An alternative synthesis of the non-small cell lung carcinoma drug afatinib

Kovačević, Tatjana; Mesić, Milan; Avdagić, Amir; Žegarac, Miroslav

doi:10.1016/j.tetlet.2018.10.026

Cited by 10 publications

(7 citation statements)

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“…The resulting aniline is then coupled with diethylphosphonoacetic acid, followed by a Horner–Wittig reaction to introduce the acrylamide moiety of 23 . Alternative synthetic methods to prepare 23 have been reported elsewhere. − …”

Section: Fda-approved Kinase Inhibitors From 2011 To 2015mentioning

confidence: 99%

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

et al. 2021

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The central role of dysregulated kinase activity in the etiology of progressive disorders, including cancer, has fostered incremental efforts on drug discovery programs over the past 40 years. As a result, kinase inhibitors are today one of the most important classes of drugs. The FDA approved 73 small molecule kinase inhibitor drugs until September 2021, and additional inhibitors were approved by other regulatory agencies during that time. To complement the published literature on clinical kinase inhibitors, we have prepared a review that recaps this large data set into an accessible format for the medicinal chemistry community. Along with the therapeutic and pharmacological properties of each kinase inhibitor approved across the world until 2020, we provide the synthesis routes originally used during the discovery phase, many of which were only available in patent applications. In the last section, we also provide an update on kinase inhibitor drugs approved in 2021.

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Section: Fda-approved Kinase Inhibitors From 2011 To 2015mentioning

confidence: 99%

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

et al. 2021

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“…The synthesis of afatinib (Scheme 1) from the commercially available 2-amino-4fluorobenzoic acid 1 was reported by Kovacevic et al [39]. The iodination of compound 1 using sodium periodate and potassium iodide afforded compound 2 which underwent intramolecular cyclization with formamide acetate to give the dihydroquinazoline 3.…”

Section: Synthesismentioning

confidence: 99%

“…The chlorination of compound 5 with thionyl chloride yielded 4-chloro-6-iodoquinazoline 6, which was reacted with 3-chloro-4-fluoroanilin 7 to give compound 8. The reaction of 8 with (E)-4-(dimethylamino)but-3-enamide 9 afforded afatinib [39].…”

Section: Synthesismentioning

confidence: 99%

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

et al. 2021

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Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.

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“…It is worth mentioning that a satisfying yield was also noticed with the phenyl group separated from the primary amide function through a double bond (76%, product 2-Acry, entry 14), but not through a triple bond (entry 15). These results were predictable since primary acrylamides have already been employed as coupling partners in copper-catalysed N-arylation under similar conditions 46 but primary propiolamides have, to the best of our knowledge, never being used in such reactions.…”

Section: Accepted Manuscriptmentioning

confidence: 83%