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EP-4735459-A1 - METHODS AND INTERMEDIATES FOR PREPARING ANTIVIRAL PRODRUGS

EP4735459A1EP 4735459 A1EP4735459 A1EP 4735459A1EP-4735459-A1

Abstract

The present invention is related to processes for preparing antiviral prodrugs, co-crystals, solvents, salts or combinations thereof, and related synthetic intermediate compounds (I).

Inventors

  • CHTCHEMELININE, Andrei
  • WILLIAMSON, Kevin S.
  • CIZIO, Gregory
  • DISCOLO, Christopher
  • ENQUIST, John
  • MAN, Lucas
  • NEVILLE, SEAN T.
  • SARMA, KESHAB
  • SHI, BING
  • SUN, Leon X.

Assignees

  • GILEAD SCIENCES, INC.

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. 1. A process for preparing a compound of formula I: or a co-crystal, solvate, salt, or combination thereof; comprising reacting a compound of formula XVII: or a co-crystal, solvate, salt, or combination thereof, with a compound of formula XVIII: wherein X is selected from halo, -OCOCIhPh, and OH, and a base, to provide the compound of formula I or a co-crystal, solvate, salt, or combination thereof.
  2. 2. The process of claim 1 , wherein X is halo.
  3. 3. The process of claim 1 or 2. wherein X is Cl.
  4. 4. The process of claim 1, wherein X is OH, and die reacting is performed in the presence of an activating reagent.
  5. 5. The process of claim 4, wherein the activating reagent comprises a chlorinating reagent. 1,1-carbonyldiimidazole, a carbodiimide, a peptide coupling reagent, or combination thereof.
  6. 6. The process of claim 4 or 5, wherein the activating reagent is selected from the group consisting of oxalyl chloride, thionyl chloride, phosphoryl chloride, 1,1 -carbonyldiimidazole, 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide, HATU, propylphosphonic anhydride, and isobutyl chloroformate.
  7. 7. The process of any one of claim 1-6, wherein the base comprises an aromatic amine, tertiary alkyl amine, carbonate, or combination thereof.
  8. 8. The process of any one of claims 1-7, wherein the base comprises an aromatic amine.
  9. 9. The process of any one of claims 1-8, wherein the base is N-methylimidazole.
  10. 10. The process of any one of claims 1-9, wherein the reacting is performed in a first solvent comprising acetone and acetonitrile.
  11. 11. The process of any one of claims 1-10, wherein the reacting is carried out in a temperature range of from about -20 °C to about 10 °C.
  12. 12. The process of any one of claims 1-11, wherein the reacting is performed in the presence of a catalyst.
  13. 13. The process of claim 12, wherein the catalyst is selected from the group consisting of 4- dimethylaminopyridine, imidazole, triphenylphosphine oxide, and l-hydroxy-7- azabenzotriazole.
  14. 14. The process of any one of claims 1-13, further comprising preparing the compound of formula XVII or a co-crystal, solvate, salt, or combination thereof by a process comprising: reacting a compound of formula XVI-A: or a co-crystal, solvate, salt, or combination thereof, wherein P 1 is H or (R 4 )sSi, wherein each R 4 is independently Ci-6 alkyl, with a de-acylation reagent, and a second base, to provide the compound of formula XVII or a co-crystal, solvate, salt, or combination thereof.
  15. 15. The process of claim 14, wherein P 1 is trimethylsilyl.
  16. 16. The process of claim 14 or 15, wherein the de-acylation reagent is a C 1-4 alcohol.
  17. 17. Tire process of any one of claims 14-16, wherein the de-acylation reagent is methanol.
  18. 18. The process of any one of claims 14-17, wherein the second base comprises a hydroxide, oxide, methoxide, rer/-butoxide, carbonate, or combination thereof.
  19. 19. The process of any one of claims 14-18, wherein the second base is sodium methoxide.
  20. 20. The process of any one of claims 14-19, wherein from about 0.02 to about 0.2 equivalents of the second base are utilized relative to the compound of formula XVI-A or a cocrystal, solvate, salt, or combination thereof.

Description

METHODS AND INTERMEDIATES FOR PREPARING ANTIVIRAL PRODRUGS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/523,555, filed on June 27, 2023, which is hereby incorporated herein by reference in its entirety for all purposes. TECHNICAL FIELD The present invention relates to methods and intermediates for the synthesis of antiviral prodrugs, co-crystals, solvates, salts, or combinations thereof, and related synthetic intermediate compounds. BACKGROUND The present disclosure relates generally to the field of organic synthetic methodology for the preparation of antiviral prodrugs and their synthetic intermediates. Positive-single stranded RNA viruses comprising the Retroviridae family include those of the subfamily Orthoretrovirinae and genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Spumavirus, and Lenttvirus, which cause many human and animal diseases. Among the Lenttvirus, HIV-1 infection in humans leads to depletion of T helper cells and immune dysfunction, producing immunodeficiency and vulnerability to opportunistic infections. One approach to treating HIV-1 infection is by administering NRTTIs. NRTTIs inhibit HIV-1 reverse transcriptase and, because reverse transcriptase function is essential for viral replication and production of viral proteins, NRTTIs can be effective against HIV-1 infection. Curr Opin HIV AIDS. 2018 July; 13(4): 294-299. HIV treatments, however, have historically led to the emergence of HIV strains that are resistant to current therapies. Expert Opin Emerg Drugs. 2018 June; 23(2): 149-157. Therefore, there is an ongoing need to discover new antiretroviral agents and to develop methods for their preparation and purification. U.S. Patent Application No. 17/642,552 discloses novel compounds useful for treating HIV infection. One specific compound identified therein is a compound of formula I: There is currently a need for improved synthetic methods and intermediates that can be used to prepare the compound of formula I and co-crystals, solvates, salts, and combinations thereof. There is also a need for improved methods for preparing intermediate compounds that can be used to prepare the compound of formula I and its co-crystals. solvates, salts, and combinations thereof. The improved methods and intermediates may reduce the cost, time, and/or the amount of waste associated with the existing methods for preparing the compound of formula 1 and co-crystals, solvates, salts, and combinations thereof. The methods disclosed herein meet these and other needs. SUMMARY The present disclosure provides, inter alia, processes of preparing a compound of formula I: or a co-crystal, solvate, salt, or combination thereof; comprising reacting a compound of formula XVII; or a co-crystal, solvate, salt, or combination thereof, with a compound of formula XVIII: wherein X is selected from halo, -OCOCHjPh, and OH, and a base, to provide the compound of formula I or a co-crystal, sol vate, salt, or combination thereof. The present disclosure further provides a process for preparing a compound of formula 1: or a co-crystal, solvate, salt, or combination thereof; comprising reacting a compound of formula XXII: or a co-crystal, solvate, salt, or combination thereof, wherein R6 is selected from C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, benzyloxy, or C6-10 aryl optionally substituted with 1 to 5 substituents independently selected from C1-4 alkyl. C1-4 haloalkyl, halo, C1-4 alkoxy, or benzyloxy, with a compound of formula XV: a silylating reagent, and a Lewis acid. to provide the compound of formula 1 or a co-crystal, solvate, salt, or combination thereof. The details of one or more embodiments of the invention are set forth in the accompanying description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION lire present disclosure provides processes of preparing a compound of formula I: and co-cry stals, solvates, salts, or combinations thereof. The compound of formula I is also known as phenylacetoxy)meihyl)tetrahydrofuran-3-yl 2-phenylacetate and is disclosed in U.S. Publication Nos. 20220323476A1 and 20220332751 Al, the disclosures of each of which are incorporated herein by reference in their entireties. The compound of formula I is a prodrug of the compound of formula XVH (/.<?., islatravir, 4 -ethyny l-2-fluoro-2'-deoxyadenosine, or , a nucleoside reverse transcriptase translocation inhibitor (NRTTI) useful for treating a Relroviridae viral infection, including an infection caused by the HIV virus. The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The