Processes for preparing antiviral compounds

Patent metadata

Field	Value
Publication number	US-9890134-B2
Application number	US-201715582224-A
Country	US
Kind code	B2
Filing date	Apr 28, 2017
Priority date	Jun 11, 2014
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

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 (I-a), stereoisomer thereof, or mixture of stereoisomers thereof:

comprising the steps of:
(a) cyclizing a compound of formula (L):

under conditions sufficient to yield a compound of formula (K):

and
(b) brominating the compound of formula (K) under conditions sufficient to yield a compound of formula (I-a),
wherein Z is hydrogen, halo, —OSO 2 R 1 , —BF 3 − , —B(OR 2 ) 2 , —CO 2 H, or —NR 1 3 wherein R 1 is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and each R 2 is independently alkyl.

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):

is prepared by contacting a compound of formula (M):

with a compound of formula (N):

under conditions sufficient to yield the compound of formula (L),
wherein X 1 is a leaving group, Y 1 is hydrogen, halo or trifluoromethanesulfonate, and Z is hydrogen, halo, —OSO 2 R 1 , —BF 3 − , —B(OR 2 ) 2 ,—CO 2 H, or —NR 1 3 wherein R 1 is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and each R 2 is independently alkyl.

9. The method of claim 8 , wherein X 1 is halo, —OH, or —S(O) 2 R 3 , and R 3 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.

12. A compound of formula (L):

wherein Z is hydrogen, halo, —OSO 2 R 1 , —BF 3 − , —B(OR 2 ) 2 , —CO 2 H, or —NR 1 3 wherein R 1 is alkyl, haloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and each R 2 is independently alkyl.

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

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

is prepared by reacting a compound of formula (M′):

with isopropylmagnesium chloride in THF and N-methoxy-N-methyl acetamide to form formula (M); wherein X 1 is a leaving group and Y 1 is hydrogen, halo or trifluoromethanesulfonate.

Assignees

• Gilead Pharmasset Llc

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

Classifications

• A61P31/14

  for RNA viruses · CPC title

• C07D405/12

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

• C07D491/052 Primary

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

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K31/4188

  condensed with other heterocyclic ring systems, e.g. biotin, sorbinil · CPC title