DESC:FIELD OF THE INVENTION
The present invention provides an improved process for preparing Venetoclax of Formula I and its pharmaceutically acceptable salts thereof, which is useful as B-Cell lymphoma 2 (BCL-2) inhibitor.

BACKGROUND OF THE INVENTION
Venetoclax is chemically known 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). Venetoclax is a BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL), as detected by an FDA approved test, who has received at least one prior therapy, which was approved by USFDA April 11, 2016 under the brand name Venclexta® by Abbieve.

Venetoclax is a white, non-hygroscopic, crystalline powder with the empirical formula C45H50ClN7O7S and molecular weight of the Venetoclax is 868.44. Venetoclax is a light yellow to yellow to dark yellow non-hygroscopic powder with a melting point of about 138º C onset. Its solubility in aqueous media is very low and it is very slightly soluble in 1% polysorbate 80 (w/v aq.). The apparent permeability is in the low to moderate range. The pKa values are 3.4 and 10.3 for the sulfonamide and piperazine groups respectively and the partition coefficient is 5.5. Venetoclax has a non-chiral molecular structure.

Venetoclax and its pharmaceutical acceptable salts are first disclosed in US 8546399 B2 and its process for the preparation comprises of condensation of 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine with methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate in presence of base and a solvent to give methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate, which is saponificated in presence of solvent and base to produce 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, followed by condensation with 3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]benzenesulfonamide in presence of base / solvent and catalyst to produce Venetoclax. The above process is schematically shown as below

Alan et al in US 9006438 B2 discloses a process for the preparation of Venetoclax comprises saponification of methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate in presence of solvent, t-butoxide salt and water to produce 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, which is followed by condensation with 3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]benzenesulfonamide in presence of DMAP / solvent to produce Venetoclax as depicted in scheme-2. The above process is schematically represented as below;

Wherein R is C1-C10 alkyl.
Anil et al in WO 2018029711 discloses a process for the preparation of venetoclax comprising condensation of methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(piperazin-1-yl)benzoate with 1-(2-(bromomethyl)-5,5-dimethylcyclohex-1-enyl)-4-chlorobenzene in presence of THF as a solvent and TEA as base to produce 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate, hydrolyzing in presence of KOH / MeOH and THF to produce 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, followed by condensation with 3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]benzenesulfonamide in presence of EDC.HCl / TEA / DCM DMAP to produce Venetoclax, followed by isolation using silica gel column chromatography (mobile phase dichloromethane: methanol (98:2)) to yield amorphous Venetoclax. The above process is schematically represented as below;

Chen et al in US 8722657 B2 also describes a process similar to scheme-1 for the preparation of Venetoclax. Further it describes different types of crystalline forms i.e. Anhydrate crystalline form A and form B of free base, hydrate crystalline form C and D of free base, Venetoclax including solvated forms like dichloromethane solvate of form E, ethylacetate solvate of form F and G, acetonitrile solvate of H and I, acetone solvate of form J of Venetoclax including salt forms like hydrochloride salt of form K and L, sulfate salt of form M, THF solvate of form N.

Further review of the available literature regarding Venetoclax discloses various other processes for its preparation but due to one or more drawbacks with respect to the production of side products. The prior art literature discloses the product was isolated by column chromatography technique. This method is time consuming and tedious especially for large samples so this technique is more complicated and expensive. Further this technique carries low purity with less than desirable yields, most of them are not particularly convenient and economical for industrial scale up.

Hence, there is an unmet need to develop improved, cost effective and industrially amenable processes for the preparation of Venetoclax involving higher yield of end product with better purity.

Therefore, inventors of the present application provide a simple high yielding process for preparation of highly pure Venetoclax, which overcomes the disadvantages associated with prior disclosed literature methods.

OBJECTIVE OF THE INVENTION
The main objective of the invention is to provide an improved process for the preparation of high purity Venetoclax.

Yet another object of the present invention is to provide an improved process for the preparation of high purity Venetoclax intermediates.

SUMMARY OF THE INVENTION
The main aspect of the present invention relates an improved process for the preparation of high purity Venetoclax (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. condensing 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine of formula (II)

with methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (III)

in the presence of base / solvent to produce crude product, followed by isolation using one or more solvents at 65-85° C to yield high pure methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl)benzoate (IV) without use of column purification

b. saponification of methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl)benzoate (IV) in the presence of acid / base and solvent to provide 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 (V);

c. condensation 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 (V) with 3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]benzenesulfonamide in presence of base, catalyst and solvent to produce Venetoclax (I).

Another aspect of the present invention relates an improved process for the preparation of high purity Venetoclax (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. condensing 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine of formula (II)

with methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (III)

in the presence of base / solvent to produce crude product, followed by isolation using one or more solvents at 65-85° C to yield high pure methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl)benzoate (IV) without use of column purification

b. conversion of methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl)benzoate (IV) to Venetoclax or its pharmaceutically acceptable salts.

Venetoclax having the purity of greater than 99.6% and total impurities A to G and impurity collectively less than 0.4% by HPLC.


DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved, commercially viable and industrially –advantageous process for the preparation of Venetoclax and its pharmaceutically acceptable salts thereof.

In one embodiment, the present invention relates an improved process for the preparation of high purity Venetoclax (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. condensing 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine of formula (II)

with methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (III)

in the presence of base / solvent to produce crude product, followed by isolation using one or more solvents at 65-85° C to yield high pure methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl)benzoate (IV) without use of column purification

c. saponification of methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl)benzoate (IV) in the presence of acid / base and solvent to provide 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 (V);

d. condensation 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 (V) with 3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]benzenesulfonamide (VI)

in presence of base, catalyst and solvent to produce Venetoclax (I).

In one embodiment the present invention relates to a process for the preparation of Venetoclax and its pharmaceutically acceptable salts comprising, condensation of 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine of formula (II) or its salts selected from hydrochloride and the like thereof with methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (III) in presence of base selected from organic base such as methylamine, triethylamine, diisoproylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate, potassium biphosphate, dipotassium biphosphate; a solvent selected from comprises one or more solvents selected from water, alcohol selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; ketone selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone, ester selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; halogenated hydrocarbon selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene, polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and the hydrocarbon solvent selected from hexane, heptane cyclohexane, N-methyl- pyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or mixtures thereof. ; at a temperature ranging from 65-85 °C for a period of 20 to 24 hours to obtain compound of formula (IV). The reaction mixture was allowed to cool to 25-30° C and the obtained solid was filtered. The solid was washed with water and suck dried. The obtained product may dried under vacuum to obtained 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl cyclohex-1-enyl) methyl)piperazin-1-yl)benzoate

According to the present invention, the said methods should in particular be more industrially scalable, allow the desired compounds to be obtained with high yields, and use cheaper reagents which are simpler to handle and industrial applicable.

On the other hand, the prior art processes involves the use of excess solvents and reagents, further involves high temperature ranging between 130-140, which leads to the formation of impurity at RRT-1.25 (HPLC). However, to overcome the formation of this impurity, the present inventors now developed a process which yields 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl cyclohex-1-enyl) methyl)piperazin-1-yl)benzoate free of this impurity.
The present inventors also found that, if the temperature is less than 65°C the reaction is incomplete, yields are low and additional purification is required due to incomplete reaction.

To overcome the above disadvantage the inventors of the present invention developed a process, which is industrially liable, viable and environmental friendly.

The above obtained pure 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate is converted to Venetoclax or its pharmaceutically acceptable salts using any of the prior art processes / process, which are feasible for a person skilled in the art.

The above obtained 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate (IV) is converted to 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 (V) comprising dissolving 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate (IV) in a suitable solvent, wherein solvent comprises one or more solvents selected from water; alcohol selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; the ketone is selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone; ester selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; halogenated hydrocarbon selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and N-methyl- pyrrolidone, hydrocarbon solvent selected from hexane, heptane, cyclohexane; in presence of base selected from such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate; or an acid is selected from Hydrochloric acid, sulfuric acid, trifluoro acetic acid, nitric acid etc; at a temperature ranging from 60-65° C and stirring for 4 hours, to the obtained solution pH was adjusted at 25-30° C and maintain the reaction mass for 4 hours at same temperature to get precipitated solid was filtered to obtain pure 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.

The prior art processes involves the use of excess solvents and reagents, further involves distillation of solvent and purifications, which leads in the formation of additional impurities in the product and also lowers the quantity of yield. However, the present inventors now developed a process for the preparation of acid in a single step, which is industrially feasible and environmental friendly.

The present process yields in 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, which is highly pure and free of these process related impurities and higher yields compared to prior art processes.
The above obtained pure 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 is converted to Venetoclax or its pharmaceutically acceptable salts using any of the prior art processes / process, which are feasible for a person skilled in the art.

The present inventors further converted above obtained pure 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 Venetoclax or its pharmaceutically acceptable salts comprises condensation 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 (V) with 3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl )amino] benzenesulfonamide (VI); in presence of base / catalyst to produce Venetoclax; wherein base used selected from organic/inorganic base such as methylamine, triethylamine, diisoproylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate; and the catalyst selected from N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide(EDC), 4-(dimethylamino) pyridine (DMAP), 2- (benzoylcarbamothioylamino)-5,5-dimethyl-4,7-dihydrothieno[2,3-c]pyran-3-carboxylic acid (CID), (benzotriazol-l -yloxy)tripyrrolidinophosphonium hexafluorophosphate (PY-BOP),or 1 -[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) at a temperature ranging from 20-45°C and for a period of 20-40 hours. After completion of reaction the precipitated reaction solid was filtered and followed by acetic acid / dichloromethane and saturated sodium bicarbonate solution through pH adjustments. The solid was filtered and purified with mixture of tetrahydrofuran and water to get Venetoclax as a solid.
Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-65°C for a time ranging from 12 to 16 hours depending upon the physical attributes of the end product obtained i.e. Pure Venetoclax or its pharmaceutically acceptable salts obtained according to the present invention is having purity greater than 99.5%. The obtained pure Venetoclax or its pharmaceutically acceptable salts having purity greater than 99.5% and substantially free from process related impurities:
The process related impurities that appear in the impurity profile of the Venetoclax may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:

The process related impurities that appear in the impurity profile of the Venetoclax (I) or its pharmaceutically acceptable salts may be substantially removed by the process of the present invention resulting in the formation of Venetoclax (I) or its pharmaceutically acceptable salts of high purity.
In another embodiment of the present invention relates to substantially pure Venetoclax having the purity of greater than 99.6% and total impurities A to 4 collectively less than 0.4% by HPLC.

The merit of the process according to the present invention resides in that product isolated after drying is directly obtained as pure Venetoclax or its pharmaceutically acceptable salts (I). Said material is found devoid of any other crystal lattice and is adequately stable to handle and store for longer time (alteast up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics. Venetoclax or its pharmaceutically acceptable salts (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99.5 % w/w, and found to be stable at different ICH conditions.

The starting materials used in the process may be synthesized by the process disclosed in the prior art. However, the processes followed by the present inventors are as summarized below:
Starting material – A Synthesis:

Starting material – B Synthesis:
Starting material – C Synthesis:

In another embodiment, the Venetoclax or its pharmaceutically acceptable salts (I) obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising Venetoclax or its pharmaceutically acceptable salts (I) obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions derived from Venetoclax or its pharmaceutically acceptable salts (I) of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES
Example-1: 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoate)
A mixture of potassium dihydrogen phosphate (30.25 g, 0.173 mol), 4-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine (42.5g, 0.133mol) (II) and Methyl-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (25g, 0.087mol) (III) are charged in to the reaction vessel containing Dimethyl sulphoxide (250 ml) at 25-30 °C. The reaction mixture was heated to about 65-85°C and maintained for 20-24 hrs. The reaction mixture was cooled to 25-30°C and charge ethyl acetate (250ml) and purified water (250ml) under stirring. Separate the two layers after 30 min at 25-30°C. The ethyl acetate layer was washed with sodium hydroxide solution (250ml) and brine solution (250ml). Ethyl acetate layer was dried with sodium sulphate and concentrated the solvent by under vacuum at 40-45°C. Charge methanol (500 ml) to the residue and stirred for 2-3 hrs. Filtered the solid, washed with n-heptane (125ml) and dried under vacuum to obtain 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy) benzoate) (IV)
Yield: 30.5 g (Molar Yield- 59.23%),
Chromatographic Purity (By HPLC): 96.15%

Example-2: 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoate)
A mixture of potassium dihydrogen phosphate (30.25 g, 0.173 mol), 4-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine (42.5g, 0.133mol) (II) and Methyl-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (25g, 0.087mol) (III) are charged in to the reaction vessel containing Dimethyl sulphoxide (250 ml) at 25-30 °C under nitrogen atmosphere. The reaction mixture was heated to about 65-85°C and maintained for 20-24 hrs. The reaction mixture was cooled to 25-30°C and charge ethyl acetate (250ml) and purified water (250ml) under stirring. Separate the two layers after 30 min at 25-30°C. The ethyl acetate layer was washed two times with sodium hydroxide solution (2X250ml) and one time with brine solution (250ml). Ethyl acetate layer was dried with sodium sulphate and concentrated the solvent by under vacuum at 40-45°C. Charge methanol (200 ml) and n-heptane (400ml) to the residue and stirred for 2-3 hrs. Filtered the solid, washed with n-heptane (100ml) and dried under vacuum to obtain 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoate) (IV)
Yield: 31g (Molar Yield- 59.6%),
Chromatographic Purity (By HPLC): 97.03%

Example-3:4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl] -2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate)
A mixture of potassium dihydrogen phosphate (30.25 g, 0.173 mol), 4-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine (42.5g, 0.133mol) (II) and Methyl-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (25g, 0.087mol) (III) are charged in to the reaction vessel containing Dimethyl sulphoxide (250 ml) at 25-30 °C under nitrogen atmosphere. The reaction mixture was heated to about 65-85°C and maintained for 20-24 hrs. The reaction mixture was cooled to 25-30°C and charge ethyl acetate (250ml) and purified water (250ml) under stirring. Separate the two layers after 30 min at 25-30°C. The ethyl acetate layer was washed two times with sodium hydroxide solution (2X250ml) and one time with brine solution (250ml). Ethyl acetate layer was dried with sodium sulphate and concentrated the solvent by under vacuum at 40-45°C. Charge acetone (150 ml) to the residue and stirred for 4-6 hrs. Filtered the solid, washed with n-heptane (100ml) and dried under vacuum to obtain 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate) (IV).
Yield: 30g (Molar Yield- 58.7%),
Chromatographic Purity (By HPLC): 95.88%

Example-4: 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate).
A mixture of potassium dihydrogen phosphate (30.25 g, 0.173 mol), 4-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine (42.5g, 0.133mol) (II) and Methyl-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (25g, 0.087mol) (III) are charged in to the reaction vessel containing Dimethyl sulphoxide (250 ml) at 25-30 °C under nitrogen atmosphere. The reaction mixture was heated to about 65-85°C and maintained for 20-24 hrs. The reaction mixture was cooled to 25-30°C and charge ethyl acetate (250ml) and purified water (250ml) under stirring. Separate the two layers after 30 min at 25-30°C. The ethyl acetate layer was washed two times with sodium hydroxide solution (2X250ml) and one time with brine solution (250ml). Ethyl acetate layer was dried with sodium sulphate and concentrated the solvent by under vacuum at 40-45°C. Charge acetone (100 ml) and n-heptane (200ml) to the residue and stirred for 4-6 hrs. Filtered the solid, washed with n-heptane (100ml) and dried under vacuum to obtain 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate) (IV).
Yield: 30.5g (Molar Yield-59.68%),
Chromatographic Purity (By HPLC): 97.78%

Example-5:4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoate).
A mixture of potassium dihydrogen phosphate (30.25 g, 0.173 mol), 4-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine (42.5g, 0.133mol) (II) and Methyl-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (25g, 0.087mol) (III) are charged in to the reaction vessel containing Dimethyl sulphoxide (250 ml) at 25-30 °C under nitrogen atmosphere. The reaction mixture was heated to about 65-85°C and maintained for 20-24 hrs. The reaction mixture was cooled to 25-30°C and charge ethyl acetate (250ml) and purified water (250ml) under stirring. Separate the two layers after 30 min at 25-30°C. The ethyl acetate layer was washed two times with sodium hydroxide solution (2X250ml) and one time with brine solution (250ml). Ethyl acetate layer was dried with sodium sulphate and concentrated the solvent by under vacuum at 40-45°C. Charge petroleum ether (500 ml) to the residue and stirred for 2-3 hrs. Filtered the solid, washed with petroleum ether (50ml) and dried under vacuum to obtain 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoate) (IV).
Yield: 31.5 g (Molar Yield-61.64%),
Chromatographic Purity (By HPLC): 93.7%

Example-6: 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoate).
A mixture of potassium dihydrogen phosphate (30.25 g, 0.173 mol), 4-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine (42.5g, 0.133mol) (II) and Methyl-2-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (25g, 0.087mol) (III) are charged in to the reaction vessel containing Dimethyl sulphoxide (250 ml) at 25-30 °C under nitrogen atmosphere. The reaction mixture was heated to about 110-115°C and maintained for 14-16 hrs. The reaction mixture was cooled to 25-30°C and charge ethyl acetate (250ml) and purified water (250ml) under stirring. Separate the two layers after 30 min at 25-30°C. The ethyl acetate layer was washed two times with sodium hydroxide solution (2X250ml) and one time with brine solution (250ml). Ethyl acetate layer was dried with sodium sulphate and concentrated the solvent by under vacuum at 40-45°C. Charge methanol (500 ml) to the residue and stirred for 2-3 hrs. Filtered the solid, washed with n-heptane (125ml) and dried under vacuum to obtain 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy) benzoate) (IV).
Yield: 31 g (Molar Yield-60.6%),
Chromatographic Purity (By HPLC): 90.51%

Example-7: 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid
4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoate) (25g, 0.0427mol) (IV) and isopropyl alcohol(300ml) was charged into a RB flask at 25-30 °C in nitrogen atmosphere. Sodium hydroxide solution (10 g, 0.25 mol) solution prepared in water (250 ml) was slowly added at 25-30 °C under stirring.The reaction mixture was stirred at 60-65 °C for 4 hrs. The reaction mixture was cooled to 25-30°C and gives two n-heptane (2X250ml) washings at 25-30°C. Adjust the pH of reaction mass (1-2) with 10% hydrochloric acid at 25-30°C and maintain the reaction mass for 4hrs at the same temperature. Filtered the solid, washed with n-heptane (50ml) and dried under vacuum to obtain 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid (V).
Yield: 18.3 g (Molar Yield-75.00%),
Chromatographic Purity (By HPLC): 97.82%, SMI-0.58%, T.I-2.18%.

Example-8:
Preparation of Venetoclax
A mixture of 4-[4-[[2-(4-chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-2-(1H- pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid (25g, 0.0437mol) (V) and trimethyl amine(8.66g, 0.0857) and Dichloro methane (300ml) were charged in to a suitable four neck round bottom flask at 25-30 °C under stirring to get a clear solution(solution-1). In a another four neck round bottom flask, 3-nitro-4(((tetrahydro-2H-pyran-4yl) methyl)amino)benzene sulphonamide (11.73g, 0.037mol) (VI), 4-dimethylamino pyridine (10.57g, 0.0866), 1-Ethyl-3-(3-dimethyl amino propyl)carbodiimide hydrochloride (11.51g, 0.0599mol) and dichloro methane (300ml) were charged under stirring. The solution-1 was added drop wise to the second flask slurry over a period of 30min at 20-250C. After that the reaction mass was maintained for 20-24hrs at 20-250C. After completion of the reaction, reaction mass was washed with two times with 10% aqueous acetic acid solution (2X250ml). The organic layer was diluted with dichloro methane (125ml) and give two times with sodium bicarbonate solution (2X250ml) and one time with brine solution (250ml) washings. Dichloro methane layer was dried with sodium sulphate and concentrated the solvent by under vacuum at 20-25°C. Charge dichloro methane (200ml), methanol (17.5ml) and ethyl acetate (225ml) to the residue and stirred for 3-4hrs at 5-100C. Filtered the solid, washed with dichloro methane (25ml) and ethyl acetate (25ml) mixture (50ml) and dried under vacuum at suitable temperature. The crude product was purified with tetrahydro furan and water solvent mixture. Finally the Venetoclax free base solid was suspended in dichloro methane (400ml) at ambient temperature to reach its solubility. After that the reaction mass was cooled to 0-50C and maintained for 6hrs. The obtained solid was filtered and dried under vacuum at ambient temperature to get pattern-A (I).
Yield: 15g (39.5% w/w),
Chromatographic Purity (By HPLC): 99.69%, IMP-G-0.1%, SMI-0.08%, T.I-0.31%,
While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
,CLAIMS:Claims:
1) An improved process for the preparation of high purity Venetoclax (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. condensing 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine of formula (II)

with methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (III)


in the presence of base / solvent to produce crude product, followed by isolation using one or more solvents at 65-85° C to yield high pure methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl)benzoate (IV) without use of column purification

b. saponification of methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl)benzoate (IV)
in the presence of acid / base and solvent to provide 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 (V);

c. condensation 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 (V) with 3-Nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]benzenesulfonamide in presence of base, catalyst and solvent to produce Venetoclax (I).

2) An improved process for the preparation of Venetoclax (I) or its pharmaceutically acceptable salts according to claim 1, wherein base used in step a) or step b) or step c) are selected from organic base such as methylamine, triethylamine, diisoproylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate, potassium biphosphate, dipotassium biphosphate.

3) A process for the preparation of Venetoclax according to claim 1, wherein the solvent comprises one or more solvents selected from water, alcohol selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; ketone selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone, ester selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; halogenated hydrocarbon selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene, polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and the hydrocarbon solvent selected from hexane, heptane cyclohexane, N-methyl- pyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or mixtures thereof.

4) An improved process for the preparation of high purity Venetoclax (I) or its pharmaceutically acceptable salts thereof

comprising the steps of
a. condensing 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine of formula (II)

with methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluorobenzoate (III)


in the presence of base / solvent to produce crude product, followed by isolation using one or more solvents at 65-85° C to yield high pure methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl)benzoate (IV) without use of column purification

b. conversion of methyl 2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl) methyl) piperazin-1-yl)benzoate (IV) to Venetoclax or its pharmaceutically acceptable salts.

5) An improved process for the preparation of Venetoclax (I) or its pharmaceutically acceptable salts according to claim 4, wherein base used in step a) or step b) or step c) are selected from organic base such as methylamine, triethylamine, diisoproylethylamine, t-butylamine, N,N-dimethylaniline, dimethylformamide, pyridine, DBU, DBN, N-methylpiperazine or inorganic base such as sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, lithium carbonate, potassium biphosphate, dipotassium biphosphate.

6) A process for the preparation of Venetoclax according to claim 4, wherein the solvent comprises one or more of water, alcohol selected from methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, and 2-pentanol; ketone selected from acetone, butanone, 2- pentanone, 3-pentanone, methylbutyl ketone, and methyl isobutyl ketone, ester selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate; halogenated hydrocarbon selected from methylene dichloride, ethylene dichloride, carbon tetrachloride and chlorobenzene, polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, and the hydrocarbon solvent selected from hexane, heptane cyclohexane, N-methyl- pyrrolidone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or mixtures thereof.

7) Venetoclax containing the process related impurities A, B, C, D, E, F and G collectively below 0.4%.

8) Venetoclax containing the process related impurities A, B, C, D, E, F and G collectively below 0.4% according to claim 7, having a purity of greater than 99.6% w/w.

9) Highly pure Venetoclax having a purity of greater than 99.6 %

10) Use of a Venetoclax and its pharmaceutical acceptable salts obtained according to any of the preceding claims in the preparation of pharmaceutical composition.