Preparation of and formulation comprising a mek inhibitor

Patent metadata

Field	Value
Publication number	US-2016168102-A1
Application number	US-201514974588-A
Country	US
Kind code	A1
Filing date	Dec 18, 2015
Priority date	Oct 19, 2012
Publication date	Jun 16, 2016
Grant date	—

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

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

the process comprising the steps of:
a) dissolving Compound A in a solution comprising (i.) a solvent system comprising an ether and optionally an alcohol, and (ii.) water to provide a solution;
b) adding a seed crystal suspension to the solution to provide a suspension mixture;
c) cooling the suspension mixture to provide a cooled suspension mixture;
d) adding water to the cooled suspension mixture to provide a treated mixture; and
e) cooling the treated mixture, to provide the crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

2 . A process of claim 1 , wherein the solution comprises (i.) a solvent system comprising an ether and an alcohol, and (ii.) water.

3 .- 12 . (canceled)

13 . The process of claim 2 , wherein the alcohol is methanol, ethanol or isopropanol.

14 . The process of claim 13 , wherein the alcohol is methanol.

15 . The process of claim 2 , wherein Compound A is dissolved in a solution comprising (i) a solvent system comprising tetrahydrofuran and methanol and (ii) water.

16 . The process of claim 2 , further comprising the step of heating the solution of step a) to an internal temperature of about 52-56° C. prior to addition of the seed crystal suspension.

17 . The process of claim 16 , further comprising the step of cooling the solution to 47-48° C. after heating to an internal temperature of about 52-56° C. and before the seed crystal is added.

18 . The process of claim 2 , wherein the water in step d) is added over a period of 10 to 25 hours.

19 . The process of claim 2 , wherein the treated mixture of step d) has a ratio of alcohol/ether/water in a range between 40/40/20 and 15/15/70 w/w/w.

20 . The process of claim 19 , wherein the treated mixture has a ratio of alcohol/ether/water of about 20/20/60 w/w/w.

21 . The process of claim 2 , wherein the treated mixture of step e) is cooled to an internal temperature of about 1-10° C.

22 . The process of claim 2 , further comprising the step of drying the crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

23 . The process of claim 2 , further comprising the step of milling the crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

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

the process comprising:
a) adding Compound A to a solution comprising (i) a solvent system comprising an ether and an alcohol, and (ii) water to provide a suspension;
a1) heating the suspension of step a) to an internal temperature between 53° C. and 56° C. to provide a solution;

a2) cooling the solution of step a1);
b) adding a seed crystal suspension to the cooled solution of step a2) to provide a suspension mixture;
c) adding water to the suspension mixture to provide a treated mixture; and
d) cooling the treated mixture to provide the crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide.

25 . The process of claim 24 , wherein the solution of step a1) is cooled to 47-48° C. in step a2).

26 . The process of claim 25 , wherein the solvent system (i) in step (a) is THF and methanol.

27 . The process of claim 26 , wherein the ratio of methanol/THF/water is 35/35/30 w/w/w.

28 . The process of claim 27 , wherein the solution in step a1) is filtered at a temperature between 53° C. and 56° C. prior to cooling in step a2).

29 . The process of claim 28 , wherein the ratio of alcohol/ether/water after addition of water in step d) is between 40/40/20 and 15/15/70 w/w/w.

30 . The process of claim 29 , wherein the ratio of alcohol/ether/water after addition of water in step d) is 20/20/60 w/w/w.

31 . The process of claim 30 , wherein the water in step d) is added over a period of 10-25 hours.

32 . The process of claim 31 , wherein the treated mixture is cooled to an internal temperature of about 3-5° C. in step d).

33 . The process of claim 32 , wherein the seed crystal suspension comprises seed crystals of crystallized compound A in water (10% m/m).

34 . The process of claim 24 , wherein the seed crystal suspension comprises seed crystals of crystallized compound A in water (10% m/m).

Assignees

• Array Biopharma Inc
• Novartis Pharma Ag

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

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• A61K9/2009

  Inorganic compounds · CPC title

• A61K9/2013

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

• C30B29/54

  Organic compounds · CPC title