Preparation of and formulation comprising a MEK inhibitor

Patent metadata

Field	Value
Publication number	US-9238627-B2
Application number	US-201314057498-A
Country	US
Kind code	B2
Filing date	Oct 18, 2013
Priority date	Oct 19, 2012
Publication date	Jan 19, 2016
Grant date	Jan 19, 2016

Abstract

The present invention relates to processes for preparing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide, processes for preparing crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide, and intermediates useful therefore. Also provided herein are pharmaceutical compositions comprising this crystallized compound.

First claim

What is claimed is:

1. A process for preparing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide:

the process comprising the steps of:
a) reacting a compound of Formula (I):

with a suitable base to form an intermediate; and

b) reacting said intermediate with a compound of Formula (II):

to provide a compound of Formula (III):

or a hydrate thereof, wherein P 1 is a protecting group;

c) dissolving said compound of Formula (III) or a hydrate thereof in a suitable solvent or solvent system; and
d) deprotecting said compound of Formula (III) or a hydrate thereof with a suitable deprotecting reagent, wherein P 1 in each occurrence may be the same or different, and is a suitable protecting group, to provide Compound A.

2. The process of claim 1 , wherein the suitable protecting group is selected from alkyl group; alkenyl groups; tertiary aryl-alkyls; groups that result in acetals; and silyl groups.

3. The process of claim 1 , further comprising isolating the intermediate.

4. The process of claim 3 , wherein the isolating step comprises crystallizing the intermediate.

5. The process of claim 3 , wherein the intermediate is a compound of Formula (V):

6. The process of claim 1 , wherein the suitable solvent or solvent system is a polar aprotic solvent.

7. The process of claim 1 , wherein the suitable deprotecting reagent is phosphoric acid.

8. The process of claim 1 , wherein said compound of formula (III) or a hydrate thereof is further reacted with a suitable base, to provide Compound A.

9. A process for preparing a compound of Formula (III),

or a hydrate thereof, wherein the process comprises the steps of:
a) reacting a compound of Formula (I):

with a suitable base to form an intermediate; and

b) reacting said intermediate with a compound of Formula (II);

wherein P 1 is a protecting group, such that the compound of Formula III or a hydrate thereof is formed.

10. The process of claim 9 , wherein the protecting group is selected from alkyl group; alkenyl groups; tertiary aryl-alkyls; groups that result in acetals; and silyl groups.

11. The process of claim 9 , wherein the suitable base is selected from sodium hydroxide, potassium hydroxide, caesium hydroxide, lithium hydroxide, potassium trimethylsilanolate, lithium trimethylsilanolate, and sodium trimethylsilanolate.

12. The process of claim 11 , wherein the intermediate is a compound of Formula (V):

13. The process of claim 11 , further comprising isolating the intermediate.

14. The process of claim 13 , wherein the step of isolating the intermediate comprises crystallizing the intermediate.

Assignees

• Novartis Ag
• Array Biopharma Inc

Inventors

• Krell Christoph Max
• Misun Marian
• Niederer Daniel Andreas
• Pachinger Werner Heinz
• Wolf Marie-Christine
• Zimmermann Daniel
• Liu Weidong
• Stengel Peter J
• Nichols Paul

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61K9/2013

  Organic compounds, e.g. phospholipids, fats · CPC title

• C07D235/08 Primary

  Radicals containing only hydrogen and carbon atoms · CPC title