DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

PROCESS FOR THE PREPARATION OF ABIRATERONE ACETATE
INTRODUCTION
The present application provides processes for the preparation of abiraterone acetate.

BACKGROUND OF THE INVENTION
The drug compound known as “abiraterone acetate” has a chemical name (3ß)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate. It has the structure of formula (I).

(I)
Abiraterone acetate the active ingredient of ZYTIGA® is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17a-hydroxylase/C17,20-lyase). Each ZYTIGA tablet contains 250 mg of abiraterone acetate.
U.S. Patent No. 5,604,213 (“the US ‘213 patent”) discloses processes for the preparation of abiraterone acetate and related analogs. One of the processes for the preparation of abiraterone acetate involves the steps of a) reacting dehydroepiandrosterone with hydrazine hydrate and hydrazine sulfate solution in the presence of ethanol at room temperature for 5 days to give dehydroepiandrosterone-17-hydrazone; b) reacting dehydroepiandrosterone-17-hydrazone with iodine in the presence of 1,1,3,3-tetramethylguanidine and tetrahydrofuran, diethyl ether as solvent to give 17-iodo-androsta-5,16-dien-3ß-ol; c) coupling 17-iodo-androsta-5,16-dien-3ß-ol with diethyl(3-pyridyl)borane in the presence of bis(triphenylphosphine) palladium (II) chloride, tetrahydrofuran and aqueous sodium carbonate at reflux temperature for 4 days followed by workup to give 17-(3-Pyridyl)androsta-5,16-dien-3ß-ol d) acetylating 17-(3-Pyridyl)androsta-5,16-dien-3ß-ol by reacting with acetic anhydride and pyridine at room temperature for 24 hours to give abiraterone acetate.
The process disclosed in the US ‘213 patent is not commercially viable as it involves longer durations of time for e.g., 5 days for reaction step a); 4 days for the reaction step c) and 24 hours for the reaction step d), leading to the formation of by-products such as dimers. Further, the process also involves the use of pyridine in the final step and the excess pyridine, acetic anhydride were removed on a rotary evaporator at higher temperature leading to a laborious work-up with decrease in the yield, purity of the product. Further, according to the US ‘213 patent, abiraterone acetate prepared by the above process showed a contamination of about 5% of 3ß-acetoxy-16-(3'-ß-acetoxyandrosta-5',16'-dien-17'-yl)-17-(3-pyridyl)androsta-5,16-diene, which originated as a by-product from the coupling reaction of step (c) and making it difficult or even precludes isolating the pure abiraterone acetate on an industrial scale production.
The other process disclosed in the US ‘213 patent involves the steps of: a) reacting dehydroepiandrosterone-3-acetate in dry dichloromethane with trifluoromethane sulphonic anhydride in the presence of 2,6-di-t-butyl-4-methylpyridine (DTBMP) for 12 hours, followed by column purification to give 3ß-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate with an yield of 58%; b) coupling 3ß-acetoxyandrosta-5,16-dien-17-yl trifluoromethanesulphonate in tetrahydrofuran with diethyl(3-pyridyl)borane in the presence of bis(triphenylphosphine) palladium(II) chloride and aqueous solution of sodium carbonate at reflux temperature, followed by chromatographic purification using light petroleum-diethyl ether (2:1) to give 3ß-acetoxy-17-(3-pyridyl)androsta-5,16-diene. The above process is not of significant practical importance as the yields obtained are poor, namely 58% for step a), involves the use of expensive reagents such as DTBMP which also results in the formation of eliminated impurities, and involves column purification for all the steps which is time consuming and requires large excess of the expensive solvents.
U.S. Patent No. 7,700,766 (“the US ‘766 patent”) discloses a process for the preparation of abiraterone acetate wherein dehydroepiandrosterone or dehydroepiandrosterone-3-acetaate is reacted with a triflating agent in the presence of a base comprising a tertiary or heterocyclic amine such that the pKa of the conjugate acid at 25°C is within the range of 5.21 to 12. Further, the US ‘766 patent discloses a process for the purification of abiraterone acetate by salt formation with the acids such as methanesulfonic acid, hydrochloric acid, sulfuric acid, tartaric acid, acetic acid, malic acid or toluoyltartaric acid. The above process is an alternate to the processes reported in the prior art involving the use of DTBMP reagent. However, according to the specification of US ‘766 patent it was observed that the product to starting material ratio remained 3:1 after the triflation step and the starting material dehydroepiandrosterone-3-acetate is carried till the final stage of the synthesis. Further US’776 describes, obtained triflate intermediate undergoes suzuki coupling with diethyl(3-pyridyl)borane in presence of Pd(PPh3)2Cl2, THF and Na2CO3 to give abiraterone acetate. Further, the above reaction involving the use of triflic anhydride (as the triflating agent) is critical, as it may result in the decomposition of the product and requires the addition of base to the reaction mixture immediately (say fifteen minutes or less) after the addition of triflic anhydride and also requires quenching the reaction mixture within a hour. Such critical requirement of the process doesn’t make the process robust and well suited for industrial scale development.
Gerard et al., in Organic Preparations and Procedures International, 1997, 29(1), 123-128 discloses a process for the preparation of abiraterone acetate which is similar to the process disclosed in the US ‘213 patent.
Chinese patent applications CN102030798, CN102838649, CN102816200, CN102816201, CN102816199, CN102731605, CN102627681, CN102558274, CN102898495 and CN103102381 also describes various processes for the preparation and purification of abiraterone acetate.
It is apparent from the processes described in the literature, palladium catalyzed reactions are used in the preparation of abiraterone or its acetate, while palladium catalyzed reactions are undoubtedly leads to the undesired outcome of contamination of reaction products by palladium, which is very difficult to separate and purify to afford compounds of formula (IA). The acceptable limits for residual palladium are quite stringent, as per regulatory guidelines. The inventors of the present application further found that by passing the reaction mass containing abiraterone acetate through 0.22 micron filter paper repeatedly or even filtering or treating with silica gel could not help in achieving abiraterone acetate with acceptable limits of residual palladium.
Despite the existence of processes for the preparation of abiraterone acetate and its intermediates, there remains a need for providing novel solution that would decrease the consumption of time and labor and it is of particular importance to develop methods that would allow for the increase in yields of particular steps, which in turn would favor an increase of the yield of the whole technology.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides process for the preparation of the compound of formula (IA)

(IA)
wherein R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
a) coupling a compound of formula (IV)

(IV)
wherein R is as defined above, with a compound of the formula (V)

(V)
in the presence of a palladium complex, a suitable ligand and a solvent mixture consisting of an alcohol solvent and water to obtain a compound of formula (IA)

(IA)
b) optionally, reacting the compound of formula (IA) with an acylating agent, to obtain a compound of formula (I), when R in the compound of formula (IA) obtained in step a) is a hydrogen.

(I)

DETAILED DESCRIPTION
In an aspect, the present application relates to process for the preparation of the compound of formula (IA)

(IA)
wherein R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
a) coupling a compound of formula (IV)

(IV)
wherein R is as defined above, with a compound of the formula (V)

(V)
in the presence of a palladium complex, a suitable ligand and a solvent mixture consisting of an alcohol solvent and water to obtain a compound of formula (IA)

(IA)
b) optionally, reacting the compound of formula (IA) with an acylating agent, to obtain a compound of formula (I), when R in the compound of formula (IA) obtained in step a) is a hydrogen.

(I)
Step a) involves reacting the compound (IV) with potassium salt of 3-(trifluoro-?4-boranyl)pyridine (compound V), in the presence of a palladium complex, a quaternary ammonium salt such as tetra-n-butylammonium bromide and a suitable ligand, in the presence of a solvent mixture consisting of an alcohol solvent and water.
Suitable ligand that may be used in the above reaction may be selected from 3-(dimethylamino)propanoic acid, 2-(dimethylamino)ethanoic acid, 2-(dimethylamino)benzoic acid, 1,1'-Bis(diphenylphosphino)ferrocene, 2-(dimethylamino)phenol, 2-butyl-1,1,3,3-tetramethylguanidine, 2-dodecyl-1,1,3,3-tetramethylguanidine or salts thereof. In a preferred embodiment, hydrochloride salt of 3-(dimethylamino)propanoic acid is used.
In a preferred embodiment, the solvent mixture used in the above is isopropyl alcohol and water.
The above reaction may be carried out at temperatures ranging from about 20 °C to about 90 °C, based on the alcohol solvent selected. In an embodiment the reaction is carried out at 65-85°C.
After the completion of the reaction of step a) the compound of formula (IA) may be isolated by known methods or by the methods disclosed in the instant application or the reaction mixture containing the compound of formula (IA) may be taken up for purification by methods disclosed in the instant application.
In an embodiment, the compound of formula (IV), when R is a lower acyl group having 2 to 4 carbon atoms is reacted with potassium salt of 3-(trifluoro-?4-boranyl)pyridine (compound V), in the presence of a palladium complex, a quaternary ammonium salt such as tetra-n-butylammonium bromide and a suitable ligand, in the presence of a solvent mixture consisting of an alcohol solvent and water to obtain a compound of formula (IA), where R is a lower acyl group having 2 to 4 carbon atoms.
In an embodiment, the compound of formula (IV), when R is an acetyl group, is reacted with potassium salt of 3-(trifluoro-?4-boranyl)pyridine (compound V), in the presence of a palladium complex, a quaternary ammonium salt such as tetra-n-butylammonium bromide and a suitable ligand, in the presence of a solvent mixture consisting of an alcohol solvent and water a compound of formula (I).
In an embodiment, the compound of formula (IV), when R is hydrogen group, is reacted with potassium salt of 3-(trifluoro-?4-boranyl)pyridine (compound V), in the presence of a palladium complex, a quaternary ammonium salt such as tetra-n-butylammonium bromide and a suitable ligand, in the presence of a solvent mixture consisting of an alcohol solvent and water to obtain a compound of formula (IA), where R is hydrogen. Said compound may optionally be further reacted with an acylating agent in step b) to obtain the compound of formula (I).
The above process of the present application involving the use ligand and a solvent mixture consisting of an alcohol and water in step a) is extremely efficient and produces high yield and purity.

DEFINITIONS
The term “alkyl” includes both straight and branched chain and preferably a methyl, ethyl, propyl or isopropyl group. An analogous convention applied to the term “alkoxy”.
The phrase “acyl group having 2 to 4 carbon atoms” includes methanoyl (formyl), ethanoyl (acetyl) or propanoyl (propionyl) groups.
The palladium complex which may be used is PdCl2(PPh3)2, Pd(OAc)2, PdCl2(dppf) and the like.
Solvents that may be used in purification of abiraterone acetate include esters such as methyl acetate, ethyl acetate, isopropyl acetate and the like; ethers such as diethyl ether, diisopropylether, methyl-tert-butyl ether, tetrahydrofuran,1,4-dioxane, petroleum ether and the like; alcohol solvents selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, t-butanol and the like; ketones such as acetone, ethyl isopropyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; hydrocarbons such as pentane, hexane, heptane, toluene, xylene, benzene and the like, water or mixtures thereof.
The alcohol solvent used may be selected from methanol, ethanol, butanol, n-propanol and isopropanol.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following, which are provided only for purposes of illustration and should not be construed as limiting the scope of the present application in any manner.
EXAMPLES
EXAMPLE 1: Preparation of (3ß)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate
(3ß)-Androsta-5,16-dien-3-ol, 17-iodo-3-acetate (10 g), potassium salt of 3-(trifluoro-?4-boranyl)pyridine (4.62 g), potassium phosphate monohydrate (31.4 g), palladium(II) acetate (25.51 mg), 3-(dimethylamino)propanoic acid hydrochloride (34.9 mg), tetra-n-butylammonium bromide (1.83 g), isopropanol (100 mL) and water (100 mL) were charged into a round bottom flask at 25-30°C under nitrogen atmosphere and the mixture was stirred. The reaction mixture was heated to a temperature of 75-85 °C and stirred at the same temperature for about 16 hours. After the completion of the reaction, the reaction mixture was allowed to cool to 25-30°C, added toluene (500 mL) and filtered through celite. The filterate was concentrated under reduced pressure at 50 oC. To the concentrated mass, 50 mL of toluene, triethylamine (6.38 mL), dimethyl amino pyridine (138 mg) and acetic anhydride (2.15 mL) were added and the reaction mixture was stirred at 40-45 °C for 150 minutes. The reaction mass was cooled to 10-15 oC and water (50 mL) was added. The aqueous and organic layers were separated. To the organic layer acetone (20 mL) and oxalic acid (3.44 g) were added and stirred for 60-90 minutes at 25-30 oC. The reaction mixture was filtered and dried at 50-55 oC for 2-3 hours. 5% sodium bicarbonate solution was added to the dried compound and stirred for 1 hour. The reaction mass was filtered and washed with demineralized water. To obtained solid was added acetone (120 mL), thiosilica gel (0.2 g) and carbon and stirred for 1 hour. The contents were filtered over Hyflow, followed by filtration over 0.2 micron filter paper. To the filtrate, water (80 mL) was added and the solid obtained was filtered and dried at 50 oC under reduced pressure to obtain the title compound.
Yield: 68 %; Purity by HPLC: 98.96 %

EXAMPLE 2: Preparation of (3ß)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate.
(3ß)-Androsta-5,16-dien-3-ol, 17-iodo-3-acetate (880 mg), potassium salt of 3-(trifluoro-?4-boranyl)pyridine (518 mg), potassium phosphate monohydrate (2.77 g), palladium(II) acetate (2.24 mg), 2-(dimethylamino)ethanoic acid hydrochloride (3.1 mg), tetra-n-butylammonium bromide (161 mg), isopropanol (9 mL) and water (9 mL) were charged into a round bottom flask at 25-30°C under nitrogen atmosphere and the mixture was stirred. The reaction mixture was heated to a temperature of 75-85 °C and stirred at the same temperature for about 18 hours. After the completion of the reaction, the reaction mixture was allowed to cool to 25-30°C, added toluene (500 mL) and filtered through celite. The filterate was concentrated under reduced pressure at 50 oC. To the concentrated mass, 50 mL of toluene, triethylamine (0.51 mL), dimethyl amino pyridine (11 mg) and acetic anhydride (0.17 mL) were added and the reaction mixture was stirred at 40-45 °C for 150 minutes. The reaction mass was cooled to 10-15 oC and water (4 mL) was added. The aqueous and organic layers were separated. To the organic layer acetone (1.6 mL) and oxalic acid (0.08 g) were added and stirred for 60-90 minutes at 25-30 oC. The reaction mixture was filtered and dried at 50-55 oC for 2-3 hours. 5% sodium bicarbonate solution was added to the dried compound and stirred for 1 hour. The reaction mass was filtered and washed with demineralized water. To obtained solid was added acetone (120 mL), thiosilica gel (0.016) and carbon and stirred for 1 hour. The contents were filtered over Hyflow, followed by filtration over 0.2 micron filter paper. To the filtrate, water (6.4 mL) was added and the solid obtained was filtered and dried at 50 oC under reduced pressure to obtain the title compound.

EXAMPLE 3: Preparation of (3ß)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate.
(3ß)-Androsta-5,16-dien-3-ol, 17-iodo-3-acetate (440 mg), potassium salt of 3-(trifluoro-?4-boranyl)pyridine (410 mg), potassium phosphate monohydrate (1.15 g), palladium(II) acetate (2.9 mg), 2-(dimethylamino)benzoic acid (4 mg), isopropanol (5 mL) and water (5 mL) were charged into a round bottom flask at 25-30°C under nitrogen atmosphere and the mixture was stirred. The reaction mixture was heated to a temperature of 75-85 °C and stirred at the same temperature for about 18 hours. After the completion of the reaction, the reaction mixture was allowed to cool to 25-30°C, added toluene (500 mL) and filtered through celite. The filterate was concentrated under reduced pressure at 50 oC. To the concentrated mass, 50 mL of toluene, triethylamine (0.25 mL), dimethyl amino pyridine (5.5 mg) and acetic anhydride (0.085 mL) were added and the reaction mixture was stirred at 40-45 °C for 150 minutes. The reaction mass was cooled to 10-15 oC and water (2 mL) was added. The aqueous and organic layers were separated. To the organic layer acetone (0.8 mL) and oxalic acid (0.04 g) were added and stirred for 60-90 minutes at 25-30 oC. The reaction mixture was filtered and dried at 50-55 oC for 2-3 hours. 5% sodium bicarbonate solution was added to the dried compound and stirred for 1 hour. The reaction mass was filtered and washed with demineralized water. To obtained solid was added acetone (120 mL), thiosilica gel (0.008 g) and carbon and stirred for 1 hour. The contents were filtered over Hyflow, followed by filtration over 0.2 micron filter paper. To the filtrate, water (3.2 mL) was added and the solid obtained was filtered and dried at 50 oC under reduced pressure to obtain the title compound.

EXAMPLE 4: Preparation of (3ß)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate.
(3ß)-Androsta-5,16-dien-3-ol, 17-iodo-3-acetate (1760 mg), potassium salt of 3-(trifluoro-?4-boranyl)pyridine (820 mg), potassium phosphate monohydrate (4.6 g), 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.8 mg), 1,1'-Bis(diphenylphosphino)ferrocene (6.65 mg), isopropanol (20 mL) and water (20 mL) were charged into a round bottom flask at 25-30°C under nitrogen atmosphere and the mixture was stirred. The reaction mixture was heated to a temperature of 75-85 °C and stirred at the same temperature for about 36 hours. After the completion of the reaction, the reaction mixture was allowed to cool to 25-30°C, added toluene (500 mL) and filtered through celite. The filterate was concentrated under reduced pressure at 50 oC. To the concentrated mass, 50 mL of toluene, triethylamine (1.1 mL), dimethyl amino pyridine (22 mg) and acetic anhydride (0.34 mL) were added and the reaction mixture was stirred at 40-45 °C for 150 minutes. The reaction mass was cooled to 10-15 oC and water (8 mL) was added. The aqueous and organic layers were separated. To the organic layer acetone (3.2 mL) and oxalic acid (0.16 g) were added and stirred for 60-90 minutes at 25-30 oC. The reaction mixture was filtered and dried at 50-55 oC for 2-3 hours. 5% sodium bicarbonate solution was added to the dried compound and stirred for 1 hour. The reaction mass was filtered and washed with demineralized water. To obtained solid was added acetone (120 mL), thiosilica gel (0.032 g) and carbon and stirred for 1 hour. The contents were filtered over Hyflow, followed by filtration over 0.2 micron filter paper. To the filtrate, water (12.8 mL) was added and the solid obtained was filtered and dried at 50 oC under reduced pressure to obtain the title compound.
,CLAIMS:We Claim:
1. A process for the preparation of the compound of formula (IA)

(IA)
wherein R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
a) coupling a compound of formula (IV)

(IV)
wherein R is as defined above, with a compound of the formula (V)

(V)
in the presence of a palladium complex, a suitable ligand and a solvent mixture consisting of an alcohol solvent and water to obtain a compound of formula (IA)

(IA)
b) optionally, reacting the compound of formula (IA) with an acylating agent, to obtain a compound of formula (I), when R in the compound of formula (IA) obtained in step a) is hydrogen.

(I)
2. The process of claim 1 wherein, the palladium complex is selected from PdCl2(PPh3)2, Pd(OAc)2, and PdCl2(dppf).
3. The process of claim 1 wherein, suitable ligand is selected from 3-(dimethylamino)propanoic acid, 2-(dimethylamino)ethanoic acid, 2-(dimethylamino)benzoic acid, 1,1'-Bis(diphenylphosphino)ferrocene, 2-(dimethylamino)phenol, 2-butyl-1,1,3,3-tetramethylguanidine, 2-dodecyl-1,1,3,3-tetramethylguanidine or salts thereof.