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-2022017499-A1
Application number	US-201917311615-A
Country	US
Kind code	A1
Filing date	Dec 12, 2019
Priority date	Dec 13, 2018
Publication date	Jan 20, 2022
Grant date	—

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

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, preferably C 1 -C 2 alkyl, most preferably ethyl 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, preferably trimethylamine with a lithium salt, preferably lithium bromide, lithium chloride or lithium hydroxide 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, preferably ammonium chloride 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, preferably lithium/TMP, 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, preferably lithium/TMP, 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, preferably copper (II) bromide or copper (I) bromide associated to an oxidant, preferably copper (II) bromide, 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, preferably sodium methoxide or potassium 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, preferably C 1 -C 2 alkyl, most preferably ethyl comprising
a. reacting a compound of Formula (II)

with
i. Hydrogen cyanide or an equivalent thereof such as TMSCN 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 such as potassium phosphate tribasic or potassium acetate

wherein R 1 is C 1 -C 4 alkyl, preferably C 1 -C 2 alkyl, most preferably ethyl to yield a compound of Formula (V)

wherein R 1 is C 1 -C 4 alkyl, preferably C 1 -C 2 alkyl, most preferably ethyl; 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, preferably C 1 -C 2 alkyl, most preferably ethyl.

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

wherein R 1 is C 1 -C 4 alkyl, preferably C 1 -C 2 alkyl, most preferably ethyl.

16 . A compound of Formula (XIII)

wherein R 1 is C 1 -C 4 alkyl, preferably C 1 -C 2 alkyl, most preferably ethyl.

17 . A compound of Formula (XIV)

Assignees

• Intervet Inc

Inventors

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

Classifications

• C07D405/04 Primary

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

• C07B2200/07

  Optical isomers · CPC title

• C07D213/64

  attached in position 2 or 6 · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title