5.13, which could readily cyclize to lactam 5.14.…”

Section: Nirmatrelvir/ritonavir (Paxlovid)mentioning

confidence: 99%

Synthetic Approaches to the New Drugs Approved During 2021

McInturff,

France,

Leverett

et al. 2023

J. Med. Chem.

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Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody−drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021. ■ SIGNIFICANCEThis publication presents a synopsis of the synthetic approaches to new drugs that were approved in 2021, based on the largest scale of synthesis that has been disclosed in primary literature and/or patents. This provides a view of the practical synthetic methods that are applicable to drug discovery and development and a holistic perspective on the molecular complexity of novel drug molecules and synthetic methods required to manufacture them.

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“…Importantly, another Pfizer team was focused on the IV candidate lufotrelvir ( 26 ), which is the phosphate pro-drug of PF-00835231 ( 25 ). Their work included significant optimization of the sequence shown in Figure a, including identification of tosylate salt 31 as a crystalline intermediate that avoided the need for chromatographic purification of intermediate 30 . Consequently, the nirmatrelvir team was able to leverage the availability of tosylate salt 31 in the preparation of carboxamide starting material 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Their work included significant optimization of the sequence shown in Figure 9 a, including identification of tosylate salt 31 as a crystalline intermediate that avoided the need for chromatographic purification of intermediate 30 . 27 Consequently, the nirmatrelvir team was able to leverage the availability of tosylate salt 31 in the preparation of carboxamide starting material 3 . The preparation of primary amide 3 is shown in Figure 9 b.…”

Section: Introductionmentioning

confidence: 99%