Processes for preparing toll-like receptor modulator compounds

Patent metadata

Field	Value
Publication number	US-12590089-B2
Application number	US-202217673141-A
Country	US
Kind code	B2
Filing date	Feb 16, 2022
Priority date	Jun 28, 2019
Publication date	Mar 31, 2026
Grant date	Mar 31, 2026

Abstract

The present disclosure provides methods for preparing (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol or a salt thereof and related key intermediates.

First claim

What is claimed is:

1 . A method for preparing a compound of Formula II:

or a salt thereof, comprising:
a) forming a first reaction mixture comprising a compound of Formula V:

a compound having the Formula PG-NHC(═NH)NH 2 or a salt thereof, a first transition-metal catalyst, a first base, and a first solvent to form the compound of Formula II, a salt thereof,

wherein
R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF 3 , C 1-3 alkyl, or C 1-3 alkoxy;
R 4 is hydrogen or methyl;
R 5 is C 3-6 alkyl;
X is F, Cl, Br, I, or OTs; and
PG is an amino protecting group.

2 . The method of claim 1 , wherein PG is 2,4-dimethoxybenzyl.

3 . A compound of Formula III:

or a salt thereof, wherein
R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF 3 , C 1-3 alkyl, or C 1-3 alkoxy;
R 4 is hydrogen or methyl;
R 5 is C 3-6 alkyl; and
X is F, Cl, Br, I, or OTs.

4 . A compound of Formula IV:

or a salt thereof, wherein
R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF 3 , C 1-3 alkyl, or C 1-3 alkoxy;
R 4 is hydrogen or methyl;
R 5 is C 3-6 alkyl;
X is F, Cl, Br, I, or OTs; and
AG 1 is Cl, Br, OSO 3 H, OSO 3 − , OMs, OTs, or OTf.

5 . A compound of Formula V:

or a salt thereof, wherein
R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF 3 , C 1-3 alkyl, or C 1-3 alkoxy;
R 4 is hydrogen or methyl;
R 5 is C 3-6 alkyl; and
X is F, Cl, Br, I, or OTs,
provided that the compound of Formula V is not
3-bromo-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,
3-bromo-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide,
3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,
3-bromo-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,
3,6-dichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,
3,6-dichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide,
3,4,5-trichloro-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide,
3,6-dichloro-N-(1-hydroxy-4,4-dimethylpentan-2-yl)picolinamide, or
3,4,5-trichloro-N-(1-hydroxy-4-methylpentan-2-yl)picolinamide.

6 . A compound of Formula XII:

or a salt thereof, wherein
R 1 , R 2 , and R 3 are each independently hydrogen, F, Cl, CN, CF 3 , C 1-3 alkyl, or C 1-3 alkoxy; and
R 6 and R 7 are each independently hydrogen, C 1-4 alkyl, or C 3-6 cycloalkyl, or
R 6 and R 7 are combined to form a 3-6 membered N-linked heterocycloalkyl, optionally having an additional 1-2 heteroatoms selected from O and S,
provided that at least one of R 1 , R 2 , and R 3 is F, Cl, CN, CF 3 , C 1-3 alkyl, or C 1-3 alkoxy.

7 . The compound of claim 6 , wherein
R 1 and R 3 are each hydrogen; R 2 is F; R 6 is hydrogen; and R 7 is tert-butyl.

Assignees

• Gilead Sciences Inc

Inventors

• Ambrosi Andrea
• Bachrach Florence J
• Badalov Pavel R
• Lathrop Stephen P
• Merit Jeffrey E
• Pritchett Beau P
• Regens Christopher S
• Vieira Tiago
• Weinstein Adam B
• Wenderski Todd A
• Zheng Zehua

Classifications

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D213/81

  Amides; Imides · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title