Chemistry:Doravirine
Doravirine, sold under the brand name Pifeltro, is a non-nucleoside reverse transcriptase inhibitor medication developed by Merck & Co. for use in the treatment of HIV/AIDS.
Doravirine was approved for medical use in the United States in August 2018.[1]
Doravirine is available in fixed-dose combinations with other HIV drugs such as doravirine/lamivudine/tenofovir (sold under the brand name Delstrigo).[2]
Synthesis
A robust kilogram scale synthesis of doravirine was recently reported:[3][4][5][6]
A reaction catalyzed with cyclooctadiene iridium methoxide dimer and bis(pinacolato)diboron followed by treatment with ozone converted 1-chloro-3-iodobenzene [625-99-0] (1) to 3-chloro-5-iodophenol [861347-86-6] (2). A SNAr reaction with 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine [628692-22-8] (3) led to diaryl ether, 2-chloro-3-(3-chloro-5-iodophenoxy)-4-(trifluoromethyl)pyridine [1338226-06-4] (4). Basic hydrolysis followed by recrystallization gave rise to 2-pyridinol, PC58460051 (5). Introduction of the nitrile using copper cyanide in NMP was achieved under relatively mild conditions. Keeping the temperature under 110 °C was critical for suppressing undesired bis-cyanation products, and that the iodide was chosen over the analogous bromide to further help ensure selectivity for the desired mono-nitrile product, PC58460048 (6). Alkylation with 5-(Chloromethyl)-2,4-dihydro-4-methyl-3H-1,2,4-triazol-3-one [1338226-21-3] (7) was possible under mild conditions to give 2-pyridone [1338226-05-3] (8). Alkylation with iodomethane and potassium carbonate in cool NMP completed the synthesis of doravirine (9).
References
- ↑ "Drug Approval Package: Pifeltro (doravirine)". 9 October 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210806Orig1s000,210807Orig1s000TOC.cfm.
- ↑ "Delstrigo EPAR". 4 August 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/delstrigo.
- ↑ "Synthetic Approaches to New Drugs Approved during 2018". Journal of Medicinal Chemistry 63 (19): 10652–10704. 8 October 2020. doi:10.1021/acs.jmedchem.0c00345. https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00345.
- ↑ "A Robust Kilo-Scale Synthesis of Doravirine". Organic Process Research & Development 20 (8): 1476–1481. 19 August 2016. doi:10.1021/acs.oprd.6b00163. https://pubs.acs.org/doi/10.1021/acs.oprd.6b00163.
- ↑ "Synthesis of Doravirine". Synfacts 12 (11): 1114–1114. 18 October 2016. doi:10.1055/s-0036-1589295. http://www.thieme-connect.de/DOI/DOI?10.1055/s-0036-1589295.
- ↑ "Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses". Bioorganic & Medicinal Chemistry Letters 24 (3): 917–22. February 2014. doi:10.1016/j.bmcl.2013.12.070. PMID 24412110.
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