A diastereoselective synthesis of boceprevir's gem-dimethyl bicyclic [3.1.0] proline intermediate from an insecticide ingredient cis-cypermethric acid

Kallam, Srinivasa Reddy; Eda, Vishnuvardhan Reddy; Sen, Saikat; Datrika, Rajender; Rapolu, Rajesh Kumar; Khobare, Sandip R.; Gajare, Vikas; Banda, Malavika; Khan, Rashid Abdul Rehman; Singh, Manpreet; Lloyd, Michael C.; Kandagatla, Bhaskar; Janagili, Moses Babu; Tadikonda, Veerabhadra Pratap; Siddaiah, Vidavalur; Iqbal, Javed; Fox, Martin E.; Dahanukar, Vilas H.; Oruganti, Srinivas

doi:10.1016/j.tet.2017.05.080

Cited by 10 publications

(4 citation statements)

References 24 publications

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“…Of note, compound 8 , a bicyclic proline methyl ester derivative containing three chiral centers, is a key building unit in the synthesis of nirmatrelvir. Since 8 is also a building block of boceprevir, many different synthetic routes have been described for it [ 27 ].…”

Section: Protease Inhibitors As Antiviralsmentioning

confidence: 99%

“…Several other peptidomimetic inhibitors of SARS-CoV-2 M pro (Figure 5A) have been developed with different warheads, including an epoxide ring (26), a fluoromethyl group (27), a cinnamic ester (28) and a vinyl ester (29). In the latter two compounds, the α,βunsaturated ester warhead acts as a Michael acceptor, reacting with the thiolate group of M Pro Cys145, thus forming an irreversible covalent adduct with the enzyme [6,34,35].…”

Section: Novel Covalent and Non-covalent Inhibitors Of Sars-cov-2 M Promentioning

confidence: 99%

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The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19

Bege,

Borbás

2024

Pharmaceutics

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The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms of action and some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. The most effective small-molecule drug approved to date for the treatment of COVID-19 is PaxlovidTM, which is a combination of two protease inhibitors, nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (Mpro) of SARS-CoV-2, which enzyme plays a crucial role in viral reproduction. In this combination, ritonavir serves as a pharmacokinetic enhancer, it irreversibly inhibits the cytochrome CYP3A4 enzyme responsible for the rapid metabolism of nirmatrelvir, thereby increasing the half-life and bioavailability of nirmatrelvir. In this tutorial review, we summarize the development and pharmaceutical chemistry aspects of Paxlovid, covering the evolution of protease inhibitors, the warhead design, synthesis and the mechanism of action of nirmatrelvir, as well as the synthesis of ritonavir and its CYP3A4 inhibition mechanism. The efficacy of Paxlovid to novel virus mutants is also overviewed.

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Section: Protease Inhibitors As Antiviralsmentioning

confidence: 99%

Section: Novel Covalent and Non-covalent Inhibitors Of Sars-cov-2 M Promentioning

confidence: 99%

The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19

Bege,

Borbás

2024

Pharmaceutics

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“…www.publish.csiro.au/ch Australian Journal of Chemistry Different synthetic routes were described for 5, usually having as starting material either a proline scaffold or a cyclopropyl group-containing compound. [13]…”

Section: Patent Synthesismentioning

confidence: 99%

Development and patent synthesis of nirmatrelvir – the main component of the first oral drug against SARS-CoV-2 Paxlovid

Cotrim

Barros

2022

Aust. J. Chem.

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Nirmatrelvir is the main component of the first oral drug against SARS-CoV-2 called Paxlovid®. Its development from an orally unavailable predecessor through hydrogen bond donors (HBD) replacement is highlighted, followed by an examination of the synthetic routes described in the original PCT application WO2021/250648. Based on its attributes, nirmatrelvir shows the potential to be a game changer in SARS-CoV-2 treatment.

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“…Cyclopropane‐fused heterocycles are common motifs in natural products and pharmacologically active analogs , . While access to these rigid bicyclic frameworks presents synthetic challenges due to the inherent conformational constraints, the preparation of a number of cyclopropylidene lactones and cyclopropylidene lactams have been developed over the years. However, there are only a few examples of cyclopropylidene iminolactones, which have occasionally been prepared through base‐mediated cyclization of the corresponding γ‐hydroxynitriles, thus severely limiting structural variation .…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Synthesis of Cyclopropylidene Iminolactones and Functionalized Cyclopropanecarboxamides Mediated by Triflic Acid

Maximiano

Mandolesi

2019

Eur J Org Chem

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A straightforward synthesis of cyclopropylidene iminolactones mediated by triflic acid under mild conditions is described. Different types of hydroxy‐substituted cyclopropanecarboxamides containing a variety of functional groups participated in this smooth cyclization through an intramolecular SN2 attack of the amidic oxygen on the protonated carbinol group with the release of water. Ten cyclopropylidene iminolactones were readily obtained in high purity after a basic work‐up with no additional chromatographic separation (62–98 % yield). Besides the simplicity, the method is highly diastereoselective and tolerates several functional groups, demonstrating the broad scope of this process. Selected iminolactones were applied in further synthetic transformations to give functionalized cyclopropanecarboxamides through hydrogenolysis or nucleophilic ring‐opening reactions.

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A diastereoselective synthesis of boceprevir's gem-dimethyl bicyclic [3.1.0] proline intermediate from an insecticide ingredient cis-cypermethric acid

Cited by 10 publications

References 24 publications

The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19

The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19

Development and patent synthesis of nirmatrelvir – the main component of the first oral drug against SARS-CoV-2 Paxlovid

Stereoselective Synthesis of Cyclopropylidene Iminolactones and Functionalized Cyclopropanecarboxamides Mediated by Triflic Acid

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