Doravirine
| Clinical data | |
|---|---|
| Trade names | Pifeltro |
| Other names | MK-1439 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a618048 |
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| Routes of administration | By mouth[1][2] |
| ATC code | |
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| DrugBank | |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.234.454 |
| Chemical and physical data | |
| Formula | C17H11ClF3N5O3 |
| Molar mass | 425.75 g·mol−1 |
| 3D model (JSmol) | |
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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.[7]
Doravirine is available in fixed-dose combinations with other HIV drugs such as doravirine/lamivudine/tenofovir (sold under the brand name Delstrigo).[8]
Synthesis
A robust kilogram scale synthesis of doravirine was recently reported:[9][10][11][12]
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
- ^ a b "Pifeltro- doravirine tablet, film coated". DailyMed. 10 October 2019. Retrieved 22 September 2020.
- ^ Collins S, Horn T. "The Antiretroviral Pipeline" (PDF). Pipeline Report. p. 10. Archived from the original (PDF) on 11 March 2016. Retrieved 6 December 2015.
- ^ "PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION : PIFELTRO" (PDF). Pdf.hres.ca. Retrieved 5 June 2022.
- ^ "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada. 14 October 2020. Retrieved 17 April 2024.
- ^ "Pifeltro 100 mg film-coated tablets - Summary of Product Characteristics (SmPC)". Medicines.org.uk. Retrieved 1 October 2020.
- ^ "Pifeltro EPAR". European Medicines Agency (EMA). 21 September 2018. Retrieved 1 October 2020.
- ^ "Drug Approval Package: Pifeltro (doravirine)". U.S. Food and Drug Administration (FDA). 9 October 2018. Retrieved 22 September 2020.
- ^ "Delstrigo EPAR". European Medicines Agency (EMA). 4 August 2023.
- ^ Flick, A. C., Leverett, C. A., Ding, H. X., McInturff, E., Fink, S. J., Helal, C. J., DeForest, J. C., Morse, P. D., Mahapatra, S., O’Donnell, C. J. (8 October 2020). "Synthetic Approaches to New Drugs Approved during 2018". Journal of Medicinal Chemistry. 63 (19): 10652–10704. doi:10.1021/acs.jmedchem.0c00345.
- ^ Campeau, L.-C., Chen, Q., Gauvreau, D., Girardin, M., Belyk, K., Maligres, P., Zhou, G., Gu, C., Zhang, W., Tan, L., O’Shea, P. D. (19 August 2016). "A Robust Kilo-Scale Synthesis of Doravirine". Organic Process Research & Development. 20 (8): 1476–1481. doi:10.1021/acs.oprd.6b00163.
- ^ "Synthesis of Doravirine". Synfacts. 12 (11): 1114–1114. 18 October 2016. doi:10.1055/s-0036-1589295.
- ^ Côté B, Burch JD, Asante-Appiah E, Bayly C, Bédard L, Blouin M, Campeau LC, Cauchon E, Chan M, Chefson A, Coulombe N, Cromlish W, Debnath S, Deschênes D, Dupont-Gaudet K, Falgueyret JP, Forget R, Gagné S, Gauvreau D, Girardin M, Guiral S, Langlois E, Li CS, Nguyen N, Papp R, Plamondon S, Roy A, Roy S, Seliniotakis R, St-Onge M, Ouellet S, Tawa P, Truchon JF, Vacca J, Wrona M, Yan Y, Ducharme Y (February 2014). "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. doi:10.1016/j.bmcl.2013.12.070. PMID 24412110.