DESC:FIELD OF THE INVENTION

The present invention relates to the improved process for the preparation of Venetoclax of Formula (I).

BACKGROUND OF THE INVENTION

Venetoclax is chemically described as 4-(4-{[2-(4-chlorophenyl)-4,4dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) having the structural Formula (I).

VENCLEXTA (Venetoclax) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy.

US 8,546,399 (IN 2012DN10067) describes Venetoclax Formula (I) and other compounds which exhibit potent binding to a Bcl-2 family protein, and pharmaceutically acceptable salts thereof. US’399 also describe the preparation method of the compound of Formula (I) as shown below in the Scheme I.

US 8,722,657(IN 2013DN05361) describes pharmaceutically acceptable salts and crystalline forms of Venetoclax.

US 9,238,652(IN 8479DELNP2015A) discloses the process for the preparation of Venetoclax.

However the prior art processes for the preparation of Venetoclax as described above have major drawbacks such as difficulties with respect to removal of process related impurities; poor commercial viability due to use of hazardous reactants; and/ or low yields and purity of intermediates and final product. Therefore, there remains a need to develop such a process, which overcomes one or more of the above drawbacks associated with prior art process for preparation of Venetoclax.

Therefore, it would be desirable to provide a simplified process which is safe and can also be carried out advantageously on an industrial scale and which supports an active compound in high yield and high purity in pharmaceutically acceptable quality.

OBJECT OF THE INVENTION

In one aspect, the present invention encompasses process for the preparation of Venetoclax of Formula (I) comprising the steps of:

a) reaction of compound of Formula (II) with compound of Formula (III) in the presence of suitable base and suitable solvent to obtain compound of Formula (IV) which is further hydrolyzed in situ in the presence of suitable base and suitable solvent to obtain compound of Formula (V);

b) reaction of the compound of Formula (V) with compound of Formula (VIII) in the presence of suitable base and suitable solvent to obtain compound of Formula (VI); and

c) reaction of the compound of Formula (VI) in the presence of suitable base and suitable solvent with compound of Formula (VII) to obtain Venetoclax of Formula (I).

In yet another aspect, the present invention encompasses compound of Formula (VI) and its use in the preparation of Venetoclax.

In yet another aspect, the present invention relates to a process for preparing stable amorphous form of Venetoclax comprising the steps of:
a) dissolving Venetoclax in one or more of suitable solvent(s) to obtain solution; and
b) isolating amorphous Venetoclax.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention encompasses process for the preparation of Venetoclax of Formula (I).

In another embodiment, the present invention encompasses process for the preparation of Venetoclax of Formula (I) which comprises the steps of:

a) reaction of compound of Formula (II) with compound of Formula (III) in the presence of suitable base and suitable solvent to obtain compound of Formula (IV) which is further hydrolyzed in situ in the presence of suitable base and suitable solvent to obtain compound of Formula (V);

b) reaction of the compound of Formula (V) with compound of Formula (VIII) in the presence of suitable base and suitable solvent to obtain compound of Formula (VI); and

c) reaction of the compound of Formula (VI) in the presence of suitable base and suitable solvent with compound of Formula (VII) to obtain venetoclax of Formula (I).

In another embodiment of present invention, suitable base used in step (a) is selected from the group comprising of sodium hydroxide, potassium hydroxide, ammnonium hydroxide, sodium carbonate, potassium carbonate, dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diisopropylethylamine, dimethylaminopyridine, triethylamine, piperidine, pyridine and N-methylmorpholine or mixtures thereof. Preferably, sodium bicarbobnate.

In another embodiment of present invention, suitable solvent used in step (a) is selected from the group comprising of methanol, ethanol, n-propanol, 2-propanol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate , acetone, methyl ethyl ketone, tetrahydrofuran, dioxane , N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidone, dichloromethane, chloroform, and 1,2-dichloroethane.Preferably, dimethylsulphoxide.

In another embodiment of present invention, suitable base used in step (a) for carrying out hydrolysis of ester of Formula (IV) is selected from the group comprising of sodium hydroxide, potassium hydroxide, ammnonium hydroxide, sodium carbonate, potassium carbonate, dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diisopropylethylamine, dimethylaminopyridine, triethylamine, piperidine, pyridine and N-methylmorpholine or mixtures thereof. Preferably, sodium hydroxide.

In another embodiment of present invention, suitable solvent used in step (a) for carrying out hydrolysis of ester of Formula (IV) is selected from the group comprising of water, methanol, ethanol, n-propanol, 2-propanol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate , acetone, methyl ethyl ketone, tetrahydrofuran, dioxane , N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidone, dichloromethane, chloroform, and 1,2-dichloroethane.Preferably, water.

In another embodiment of present invention, reaction may be carried out at temperature ranging from about 100?C to about 130?C or higher to obtain ester of Formula (V). The reaction may be carried out for time periods ranging from about 30 minutes to about 3 hours, or longer.

In another embodiment of present invention, hydrolysis may be carried out at temperature ranging from about 40?C to about 60?C or higher to obtain Formula (IV). The reaction may be carried out for time periods ranging from about 30 minutes to about 3 hours, or longer.

In another embodiment of present invention, encompasses compound of Formula (VIII) Wherein R is selected from the group comprising mesyl, tosyl, nosyl, brosyl, benzene sulphonyl and hydrogen.

The use of benzotriazole for the activation of carboxylic acid is
beneficial for use in industrial manufacturing and found to be chemically efficient (i.e. to be reactive with a wide variety of substrates; reactive in stoichiometric quantities; can be simply monitored during the coupling reaction; prone to only no or few side reactions; simple to purify from its secondary products after coupling; exhibit a high conversion rate at mild conditions), cost efficient and safe for use (i.e safe for the environment; be non-toxic, non-corrosive and not self-reactive; and be stable with relatively low sensitivity to friction, spark, and electrostatic discharge, particularly during transportation and subsequent storage).

In another embodiment of the present invention, suitable base used in step (b) is selected from the group comprising of sodium hydroxide, potassium hydroxide, ammnonium hydroxide, sodium carbonate, potassium carbonate, dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diisopropylethylamine, dimethylaminopyridine, triethylamine, piperidine, pyridine and N-methylmorpholine or mixtures thereof. Preferably, triethyl amine.

In another embodiment of present invention, suitable solvent used in step (b) is selected from the group comprising of methanol, ethanol, n-propanol, 2-propanol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate , acetone, methyl ethyl ketone, tetrahydrofuran, dioxane , N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidone, dichloromethane, chloroform, and 1,2-dichloroethane.Preferably, tetrahydrofuran.
In another embodiment of present invention, suitable base used in step (c) is selected from the group comprising of sodium hydroxide, potassium hydroxide, ammnonium hydroxide, sodium carbonate, potassium carbonate, dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diisopropylethylamine, dimethylaminopyridine, triethylamine, piperidine, pyridine and N-methylmorpholine or mixtures thereof. Preferably, dimethylaminopyridine.

In another embodiment of present invention, suitable solvent used in step (c) is selected from the group comprising of water, methanol, ethanol, n-propanol, 2-propanol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate , acetone, methyl ethyl ketone, tetrahydrofuran, dioxane , N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidone, dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline. Preferably, toluene.

In another embodiment, the present invention encompasses compound of Formula (VI)

and its use in the preparation of Venetoclax.

In yet another embodiment, the present invention encompasses optional purification of intermediates and Venetoclax such purification includes recrystallization, column chromatography, distillation, acid base treatment, by preparing salt/co-crystal/solvate/hydrate and other methods as well known to those skilled in the art.

In yet another embodiment, the present invention uses distillation, distillation under reduced pressure or vacuum, evaporation, solvent-anti-solvent, spray drying, lyophilization or freeze drying techniques for obtaining amorphous form of venetoclax.

Advantages of the invention
1. The invention provides process for preparation of a highly pure Venetoclax of the Formula 1.
2. The process for the preparation of Venetoclax is simple, commercially viable and economical.
3. The invention provides intermediates of Venetoclax and process for the preparation thereof.
In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Examples

Example 1: Preparation of 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
To a solution of 1-{[3-(4-chlorophenyl)-4,4-dimethylcyclohex-2-en-1-yl] methyl}piperazine dihydrochloride (171.1 g) in DMSO (25 ml) and sodium bicarbonate (117.36 g) were added methyl 4-fluoro-2-(1H-pyrrolo[2,3-b] pyridin-5-yloxy)benzoate (100 g) in DMSO (25 ml) at 110-120°C.The resulting reaction mixture was cooled to 60-70°C. The obtained salt was filtered and washed with (50.0 mL) of DMSO 60-70°C. Sodium hydroxide (41.92 g) and water (209.6 mL) was added to the reaction mixture at 50-60°C and filtered. To the obtained filtrate formic acid (57.88 g), water (385.66 mL) was added at 50-60°C. The reaction mixture was stirred for 2 hrs at 50-60°C and the obtained solid was filtered. The solid was added to acetone (500 mL) at room temperature and refluxed at 50-60°C, stirred for 1hr and was cooled to room temperature to precipitate the solid. The obtained solid was filtered and dried to afford 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid (140 g).

Example 2: Preparation of (2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)phenyl)(1H-benzo[d][1,2,3]triazol-1-yl)methanone
To a solution of 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid (1.0 g) and triethyl amine (0.28 g) in tetrahydrofuran (50 ml) was added 1-(methylsulfonyl)-1H-benzotriazole (0.48 g).The resulting reaction mixture was stirred, tetrahydrofuran was distilled to afford (2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)phenyl)(1H-benzo[d][1,2,3]triazol-1-yl)methanone(3,900 mg).

Example 3: Preparation of Venetoclax
To a solution of (2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)phenyl)(1H-benzo[d][1,2,3]triazol-1-yl)methanone (500 mg) in toluene (15 ml) were added 3-nitro-4-((tetrahydro-2H-pyran-4yl)methylmaino)benzenesulfonamide (234 mg) and 4-dimethylaminopyridine (136 mg).The resulting reaction mixture was refluxed for 24 hours, toluene was distilled. Dimethylformamide (250 mL) was added to the residue at room temperature and further heated at 50-60°C. Methanol (187.5 mL) was added to the reaction mixture at 50-60°C. The reaction mixture was cooled to room temperature and stirred for 4 hrs to precipitate the solid. The obtain solid was filtered at room temperature to afford Venetoclax ( 516 mg).
,CLAIMS:WE CLAIM:

1. A process for the preparation of Venetoclax of Formula (I) which comprises the steps of:

a) reaction of the compound of Formula (V) with compound of Formula (VIII) in the presence of suitable base and suitable solvent to obtain compound of Formula (VI); and

b) reaction of the compound of Formula (VI) in the presence of suitable base and suitable solvent with compound of Formula (VII) to obtain Venetoclax of Formula (I).

2. The process for the preparation of Venetoclax of Formula (I) as claimed in claim 1, wherein the compound of Formula (V) is prepared by a process comprises reaction of compound of Formula (II) with compound of Formula (III) followed by hydrolyzing the resulting compound.

3. The process as claimed in claim 1, wherein the group represented by R in compound of Formula (VIII) is selected from the group comprising mesyl, tosyl, nosyl, brosyl, benzene sulphonyl and hydrogen.

4. The process as claimed in claim 1, wherein the suitable solvent is selected from the group comprising methanol, ethanol, n-propanol, 2-propanol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate , acetone, methyl ethyl ketone, tetrahydrofuran, dioxane , N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidone, dichloromethane, chloroform, toluene and 1,2-dichloroethane or mixtures thereof.

5. The process as claimed in claim 1, wherein suitable base is selected from the group comprising of sodium hydroxide, potassium hydroxide, ammnonium hydroxide, sodium carbonate, potassium carbonate, dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diisopropylethylamine, dimethylaminopyridine, triethylamine, piperidine, pyridine and N-methylmorpholine or mixtures thereof.

6. A compound of Formula (VI)

Dated this 04th day of July 2018

Dr. S. Ganesan