Doravirine

Doravirine
Clinical data
Trade names	Pifeltro
Other names	MK-1439
AHFS/Drugs.com	Monograph
MedlinePlus	a618048
License data	US DailyMed: Doravirine;
Routes of; administration	By mouth
ATC code	J05AG06 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only; EU: Rx-only;
Identifiers
	IUPAC name 3-Chloro-5-({1-[(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-2-oxo-4-(trifluoromethyl)-1,2-dihydro-3-pyridinyl}oxy)benzonitrile;
CAS Number	1338225-97-0;
PubChem CID	58460047;
DrugBank	DB12301;
ChemSpider	28424197;
UNII	913P6LK81M;
KEGG	D10624;
ChEMBL	ChEMBL2364608;
PDB ligand	2KW (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID30158386 ;
ECHA InfoCard	100.234.454
Chemical and physical data
Formula	C17H11ClF3N5O3
Molar mass	425.75 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES Cn1c(n[nH]c1=O)Cn2ccc(c(c2=O)Oc3cc(cc(c3)Cl)C#N)C(F)(F)F;
	InChI InChI=1S/C17H11ClF3N5O3/c1-25-13(23-24-16(25)28)8-26-3-2-12(17(19,20)21)14(15(26)27)29-11-5-9(7-22)4-10(18)6-11/h2-6H,8H2,1H3,(H,24,28); Key:ZIAOVIPSKUPPQW-UHFFFAOYSA-N;

Doravirine, sold under the brand name Pifeltro, is a medication used in the treatment of HIV/AIDS.^[1] It is a non-nucleoside reverse transcriptase inhibitor developed by Merck.^[1]

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 kilogram scale synthesis of doravirine was 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 functional group 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). Temperature controlled alkylation with iodomethane and potassium carbonate completed the synthesis of doravirine (9).

References

1 2 3 4 "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.
↑ "Pifeltro Monograph" (PDF). Health Canada. 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., et al. (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., et al. (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, et al. (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.

[Pifeltro_FDA_label-1] 1 2 3 4 "Pifeltro- doravirine tablet, film coated". DailyMed. 10 October 2019. Retrieved 22 September 2020.

[2] 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.

[3] "Pifeltro Monograph" (PDF). Health Canada. Retrieved 5 June 2022.

[4] "Drug and medical device highlights 2018: Helping you maintain and improve your health". Health Canada. 14 October 2020. Retrieved 17 April 2024.

[5] "Pifeltro 100 mg film-coated tablets - Summary of Product Characteristics (SmPC)". Medicines.org.uk. Retrieved 1 October 2020.

[6] "Pifeltro EPAR". European Medicines Agency (EMA). 21 September 2018. Retrieved 1 October 2020.

[7] "Drug Approval Package: Pifeltro (doravirine)". U.S. Food and Drug Administration (FDA). 9 October 2018. Retrieved 22 September 2020.

[8] "Delstrigo EPAR". European Medicines Agency (EMA). 4 August 2023.

[9] Flick, A. C., Leverett, C. A., Ding, H. X., McInturff, E., Fink, S. J., Helal, C. J., et al. (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.

[10] Campeau, L.-C., Chen, Q., Gauvreau, D., Girardin, M., Belyk, K., Maligres, P., et al. (19 August 2016). "A Robust Kilo-Scale Synthesis of Doravirine". Organic Process Research & Development. 20 (8): 1476–1481. doi:10.1021/acs.oprd.6b00163.

[11] "Synthesis of Doravirine". Synfacts. 12 (11): 1114–1114. 18 October 2016. doi:10.1055/s-0036-1589295.

[pmid24412110-12] Côté B, Burch JD, Asante-Appiah E, Bayly C, Bédard L, Blouin M, et al. (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.

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