Process for preparing 1-([3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide

Patent metadata

Field	Value
Publication number	US-12479835-B2
Application number	US-201917311615-A
Country	US
Kind code	B2
Filing date	Dec 12, 2019
Priority date	Dec 13, 2018
Publication date	Nov 25, 2025
Grant date	Nov 25, 2025

Abstract

The application relates to processes for the preparation of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl) amino]pyrazole-4-carboxamide (I) which include (i) a synthesis for bromo and iodo pyridine intermediates, (ii) a synthesis of a pyrazole ester intermediate which can be obtained in enantiopure form and (iii) the combination of these intermediates into compound (I).

First claim

The invention claimed is:

1 . A process for making a compound of Formula (I)

comprising
a. reacting a compound of Formula (VI)

wherein R 1 is C 1 -C 4 alkyl
with a compound of Formula (XII)

in the presence of a catalyst and of a base wherein R is I or Br, to yield a compound of Formula (XIII)

 and
b. converting the compound of Formula (XIII) to the compound of Formula (I).

2 . The method of claim 1 , further comprising a. reacting the compound of Formula (XIII) in the presence of a trialkylamine with a lithium salt, to yield a compound of Formula (XIV)

and
b. converting the compound of Formula (XIV) to the compound of Formula (I).

3 . The method of claim 2 , further comprising forming an active intermediate of the compound of Formula (XIV) and then reacting with ammonia or an ammonia equivalent, in the presence of a base to yield the compound of Formula (I).

4 . A process for making a compound of Formula (XII),

wherein R is I,
comprising
a. reacting a compound of Formula (IX)

with iodine and a lithium amide base, to yield a compound of Formula (X)

 and
b. converting the compound of Formula (X) to the compound of Formula (XII).

5 . The process of claim 4 , further comprising in step b reacting the compound of Formula (X) in the presence of a lithium amide base to yield a compound of Formula (XII)a

6 . The process of claim 5 , wherein the compound of Formula (X) is not isolated and purified before being carried on to the compound of Formula (XIIa).

7 . A process for making a compound of Formula (XII),

wherein R is Br,
comprising
a. reacting a compound of Formula (VII)

with an iridium catalyst and bis (pinacolato) diboron to yield a compound of Formula (VIII)

 and
b. converting the compound of Formula (VIII) to the compound of Formula (XII).

8 . The process of claim 7 , further comprising
a. reacting the compound of Formula (VIII) with a brominating agent to yield a compound of Formula (XI)

 and
b. converting the compound of Formula (XI) to the compound of Formula (XII).

9 . The process of claim 8 , further comprising reacting the compound of Formula (XI) with an alkali methoxide, to yield a compound of Formula (XIIb)

10 . A process for making a compound of Formula (VI)

wherein R 1 is C 1 -C 4 alkyl
comprising
a. reacting a compound of Formula (II)

with
i. Hydrogen cyanide or an equivalent thereof and
ii. POCl 3 or SOCl 2
to yield a compound of Formula (III)

 and
b. converting the compound of Formula (III) to the compound of Formula (VI).

11 . The process of claim 10 , further comprising
a. reacting the compound of Formula (III) with a compound of Formula (IV) in the presence of a base

wherein R 1 is C 1 -C 4 alkyl
to yield a compound of Formula (V)

wherein R 1 is C 1 -C 4 alkyl; and
b. converting the compound of Formula (V) to the compound of Formula (VI).

12 . The process of claim 11 , further comprising separating the enantiomers of the compound of Formula (V) to give the compound of Formula (VI).

13 . The process of claim 12 , wherein the separation of enantiomers is achieved by chiral chromatography.

14 . A compound of Formula (V)

wherein R 1 is C 1 -C 4 alkyl.

15 . The compound of claim 14 , wherein the compound is the compound of Formula (VI)

wherein R 1 is C 1 -C 4 alkyl.

16 . A compound of Formula (XIII)

wherein R 1 is C 1 -C 4 alkyl.

17 . A compound of Formula (XIV)

18 . The process of claim 1 , wherein in R 1 of the compound of Formula (VI) is ethyl.

19 . The process of claim 10 , wherein in R 1 of the compound of Formula (VI) is ethyl.

20 . The compound of claim 14 , wherein in R 1 is ethyl.

21 . The compound of claim 15 , wherein in R 1 is ethyl.

22 . The compound of claim 16 , wherein in R 1 is ethyl.

23 . The process of claim 8 , wherein the brominating agent is copper (II) bromide or copper (I) bromide associated to an oxidant.

24 . The process of claim 10 , wherein the hydrogen cyanide equivalent is trimethylsilyl cyanide (TMSCN).

25 . The process of claim 11 , wherein the base is potassium phosphate tribasic or potassium acetate.

Assignees

• Intervet Inc

Inventors

• Chassaing Christophe Pierre Alain
• Yin Jingjun
• Song Lichen
• Xiao Wensong
• Cleator Edward
• Dahmen Thomas
• Salanta Daniel
• Scheipers Claudia
• Schmitt Harald

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D213/64

  attached in position 2 or 6 · CPC title

• C07B2200/07

  Optical isomers · CPC title

• C07D405/04 Primary

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