Preparation of the HIV Attachment Inhibitor BMS-663068. Part 8. Installation of the Phosphonoxymethyl Prodrug Moiety

Fox, Richard J.; Cohen, Benjamin; Cruz, Thomas E. La; Simpson, James H.; Freitag, Adam; Saurer, Eric M.; Tripp, Jonathan C.; Chen, Chien-Kuang; Beutner, Gregory L.; Rosso, Victor W.; Borgeson, Elizabeth; Glace, Andrew W.; Eastgate, Martin D.; Schild, Richard L.; Sweeney, Jason T.; Conlon, David A.

doi:10.1021/acs.oprd.7b00135

Cited by 6 publications

(3 citation statements)

References 5 publications

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“…The choice of base in the reaction was investigated first. Similar to other literature examples using 3 , − it was found that when inorganic bases were used at reduced temperatures, the reaction was selective for alkylation at N-1. In contrast, when mild organic bases were used under ambient or increased temperatures, the reaction was completely selective for N-7.…”

Section: Resultssupporting

confidence: 83%

Mechanistic Evaluation and Solvent-Based Linear Free Energy Relationship in the Alkylation of ABT-199 Using Di-tert-butyl Chloromethyl Phosphate

Harper

Klix

et al. 2021

Org. Process Res. Dev.

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To ensure successful scale-up for a prodrug of ABT-199, the key alkylation step was optimized, and the mechanism was explored. The use of 1,8-bis(dimethylamino)naphthalene was essential for high conversion and selectivity, and statistical experimental design yielded the optimal stoichiometries to maximize the yield and minimize impurities. Kinetic interrogation demonstrated that the rate-determining step was phosphate activation and not alkylation as might be presumed, and evidence for a radical chain mechanism was uncovered. Further support for a radical chain mechanism was found in a novel solvent-based linear free energy relationship between the Hansen solubility parameters and the observed rate. The level of mechanistic understanding informed successful scale up to 1, 10, and 20 kg.

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Section: Resultssupporting

confidence: 83%

Mechanistic Evaluation and Solvent-Based Linear Free Energy Relationship in the Alkylation of ABT-199 Using Di-tert-butyl Chloromethyl Phosphate

Harper

Klix

et al. 2021

Org. Process Res. Dev.

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“…Fostemsavir was synthesized in a linear sequence as described in Schemes and . The evolution of the synthetic approach to this molecule from the initial medicinal chemistry route to commercial routes (scaled to >1000 kg) has been described in a series of literature reports from Bristol-Myers Squibb. ,,− Sulfonyl pyrrole 27 underwent a three-step sequence involving a Friedel–Crafts acylation using acetyl chloride and AlCl 3 , an α-chlorination of the resulting ketone using N -chlorosuccinimide (NCS) and MsOH, and a displacement of the resulting chloroketone with sodium tosylamide 28 . This three-step, telescoped sequence rapidly resulted in the delivery of ketopyrrole 29 in 62–75% yield .…”

Section: Anti-infective/antibiotic Drugsmentioning

confidence: 99%

“…The final step was deprotection of the t -Bu phosphonate ester in 39 to reveal the phosphoric acid moiety in fostemsavir. Hydrolysis was achieved by treatment with acetic acid, and the addition of tris (hydroxymethyl)aminomethane (TRIS) in acetone resulted in precipitation of the TRIS salt of fostemsavir ( IV ) as a white, crystalline solid in 88% yield …”

Section: Anti-infective/antibiotic Drugsmentioning

confidence: 99%

Synthetic Approaches to the New Drugs Approved During 2020

et al. 2022

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New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody–drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.

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Large‐Scale Synthesis

Cole

2021

Burger's Medicinal Chemistry and Drug Discovery

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Large‐scale synthesis enables drug discovery, clinical development, and commercialization for new small molecule medicines. Several key disciplines collaborate to develop and define chemical processes, and ensure that they are suitable for large‐scale manufacturing activities. This article will discuss how new drugs transition from the medicinal chemistry laboratory, to kilo‐scale facilities, to pilot, and eventually to commercial scale. Important topics along the way include route selection, process safety, environmental considerations, equipment and facility types, scale‐dependent phenomenon, continuous processing, outsourcing, development models, and regulatory considerations. The article concludes with recent two case studies that highlight some of the topics covered and exemplify the power of process development and large‐scale production for modern small molecule drugs.

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Preparation of the HIV Attachment Inhibitor BMS-663068. Part 8. Installation of the Phosphonoxymethyl Prodrug Moiety

Cited by 6 publications

References 5 publications

Mechanistic Evaluation and Solvent-Based Linear Free Energy Relationship in the Alkylation of ABT-199 Using Di-tert-butyl Chloromethyl Phosphate

Mechanistic Evaluation and Solvent-Based Linear Free Energy Relationship in the Alkylation of ABT-199 Using Di-tert-butyl Chloromethyl Phosphate

Synthetic Approaches to the New Drugs Approved During 2020

Large‐Scale Synthesis

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