Processes for preparing antiviral compounds

Patent metadata

Field	Value
Publication number	US-9670187-B2
Application number	US-201514733139-A
Country	US
Kind code	B2
Filing date	Jun 8, 2015
Priority date	Jun 11, 2014
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

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.

First claim

The invention claimed is:

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

comprising the steps of:
(a) contacting a compound of formula (I), stereoisomer thereof, or mixture of stereoisomers thereof:

with a compound of formula (J) or salt thereof:

under conditions sufficient to yield a compound of formula (G), stereoisomer thereof, or mixture of stereoisomers thereof:

(b) contacting the compound of formula (G) with a compound of formula (H) or salt thereof:

under conditions sufficient to yield a compound of formula (B), stereoisomer thereof, or mixture of stereoisomers thereof:

(c) cyclizing a compound of formula (B) under conditions sufficient to yield a compound of formula (C):

(d) dehydrogenating the compound of formula (C) under conditions sufficient to yield a compound of formula (D):

wherein the reaction conditions of step (d) comprise an additive selected from the group consisting of a carbonate base, an amine, an acid, and an acetate salt;
(e) deprotecting the compound of formula (D) under conditions sufficient to yield a compound of formula (E) or a salt thereof:

and
(f) contacting the compound of formula (E) with a compound of formula (F):

under conditions sufficient to yield a compound of formula (A),

wherein PG is an amine protecting group, X and Y are each independently selected from the group consisting of halo, —OSO 2 R, OP(O)OR, and OP(O)(OR) 2 , wherein R is alkyl, haloalkyl, aryl, or substituted aryl.

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).

Assignees

• Gilead Pharmasset Llc

Inventors

• Allan Kevin M
• Fujimori Shinji
• Heumann Lars V
• Huynh Grace May
• Keaton Katie Ann
• Levins Christopher M
• Pamulapati Ganapati Reddy
• Roberts Benjamin James
• Sarma Keshab
• Teresk Martin Gerald
• Wang Xiang
• Wolckenhauer Scott Alan

Classifications

• A61P31/14

  for RNA viruses · CPC title

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• C07D491/052 Primary

  the oxygen-containing ring being six-membered · CPC title

• C07D311/78 Primary

  Ring systems having three or more relevant rings · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title