Processes for preparing antiviral compounds

• US 9,670,187 B2
• Filed: 06/08/2015
• Issued: 06/06/2017
• Est. Priority Date: 06/11/2014
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Wolckenhauer, Scott Alan, Allan, Kevin M., Fujimori, Shinji, Heumann, Lars V., Huynh, Grace May, Keaton, Katie Ann, Levins, Christopher M., Pamulapati, Ganapati Reddy, Teresk, Martin Gerald, Roberts, Benjamin James, Wang, Xiang, Sarma, Keshab
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US14/733,139
• Publication Number:
  US 20150361073A1
• Time in Patent Office: 729 Days
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 49/755 a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
• CPC Class Codes: C07C 49/80 containing halogen
• CPC Class Codes: C07C 49/82 containing hydroxy groups
• CPC Class Codes: C07D 311/78 Ring systems having three or more relevant rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 491/052 the oxygen-containing ring being six-membered

Abstract

The present disclosure provides processes for the preparation of a compound of formula:

which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates.

Claims

1. A method for preparing a compound of formula (A), a salt thereof, or solvate thereof:

2. The method of claim 1, wherein X is bromo and Y is bromo.

3. The method of claim 1, wherein the reaction conditions of step (a) comprise a solvent selected from the group consisting of dichloromethane, 2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, dimethylformamide, acetone, methyl ethyl ketone, and methyl isobutyl ketone.

4. The method of claim 1, wherein the reaction conditions of step (a) comprise a temperature of from about 10°

C. to about 60°

C. or from about 10°

C. to about 30°

C.

5. The method of claim 1, wherein the reaction conditions of step (a) comprise a phosphate salt or a carbonate salt.

6. The method of claim 1, wherein the salt of the compound of formula (J) is a potassium, a sodium, or a cesium salt.

7. The method of claim 1, wherein the reaction conditions of step (b) comprise a solvent selected from the group consisting of tetrahydrofuran, 2-m ethyltetrahydrofuran, dichloromethane, toluene, isopropyl acetate, ethyl acetate, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, acetone, methyl ethyl ketone, methyl isobutyl ketone, and a mixture thereof.

8. The method of claim 1, wherein the reaction conditions of step (b) comprise a temperature of from about 40°

C. to about 60°

C. or from about 40°

C. to about 50°

C.

9. The method of claim 1, wherein the reaction conditions of step (b) comprise a phosphate salt or a carbonate salt.

10. The method of claim 1, wherein the salt of the compound of formula (H) is a potassium, a sodium, or a cesium salt.

11. The method of claim 1, wherein the reaction conditions of step (c) comprises an amine reagent, wherein the amine reagent comprises ammonium acetate, hexamethyldisilzane, ammonia, ammonium formate, ammonium propionate, ammonium hexanoate, or ammonium octanoate.

12. The method of claim 1, wherein the reaction conditions of step (c) comprise a solvent selected from the group consisting of toluene, xylene, an alcohol, and a mixture thereof.

13. The method of claim 1, wherein the reaction conditions of step (c) comprise a temperature of from about 60°

C. to about 110°

C. or from about 85°

C. to about 95°

C.

14. The method of claim 1, wherein the reaction conditions of step (d) comprise an oxidant.

15. The method of claim 14, wherein the oxidant is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

16. The method of claim 1, wherein the additive is acetic acid.

17. The method of claim 1, wherein the reaction conditions of step (d) comprise 2-methyltetrahydrofuran or a mixture of toluene and tetrahydrofuran.

18. The method of claim 1, wherein the reaction conditions of step (d) comprise a temperature of from about −

10°

C. to about 80°

C. or from about −

15°

C. to about 10°

C.

19. The method of claim 1, wherein step (e) further comprises neutralizing the compound of formula (E).