Granted Patent B2

US 12,503,470 · App. 17/929,027 · Granted Dec 23, 2025

Inventors: Nathalie Chauret (Laval, CA); Jeremy Green (Waltham, MA); David R. Kronenthal (Yardley, PA); Karine Villeneuve (Laval, CA)

Assignee: GlaxoSmithKline Intellectual Property (No.3) Limited

C07D471/04C07D265/30C07F9/4006

Abstract

Claims (50)

1 . A process for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1):

comprising contacting a compound with the structure:

with an amide coupling reagent and methylamine or a salt of methylamine.

2 . The process of claim 1 , wherein the amide coupling reagent is carbonyldiimidazole.

3 . The process of claim 1 , wherein the amide coupling reagent is propanephosphonic acid anhydride (T3P).

4 . The process of claim 1 , wherein the compound with the structure:

is prepared by a process comprising contacting a compound with the structure:

with 2-amino-4-methylpyridine and optionally sodium borohydride.

5 . The process of claim 1 , wherein the compound with the structure:

is prepared by a process comprising contacting a compound with the structure:

with a brominating reagent.

6 . The process of claim 5 , wherein the brominating agent is N-bromosuccinimide in the presence of acid.

7 . The process of claim 5 , wherein the compound with the structure:

is prepared by a process comprising contacting a compound with the structure:

with methyl chloroformate and a base.

8 . The process of claim 7 , wherein the base is sodium bicarbonate.

9 . The process of claim 7 , wherein the compound with the structure:

is prepared by a process comprising contacting a compound with the structure:

with hydrogen chloride in the presence of a solvent.

10 . The process of claim 9 , wherein the solvent is ethyl acetate.

11 . The process of claim 9 , wherein the compound with the structure:

is prepared by a process comprising contacting a compound with the structure:

with a hydrogenation catalyst and hydrogen.

12 . The process of claim 11 , wherein the hydrogenation catalyst is palladium on carbon, palladium hydroxide, rhodium on carbon, rhodium on alumina, platinum oxide, or platinum on carbon.

13 . The process of claim 12 , wherein the hydrogenation catalyst is palladium on carbon.

14 . The process of claim 11 , wherein the compound with the structure:

is prepared by a process comprising contacting a compound with the structure:

with a compound with the structure:

with a base.

15 . The process of claim 14 , wherein the base is a mixture of potassium bicarbonate and potassium carbonate.

16 . The process of claim 14 , wherein the compound with the structure:

is prepared by a process comprising contacting a compound with the structure:

with 2,2,6,6-tetramethylpiperidine 1-oxyl or T3P.

17 . A process for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), comprising:

A) the reaction of a compound with the structure:

with 2,2,6,6-tetramethylpiperidine 1-oxyl or T3P to produce a compound with the structure:

B) followed by the reaction of the compounds with the structures:

with potassium carbonate and potassium bicarbonate to produce a compound with the structure:

C) followed by the reaction of the compound with the structure:

with palladium on carbon and hydrogen to produce a compound with the structure:

D) followed by the reaction of the compound with the structure:

with hydrogen chloride in ethyl acetate to produce a compound with the structure;

E) followed by the reaction of the compound with the structure:

with methyl chloroformate and sodium bicarbonate to produce a compound with the structure:

F) followed by the reaction of the compound with the structure:

with N-bromosuccinimide and acid to produce a compound with the structure:

G) followed by the reaction of the compound with the structure:

with 2-amino-4-methylpyridine and optionally sodium borohydride to produce a compound with the structure:

H) followed by the reaction of the compound with the structure:

with carbonyldiimidazole and methylamine to produce a compound with the structure:

Assignments (6)

Continuity (3)

References Cited (26)