Synthesis of an antiviral compound

Patent metadata

Field	Value
Publication number	US-9440991-B2
Application number	US-201414576143-A
Country	US
Kind code	B2
Filing date	Dec 18, 2014
Priority date	Dec 23, 2013
Publication date	Sep 13, 2016
Grant date	Sep 13, 2016

Abstract

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

which is useful as an antiviral agent. The disclosure also provides compounds and processes for the preparation of the compounds that are synthetic intermediates to the compound of formula I.

First claim

What is claimed is:

1. A process for preparation of a compound of formula V:

or a salt thereof;
comprising contacting a compound of formula III or a salt thereof, with a compound of formula IV:

under O-arylation conditions to provide the compound of formula V or a salt thereof, wherein R is C 1-6 alkyl, PG is a protective group, and R 1 is a leaving group.

2. A process for preparation of a compound of formula I:

or a pharmaceutically acceptable salt thereof; comprising:
a) preparing a compound of formula V:

or a salt thereof according to the process of claim 1 ;
b) subjecting the compound of formula V or a salt thereof to N-deprotection conditions to provide a compound of formula VI:

or a salt thereof;
c) contacting the compound of formula VI or a salt thereof with a compound of formula VII:

or a salt thereof,
under amide coupling conditions to provide a compound of formula VIII:

or a salt thereof;
d) performing ring closing metathesis of the compound of formula VIII or a salt thereof to provide a compound of formula IX:

or a salt thereof;
e) hydrogenating the compound of formula IX or a co-crystal, or a salt thereof in presence of a catalyst to provide a compound of formula X:

or a salt thereof;
f) hydrolyzing the compound of formula X or a salt thereof to provide a compound of formula XI:

or a salt thereof;
g) contacting the compound of formula XI or a salt thereof with a compound of formula

or a salt thereof;
under amide coupling conditions to provide the compound formula I:

or a pharmaceutically acceptable salt thereof, wherein R is C 1-6 alkyl, PG is a protective group, and R 1 is a leaving group.

3. A process for preparation of a compound of formula I:

or a pharmaceutically acceptable salt thereof, comprising:
a) preparing a compound of formula V

or a salt thereof according to the process of claim 1 ;
b) contacting the compound of formula V or a salt thereof with an acid under N-deprotection conditions to provide a compound of formula VI:

or a salt thereof;
c) contacting the compound of formula VI or a salt thereof with a compound of formula VII:

or a salt thereof,
under amide coupling conditions to provide a compound of formula VIII:

or a salt thereof;
d) hydrolyzing the compound of formula VIII or a salt thereof to provide a compound of formula XVIII:

or a salt thereof;
e) performing ring closing metathesis of the compound of formula XVIII or a salt thereof in presence of a catalyst to provide a compound of formula XIX:

or a salt thereof;
f) hydrogenating the compound of formula XIX in presence of a catalyst to provide a compound of formula XI:

or a salt thereof;
g) contacting the compound of formula XI or a salt thereof with a compound of formula XII:

or a salt thereof;
under amide coupling conditions to provide the compound formula I:

or a pharmaceutically acceptable salt thereof, wherein R is C 1-6 alkyl, PG is a protective group, and R 1 is a leaving group.

4. A process for preparation of a compound of formula XV:

or a salt thereof, comprising contacting a compound of formula XIII:

or a salt thereof,
with a compound of formula XIV:

or a salt thereof,
under cross-metathesis conditions to provide the compound of formula XV or a salt thereof, wherein R is C 1-6 alkyl and PG is a protective group.

5. A process for preparation of a compound of formula I:

or a pharmaceutically acceptable salt thereof, comprising:
a) preparing a compound of formula XV:

or a salt thereof according to the process of claim 4 ,
b) hydrogenating the compound of formula XV or a salt thereof in presence of a catalyst to provide a compound of formula XVI:

or a salt thereof;
c) subjecting the compound of formula XVI or a salt thereof to N-deprotection conditions to provide a compound of formula XVII:

or a salt thereof;
d) contacting the compound of formula XVII with an amide coupling agent under lactamization conditions to give a compound of formula X:

or a salt thereof;
e) hydrolyzing the compound of formula X or a salt thereof to provide a compound of formula XI:

or a salt thereof; and
contacting the compound of formula XI or a salt thereof with a comp

Assignees

• Gilead Sciences Inc

Inventors

• Cagulada Amy
• Chan Johann
• Chan Lina
• Colby Denise A
• Karki Kapil Kumar
• Kato Darryl
• Keaton Katie Ann
• Kondapally Sudha
• Levins Chris
• Littke Adam
• Martinez Ruben
• Pcion Dominika
• Reynolds Troy
• Ross Bruce
• Sangi Michael
• Schrier Adam J
• Seng Pamela
• Siegel Dustin
• Shapiro Nathan
• Tang Donald
• Taylor James G
• Tripp Jonathan
• Waltman Andrew W
• Yu Lawrence

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07K5/0808

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title

• C07C205/57

  having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton · CPC title

• C07C233/09

  with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic unsaturated carbon skeleton · CPC title