Processes for preparing antiviral compounds

• US 9,890,134 B2
• Filed: 04/28/2017
• Issued: 02/13/2018
• Est. Priority Date: 06/11/2014
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Allan, Kevin M., Fujimori, Shinji, Heumann, Lars V., Huynh, Grace May, Keaton, Katie Ann, Levins, Chrisopher M., Pamulapati, Ganapati Reddy, Roberts, Benjamin James, Sarma, Keshab, Teresk, Martin Gerald, Wang, Xiang, Wolckenhauer, Scott Alan
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US15/582,224
• Publication Number:
  US 20170283390A1
• Time in Patent Office: 291 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 (I-a), stereoisomer thereof, or mixture of stereoisomers thereof:

2. The method of claim 1, wherein the reaction conditions of step (a) comprise a solvent selected from the group consisting of N,N-dimethylacetamide, N,N-dimethylformamide, and acetonitrile.

3. The method of claim 1, wherein the reaction conditions of step (a) comprise a temperature of from about 20°

C. to about 80°

C.

4. The method of claim 1, wherein the reaction conditions of step (a) comprise at least one of a palladium catalyst, a carbonate salt, and a phosphine reagent.

5. The method of claim 1, wherein the reaction conditions of step (b) comprise a brominating reagent selected from the group consisting of pyridiniumtribomide, bromine, and N-bromosuccinimide.

6. The method of claim 1, wherein the reaction conditions of step (b) comprise a solvent selected from the group consisting of dichloromethane, methanol, and a mixture thereof.

7. The method of claim 1, wherein the reaction conditions of step (b) comprise a temperature of about 20°

C.

8. The method of claim 1, wherein the compound of formula (L):

9. The method of claim 8, wherein X¹ is halo, —

OH, or —

S(O)₂R³, and R³ is alkyl, haloalkyl, or aryl, and the aryl is optionally substituted with halo, alkyl, or haloalkyl.

10. The method of claim 8, wherein the reaction conditions comprise a solvent selected from the group consisting of N,N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, and acetonitrile.

11. The method of claim 8, wherein the reaction conditions comprise a temperature of from about 20°

C. to about 70°

C.

14. The method of claim 8 where the compound of formula (M):

12. A compound of formula (L):

13. The compound of claim 12, wherein Z is bromo.