WO2014083512A1 - Procédé de préparation de l'acétate d'abiraterone - Google Patents

Procédé de préparation de l'acétate d'abiraterone Download PDF

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Publication number
WO2014083512A1
WO2014083512A1 PCT/IB2013/060441 IB2013060441W WO2014083512A1 WO 2014083512 A1 WO2014083512 A1 WO 2014083512A1 IB 2013060441 W IB2013060441 W IB 2013060441W WO 2014083512 A1 WO2014083512 A1 WO 2014083512A1
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Prior art keywords
formula
compound
solvent
abiraterone acetate
reaction mixture
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PCT/IB2013/060441
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English (en)
Inventor
Vilas Hareshwar Dahanukar
Goverdhan Gilla
Syam Kumar Unniaran KUNHIMON
Nageshwar Gunda
Venkata Rao Badisa
Shravankumar KOMATI
Srinivas Benda
Tridib MAHAPATRA
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Dr. Reddy's Laboratories Limited
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Publication of WO2014083512A1 publication Critical patent/WO2014083512A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/002—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 13 (17)

Definitions

  • the present application provide processes for the preparation of abiraterone acetate, its salts and intermediates thereof, crystalline forms of abiraterone acetate salts and purification of abiraterone acetate.
  • the drug compound known as "abiraterone acetate” has a chemical name (33)-17-(3-pyridinyl)androsta-5, 16-dien-3-yl acetate. It has the structure of formula
  • Abiraterone acetate the active ingredient of ZYTIGA ® is the acetyl ester of abiraterone.
  • Abiraterone is an inhibitor of CYP17 (17ohydroxylase/C17,20-lyase).
  • Each ZYTIGA tablet contains 250 mg of abiraterone acetate.
  • U.S. Patent No. 5,604,213 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-33-ol; c) coupling 17-iodo-androsta-5, 16-dien-33-ol with diethyl(3-pyridyl)bor
  • 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.
  • abiraterone acetate prepared by the above process showed a contamination of about 5% of 33-acetoxy-16-(3'-3-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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • the inventors of the present application developed an improved route in which the formation of the undesirable by-products in the reaction steps is kept down to acceptable levels, thereby eliminating expensive and time-consuming column chromatography.
  • the inventors of the present application developed a process in which the formation of the undesirable palladium content in the reaction steps is kept down to acceptable levels.
  • the inventors of the present application developed an improved process for the purification of abiraterone acetate by preparation of abiraterone acetate oxalic acid salt, using an oxalic acid having a particle size distribution D (90) of not less than 500 ⁇ , which helps in faster filtration at industrial scale, which in turn helps in avoiding the formation of abiraterone impurities upon exposure to atmosphere.
  • An aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R is as defined above;
  • Another aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises: a) reacting a compound of formula (II)
  • R is as defined above;
  • Another aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R is as defined above;
  • An aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R is as defined above;
  • step b) converting the compound of formula (IV) to a compound of formula (IA), wherein in prior to step b) the compound of formula (III) is not isolated in a solid form from the reaction mixture of step a).
  • Another aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • step 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 hyd
  • Another aspect of the present application relates to process for the preparation of the compound of formula (I)
  • Another aspect of the present application provides a process for the purification of abiraterone acetate of formula (I), which process comprises: a) combining abiraterone acetate, an acid selected from citric acid, oxalic acid, per chloric acid, trifluoroacetic acid, p-toluene sulfonic acid or phosphoric acid, and an organic solvent;
  • the present application provides crystalline Form-A of abiraterone acetate citric acid salt.
  • the present application provides crystalline Form-A of abiraterone acetate oxalic acid salt.
  • Another aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises: a) coupling a compound of formula (IV)
  • step 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 hyd
  • Another aspect of the present application relates to process for the preparation of the compound of formula (I)
  • Another aspect of the present application relates to process for the preparation of the compound of formula (I)
  • Another aspect of the present application relates to process for the purification of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R is as defined above, with palladium scavenger
  • Another aspect of the present application provides a process for the preparation of abiraterone acetate oxalic acid salt, which comprises:
  • Another aspect of the present application provides a process for the preparation of epoxide impurities of formula (M), formula (N) and isomers thereof comprising:
  • Formula (M) Formula (N) a) adding abiraterone acetate to hydrogen peroxide and acetic acid;
  • Figure 1 is X-Ray powder diffraction ("XRPD") pattern of the crystalline abiraterone acetate prepared according to Example 7.
  • Figure 2 is X-Ray powder diffraction ("XRPD") pattern of the crystalline abiraterone prepared according to Example 9.
  • Figure 3 is X-Ray powder diffraction ("XRPD") pattern of the crystalline Form-A of abiraterone acetate citric acid salt.
  • Figure 4 is X-Ray powder diffraction ("XRPD") pattern of the crystalline Form-A of abiraterone acetate oxalic acid salt.
  • An aspect of the present application relates to process for the preparation of the compound of formula
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R is as defined above;
  • the starting compound of formula (II) may be obtained by known processes.
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms. In an embodiment, R represents an acetyl group. In an embodiment, R represents a hydrogen.
  • step a) is carried by reacting the compound of formula (II) with hydrazine hydrate in the presence of a solvent mixture comprising an ester solvent.
  • the reaction of step a) is carried by reacting the compound of formula (II) with hydrazine hydrate in the presence of a solvent mixture comprising an ester solvent and a co-solvent.
  • the solvent mixture used in step a) consists of an ester solvent and an ether solvent selected from 1 ,4-dioxane, diethyl ether, tetrahydrofuran, diisopropyl ether and methyl tert-butyl ether.
  • the solvent mixture used in step a) consists of an ester solvent and an alcohol solvent selected from methanol, ethanol, isopropanol, n- butanol and the like.
  • the solvent mixture used in step a) consists of an ester solvent and 1 ,4-dioxane. In another embodiment, the solvent mixture used in step a) consists of an ester solvent and dimethyl formamide. In an embodiment, the above reaction may be carried out at temperatures ranging from about 25°C to about 80°C or 50°C to about 75°C or 60°C to 70°C or about 70°C to 80°C.
  • the compound of formula (III) may optionally be isolated as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of formula (III) may be taken forward for the next steps, with out isolating the compound of formula (III).
  • reaction mixture comprising the compound of formula (III) is diluted with an ester solvent used in the reaction, washed with aqueous sodium chloride solution and the organic layer comprising the compound of formula (III), is optionally distilled and taken forward for the next step.
  • step b) involves converting the compound of formula (I II) to the compound of formula (IA).
  • the compound of formula (III) may be converted to the compound of formula (IA) by known method for e.g., as per the methods disclosed in the US '213 patent or WO-A-95/09178 and Ren et al., in Journal of Labelled Compounds and Radiopharmaceuticals (2006), 49(1 1 ), 959-963 or by the processes disclosed in the instant application.
  • the present application relates to process for the preparation of the compound of formula (I)
  • Another aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R represents an acetyl group. In an embodiment, R represents hydrogen.
  • the inventors of the present application have surprisingly found that, carrying out the reaction of the compound of formula (II) or (I I A.) with hydrazine hydrate in a solvent mixture comprising an ester solvent or preferably in a solvent mixture comprising an alcohol solvent and an ester solvent resulted in the faster completion of reaction with optimum purity as compared to the known process which involves the use of ethanol as the solvent.
  • the present application relates compound of formula (IIIA) with less than 2%, preferably less than 1 %, more preferably less than 0.5% of the dimer impurity (Impurity B).
  • the present application relates to process for the preparation of the compound of formula (I) with less than 2%, preferably less than 1 %, more preferably less than 0.5% of the dimer impurity i.e., Impurity B.
  • Another aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R is as defined above;
  • the starting compound of formula (III) may be obtained by known processes or by the processes described in the present application.
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms. In an embodiment, R represents an acetyl group. In an embodiment, R represents hydrogen.
  • step a) is carried out by reacting the compound of formula (III) with iodine in the presence of a base and in the presence of a solvent comprising an ester solvent.
  • the above reaction may be carried out at temperatures ranging from about -30°C to about 10°C, based on the solvent and base selected.
  • the compound of formula (IV) may optionally be isolated as per the methods known in the art or by the process disclosed in the present application.
  • the reaction mass is filtered, washed with ethylacetate, concentrated under reduced pressure, and the compound of formula (IV) may isolated by crystallization from a solvent such as methanol, 2-butanol, isopropanol, ethylacetate, isopropyl acetate, acetone, acetonitrile, n-heptane, methyl tert-butyl ether, and diisopropyl ether to give the compound of formula (IV).
  • the compound of formula (IV) may be isolated by crystallization from acetonitrile and/or isopropyl alcohol.
  • step b) involves converting the compound of formula (IV) to the compound of formula (IA).
  • the compound of formula (IV) may be converted to the compound of formula (IA) by known method for e.g., as per the methods disclosed in the US '213 patent or WO-A-95/09178 or by the processes disclosed in the instant application.
  • the inventors of the present application have surprisingly found that, carrying out the reaction of compound of formula (III) or (IIIA) with iodine in the presence of a base and an ester solvent to obtain a compound of formula (IV) or (IVA) as described above resulted in the faster completion of reaction with optimum purity as compared to the known process which involves the use of tetrahydrofuran (an ether) as the solvent.
  • the present invention demonstrates a process for the compound of formula (IV) or (IVA) that is extremely efficient and produces optimum yield and purity.
  • the present application provides process for the preparation of the compound of formula (IVA) with less than 1 %, preferably less more preferably less than 0.5% of the impurity I.
  • An aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R is as defined above;
  • R is as defined above;
  • step b) converting the compound of formula (IV) to a compound of formula (IA), wherein in prior to step b) the compound of formula (III) is not isolated in a solid form from the reaction mixture of step a).
  • Step a) involves reacting the compound of formula (II) with hydrazine hydrate to provide a reaction mixture containing a compound of formula (IV).
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms. In an embodiment, R represents an acetyl group. In an embodiment, R represents hydrogen.
  • step a) may be carried out by reacting the compound of formula (II) with hydrazine hydrate in the presence of a solvent comprising an ester solvent.
  • reaction of step a) may be carried by reacting the compound of formula (II) with hydrazine hydrate in the presence of a solvent mixture comprising an ester solvent and a co-solvent.
  • the solvent mixture used in step a) consists of an ester solvent and an ether solvent selected from 1 ,4-dioxane, diethyl ether, tetrahydrofuran, diisopropyl ether and methyl tert-butyl ether.
  • the solvent mixture used in step a) consists of an ester solvent and an alcohol solvent selected from methanol, ethanol, isopropanol, n- butanol and the like.
  • the solvent mixture used in step a) consists of an ester solvent and 1 ,4-dioxane. In another embodiment, the solvent mixture used in step a) consists of an ester solvent and dimethyl formamide.
  • the reaction of step a) may be carried out at temperatures ranging from about 25°C to about 80°C or 50°C to about 75°C or 60°C to 70°C or about 70°C to 80°C.
  • the reaction mixture comprising the compound of formula (III) may optionally be distilled or concentrated for removing the solvent or co-solvent to the desired extent and the reaction mixture comprising the compound of formula (III) is taken forward for the next steps, with out isolating the compound of formula (III) as a solid.
  • reaction mixture comprising the compound of formula (III) is diluted with an ester solvent used in the reaction, washed with aqueous sodium chloride solution and the organic layer comprising the compound of formula (III) is optionally distilled and taken forward for the next step.
  • the inventors of the present application have surprisingly found that, carrying out the reaction in a solvent system comprising an ester solvent resulted in the faster completion of reaction with optimum purity, facilitating easy workup procedure, which helps in carrying out further reaction steps in-situ without isolating the compound of formula (III) as a solid.
  • step b) involves reacting the compound of formula (III) obtained in step a) with iodine in the presence of a base and in the presence of a solvent comprising an ester solvent.
  • the ester solvent used in step b) is same as the ester solvent used in step a).
  • the above reaction may be carried out at temperatures ranging from about -30°C to about 10°C, based on the solvent and base selected.
  • the inventors of the present application have surprisingly found that, carrying out the reaction in the presence of an ester solvent resulted in the faster completion of reaction with optimum purity as compared to the known process which involves the use of tetrahydrofuran (an ether) as the solvent.
  • the present invention demonstrates a process for the compound of formula (IV) that is extremely efficient and produces optimum yield and purity.
  • the compound of formula (IV) may optionally be isolated as per the methods known in the art or by the process disclosed in the present application.
  • the reaction mass is filtered, washed with ethylacetate, concentrated under reduced pressure, and the compound of formula (IV) may isolated by crystallization from a solvent such as methanol, 2-butanol, isopropanol, ethylacetate, isopropyl acetate, acetone, acetonitrile, n-heptane, methyl tert-butyl ether, and diisopropyl ether to give the compound of formula (IV).
  • the compound of formula (IV) may be isolated by crystallization from acetonitrile and/or isopropyl alcohol.
  • step b) involves converting the compound of formula (IV) to the compound of formula (IA).
  • the compound of formula (IV) may be converted to the compound of formula (IA) by known method for e.g., as per the methods disclosed in the US '213 patent or WO-A-95/09178 or by the processes disclosed in the instant application.
  • step b) without isolating the compound of formula (III) as a solid prior to step b) described above is advantageous in that it helps to avoid over all reaction time of the process and doesn't require the use of different solvent systems for step a) and b) as compared to the known processes which involved the use of ethanol for step a) and tetrahydrofuran for step b).
  • the present application relates to process for the preparation of the compound of formula (I)
  • step b) wherein in prior to step b) the compound of formula (IIIA) is not isolated in a solid form from the reaction mixture of step a).
  • Another aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R is as defined above;
  • step 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 hydro
  • Step a) involves reacting the compound of formula (IV) with a (3-pyridyl)- substituted borane compound of the formula (V), in the presence of a palladium complex, a solvent mixture consisting of an alcohol solvent and water to obtain a compound of formula (IA).
  • step a) is carried out by reacting the compound of formula (IV) with a (3-pyridyl)-substituted borane compound of the formula (V), in the presence of a palladium complex, a solvent mixture consisting of an alcohol solvent and water and a base to obtain a compound of formula (IA).
  • the starting compound of formula (IV) may be obtained by known processes or by the processes described in the present application.
  • the above reaction may be carried out at temperatures ranging from about 25°C to about 90°C, based on the alcohol solvent selected. In an embodiment the reaction is carried out at 65-80°C.
  • 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.
  • the compound of formula (IV), when R is a lower acyl group having 2 to 4 carbon atoms is reacted with a (3-pyridyl)-substituted borane compound of the formula (V), in the presence of a palladium complex, 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
  • the compound of formula (IV), when R is an acetyl group, is reacted with a (3-pyridyl)-substituted borane compound of the formula (V), in the presence of a palladium complex, a solvent mixture consisting of an alcohol solvent and water to obtain a compound of formula (I).
  • the compound of formula (IV), when R is hydrogen group, is reacted with a (3-pyridyl)-substituted borane compound of the formula (V), in the presence of a palladium complex, 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 of a solvent mixture consisting of an alcohol and water in step a) is extremely efficient and produces high yield and purity.
  • This process has not been described before for the manufacture of abiraterone acetate and leads to a series of major improvements over those in the prior art processes (involving the use of tetrahydrofuran as the solvent), such as being able to complete the reaction is less than 12 hours as compared to the reported reaction condition which took more than 40 hours; facilitates easy workup procedure wherein the compound of formula (IA) may be isolated by adding water to the reaction mass; and eliminates the need for the solvent swap to a non-miscible solvent as provided in the processes disclosed in Examples 19(c) of the US '213 patent.
  • the above process provides the compound of formula (I) with less than 2% of the dimer impurity i.e., Impurity J.
  • Step b) involves 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
  • the reaction of step b) may be carried out in the present of a base selected from an organic base such as triethylamine, diisopropylethylamine, dimethyl amino pyridine, N-methyl morpholine or the like.
  • Acetylating agents used in step b) may be selected from acetic anhydride or acetyl chloride.
  • the above reaction may be carried out at temperatures ranging from about 5°C to about 40°C. In an embodiment the reaction is carried out at 25-30°C.
  • the compound of formula (I) may be isolated or the reaction mixture comprising the compound of formula (I) may be taken forward for further purification.
  • Zi and Z 2 represent a hydroxy group or an alkoxy group of 1-3 carbon atoms or an alkyl group of 1-3 carbon atoms, in the presence of a palladium complex and a solvent mixture consisting of an alcohol solvent and water to obtain a compound of formula (I).
  • Another aspect of the present application relates to process for the preparation of the compound of formula (I)
  • Another aspect of the present application provides a process for the purification of abiraterone acetate of formula (I), which process comprises:
  • abiraterone acetate an acid selected from citric acid, oxalic acid, per chloric acid, trifluoroacetic acid, p-toluene sulfonic acid or phosphoric acid, and an organic solvent;
  • Organic solvent which may be used in the above steps for the purification of abiraterone acetate includes ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate or the like and alcohol solvent such as methanol, ethanol, butanol, isopropanol or the like and a mixture of both.
  • Another aspect of the present application provides a process for the purification of abiraterone acetate of formula (I), which process includes a step of recovering a salt of abiraterone acetate from acetone.
  • a salt of abiraterone acetate comprises the salt of abiraterone with acid such as citric acid, oxalic acid, per chloric acid, trifluoroacetic acid, p-toluene sulfonic acid or phosphoric acid, hydrochloric acid, methanesulfonic acid, and tartaric acid.
  • acid such as citric acid, oxalic acid, per chloric acid, trifluoroacetic acid, p-toluene sulfonic acid or phosphoric acid, hydrochloric acid, methanesulfonic acid, and tartaric acid.
  • An aspect of the present application also provides a process for the purification of abiraterone acetate, which process comprises crystallizing abiraterone acetate from the solvents such as ethylacetate, isopropyl alcohol, acetonitrile, acetone, dimethyl formamide, water or mixture thereof and a mixture of ethylacetate and pet ether.
  • solvents such as ethylacetate, isopropyl alcohol, acetonitrile, acetone, dimethyl formamide, water or mixture thereof and a mixture of ethylacetate and pet ether.
  • the above processes for the purification of the abiraterone acetate of formula (I) may be carried out as per the procedures disclosed in the present application.
  • abiraterone acetate provides substantially pure abiraterone acetate having purity greater than or equal to about 99.5%, or greater than or equal to about 99.8%, by weight as determined using HPLC.
  • the present invention includes substantially pure abiraterone acetate, wherein the amount of each individual process-related impurity listed in Table 1 is less than about 0.15%, or less than about 0.1 %, by weight, and/or the sum of all of these impurities is less than about 0.2%, by weight.
  • Table-1 the amount of each individual process-related impurity listed in Table 1 is less than about 0.15%, or less than about 0.1 %, by weight, and/or the sum of all of these impurities is less than about 0.2%, by weight.
  • substantially pure abiraterone acetate shall be understood to mean abiraterone acetate formed with little or no content of the impurities.
  • the amount of any impurity of abiraterone acetate resulting from the process of the preparation will be relatively minor, e.g., less than about 0.15 weight percent, or less than about 0.1 weight percent, or less than about 0.05 weight percent, of any impurity of abiraterone acetate
  • the crystalline abiraterone acetate product obtained by the process of the present application may be optionally milled to obtain desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller, and hammer mills, and jet mills.
  • abiraterone acetate obtained by a process of the present application may have a mean particle size d(4,3) less than about 150 ⁇ .
  • the present application provides crystalline abiraterone acetate characterized by a PXRD pattern as illustrated by Figure 1.
  • Another aspect of the present application provides a process for the purification of abiraterone acetate of formula (I), which process comprises:
  • abiraterone acetate an acid selected from citric acid, oxalic acid, per chloric acid, trifluoroacetic acid, p-toluene sulfonic acid or phosphoric acid, and solvent;
  • Step a) involving combining abiraterone acetate, an acid selected from citric acid, oxalic acid, per chloric acid, trifluoroacetic acid, p-toluene sulfonic acid or phosphoric acid and an organic solvent. Acid used may be added as such or may be added as a solution with solvent(s) selected in step a).
  • Solvents that may be used in step a) 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, h
  • the reaction mixture of step a) is maintained for a suitable time period to facilitate the complete formation of the abiraterone acetate acid addition salt.
  • the reaction mixture of step b) may be maintained at a temperature of about 25°C to about 35°C.
  • the product obtained may be isolated by techniques known in the art and optionally be dried to provide crystalline Forms of abiraterone acetate acid addition salt.
  • Step c) involving converting the salt of abiraterone acetate obtained in step b) to abiraterone acetate freebase of formula (I).
  • Abiraterone acetate freebase of formula (I) may be obtained from salt of abiraterone acetate using a base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or ammonia. Base used may be added as such or may be added as a solution with water.
  • the present application provides crystalline form of abiraterone acetate citric acid salt, abiraterone acetate citric acid salt.
  • the present application provides crystalline Form-A of abiraterone acetate citric acid salt.
  • the present application provides crystalline Form-A of abiraterone acetate citric acid salt characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 3.
  • Another aspect of the present application provides a process for the preparation of crystalline Form-A of abiraterone acetate citric acid salt, which process comprises:
  • Ester solvents that may be used in step a) may be selected from methyl acetate, ethyl acetate, isopropyl acetate or the like.
  • Ether solvents that may be used in step a) may be selected from diethyl ether, diisopropylether, methyl-tert-butyl ether or the like.
  • the solution of abiraterone acetate may be obtained at temperatures ranging from about 0°C to about reflux temperature of the solvent mixture. In an embodiment, the solution may be obtained at a temperature of about 25°C to about 35°C.
  • Step b) involving adding citric acid to the solution of step a Citric acid may be added as such or may be added as a solution with solvent(s) selected in step a). Citric acid may be added to the solution of step a) at the same temperature ranges as defined in step a). In an embodiment, citric acid may be added at a temperature of about 25°C to about 35°C.
  • the reaction mixture of step a) is maintained for a suitable time period to facilitate the complete formation of the abiraterone acetate citric acid salt.
  • the reaction mixture of step b) may be maintained at a temperature of about 25°C to about 35°C.
  • the product obtained may be isolated by techniques known in the art and optionally be dried to provide crystalline Form-A of abiraterone acetate citric acid salt.
  • the present application provides crystalline Form-A of abiraterone acetate oxalic acid salt.
  • the present application provides crystalline Form-A of abiraterone acetate oxalic acid salt characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 4.
  • Another aspect of the present application provides a process for the preparation of crystalline Form-A of abiraterone acetate oxalic acid salt, which process comprises:
  • Ether solvents that may be used in step a) may be selected from diethyl ether, diisopropylether, methyl-tert-butyl ether or the like.
  • the solution of abiraterone acetate may be obtained at temperatures ranging from about 0°C to about reflux temperature of the solvent mixture. In an embodiment, the solution may be obtained at a temperature of about 25°C to about 35°C.
  • Oxalic acid may be added as such or may be added as a solution with solvent(s) selected in step a).
  • Oxalic acid may be added to the solution of step a) at the same temperature ranges as defined in step a).
  • oxalic acid may be added at a temperature of about 25°C to about 35°C.
  • the reaction mixture of step a) is maintained for a suitable time period to facilitate the complete formation of the abiraterone acetate oxalic acid salt.
  • the reaction mixture of step b) may be maintained at a temperature of about 25°C to about 35°C.
  • the product obtained may be isolated by techniques known in the art and optionally be dried to provide crystalline Form-A of abiraterone acetate oxalic acid salt.
  • All PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer, or a PANalytical X-ray Diffractometer, using copper Ka radiation.
  • Another aspect of the present application relates to process for the preparation of the compound of formula (IA)
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R is as defined above;
  • step 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 hydro
  • Step a) involves reacting the compound of formula (IV) with a tris(3-pyridyl)boroxin compound of the formula (VA), in the presence of a palladium complex and an alcohol solvent to obtain a compound of formula (IA).
  • step a) is carried out by reacting the compound of formula (IV) with a tris(3-pyridyl)boroxin compound of the formula (VA), in the presence of a palladium complex, an alcohol solvent and a base to obtain a compound of formula (IA).
  • the starting compound of formula (IV) may be obtained by known processes or by the processes described in the present application.
  • the above reaction may be carried out at temperatures ranging from about 25°C to about 90°C, based on the alcohol solvent selected. In an embodiment the reaction is carried out at 65-80°C.
  • 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.
  • the compound of formula (IV), when R is a lower acyl group having 2 to 4 carbon atoms is reacted with a tris(3-pyridyl)boroxin compound of the formula (VA), in the presence of a palladium complex, an alcohol solvent to obtain a compound of formula (IA), where R is a lower acyl group having 2 to 4 carbon atoms
  • the compound of formula (IV), when R is an acetyl group, is reacted with a tris(3-pyridyl)boroxin compound of the formula (VA), in the presence of a palladium complex and an alcohol solvent to obtain a compound of formula (I).
  • the compound of formula (IV) when R is hydrogen group, is reacted with a tris(3-pyridyl)boroxin compound of the formula (VA), in the presence of a palladium complex and an alcohol solvent 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 of tris(3- pyridyl)boroxin in step a) is extremely efficient and produces high yield and purity.
  • Zi and Z 2 represent a hydroxy group or an alkoxy group of 1-3 carbon atoms or an alkyl group of 1-3 carbon atoms, in the presence of a palladium complex and an alcohol solvent to obtain a compound of formula (I).
  • Another aspect of the present application relates to process for the preparation of the compound of formula (I)
  • the crystalline abiraterone acetate product obtained by the process of the present application may be optionally milled to obtain desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller, and hammer mills, and jet mills.
  • Another aspect of the present application relates to process for the preparation of the compound of formula (I)
  • Zi and Z 2 represent a hydroxy group or an alkoxy group of 1-3 carbon atoms or an alkyl group of 1-3 carbon atoms, in the presence of a palladium complex and an alcohol solvent;
  • Step a) involves reacting the compound of formula (IV) with a tris(3- pyridyl)boroxin compound of the formula (VA), in the presence of a palladium complex and an alcohol solvent to obtain a compound of formula (I).
  • step a) is carried out by reacting the compound of formula (IV) with a tris(3-pyridyl)boroxin compound of the formula (VA), in the presence of a palladium complex, an alcohol solvent and a base to obtain a compound of formula (I).
  • the starting compound of formula (IV) may be obtained by known processes or by the processes described in the present application.
  • the above reaction may be carried out at temperatures ranging from about 25°C to about 90°C, based on the alcohol solvent selected. In an embodiment the reaction is carried out at 65-80°C.
  • the compound of formula (I) may be isolated by known methods or by the methods disclosed in the instant application or the reaction mixture containing the compound of formula (I) may be taken up for purification by methods disclosed in the instant application.
  • the compound of formula (IV), when R is a lower acyl group having 2 to 4 carbon atoms is reacted with a tris(3-pyridyl)boroxin compound of the formula (VA), in the presence of a palladium complex, an alcohol solvent to obtain a compound of formula (I), where R is a lower acyl group having 2 to 4 carbon atoms
  • the compound of formula (IV), when R is an acetyl group, is reacted with a tris(3-pyridyl)boroxin compound of the formula (VA), in the presence of a palladium complex and an alcohol solvent to obtain a compound of formula (I).
  • the compound of formula (I) obtained after completion of reaction of step a) may be isolated by extraction with toluene and concentrated under vacuum to obtain a compound of formula (I).
  • the compound of formula (I) obtained by extracting with toluene may be concentrated up to about 2 volumes to about 4 volumes of the reaction mass, azeotropically distilled to remove water and obtained concentrated reaction mass may be used for the further processing steps.
  • Step b) involves purifying the compound of formula (I).
  • purification of compound of formula (I) is carried out by acylating the abiraterone associated with compound of formula (I) obtained in step a) with acetic anhydride and triethyl amine in presence of 4-dimethylaminopyridine (DMAP).
  • DMAP 4-dimethylaminopyridine
  • the above reaction may be carried out at temperatures ranging from about 10°C to about 50°C. In an embodiment the reaction is carried out at 25-30°C.
  • the compound of formula (I) may be isolated by known methods or by the methods disclosed in the instant application or the reaction mixture containing the compound of formula (I) may be taken up for purification by methods disclosed in the instant application.
  • water is added to the reaction mixture and separated the organic layer.
  • the organic layer containing a compound of formula (I) is reacted with oxalic acid dihydrate in presence of acetone solvent.
  • the above reaction may be carried out at temperatures ranging from about 10°C to about 40°C. In an embodiment the reaction is carried out at 20-25°C.
  • the reaction mixture is maintained for a suitable time period to facilitate the complete formation of the abiraterone acetate oxalic acid salt.
  • abiraterone acetate oxalic acid salt may be isolated by known methods or by the methods disclosed in the instant application or the reaction mixture containing abiraterone acetate oxalic acid salt may be taken up for purification by methods disclosed in the instant application.
  • the obtained abiraterone acetate oxalic acid salt may be filtered, washed with toluene to obtain abiraterone acetate oxalic acid salt.
  • Abiraterone acetate oxalic acid salt obtained may be treated with sodium bicarbonate solution in presence of water.
  • the pH of the abiraterone acetate oxalate in water may be adjusted to pH of 7 to 8 using sodium bicarbonate solution.
  • the reaction mixture is maintained for a suitable time period to facilitate the complete formation of the abiraterone acetate.
  • the reaction mixture is stirred for about 2 hours.
  • abiraterone acetate may be isolated by known methods or by the methods disclosed in the instant application or the reaction mixture containing abiraterone acetate may be taken up for purification by methods disclosed in the instant application.
  • the precipitated abiraterone acetate is filtered and suck dried.
  • the obtained abiraterone acetate is further purified by treating with acetone and water to obtain pure abiraterone aceate of formula (I).
  • the abiraterone acetate is treated with acetone at a temperature of about 50°C to about 60°C.
  • abiraterone acetate in acetone may be stirred for a suitable time period at 50°C to 60°C and filtered.
  • water is added to the filtrate containing abiraterone acetate and stirred for a suitable time period at 25-30°C.
  • abiraterone acetate may be isolated by known methods or by the methods disclosed in the instant application.
  • the present application provides pharmaceutical compositions comprising crystalline abiraterone acetate obtained by the process of the present application, together with one or more pharmaceutically acceptable excipients.
  • An aspect of the present application relates to process for the purification of the compound of formula (IA
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms, which comprises:
  • R is as defined above, with palladium scavanger
  • the starting compound of formula (IA) may be obtained by known processes.
  • R represents hydrogen or a lower acyl group having 2 to 4 carbon atoms. In an embodiment, R represents an acetyl group. In an embodiment, R represents a hydrogen.
  • step a) is carried by treating the compound of formula (IA) with palladium scavenger in the presence of a solvent mixture comprising an acetone, ethyl isopropyl ketone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, diethyl ketone or the like.
  • Palladium scavenger which may be used in the process of the present application includes active scavengers such as thiosilica gel, 2,4,6- trimercaptotriazine silica gel, macroporous polystyrene-2,4,6-trimercaptotriazine, sodium thiosulphate, sompex resin bonded silica , cellulose, 3-mercaptopropyl ethyl sulfide silica, 2-mercaptoethyl ethyl sulfide silica, triamine ethyl sulfide amide silica, N-acetyl-L-cysteine ethyl Silica, 2-Aminoethyl sulfide ethyl Silica, Thio- functionalized polysiloxane (Deloxan® MP), methyl thiourea ethyl sulfide ethyl silica, ethylene diamine modified silica
  • Sodium thiosulphate (Na 2 S 2 03) which may be used in the process of the present application includes Sodium thiosulphate pentahydrate, Na 2 S 2 0 3 -5H 2 0.
  • the above reaction may be carried out at temperatures ranging from about 25°C to about 80°C or 30°C to about 75°C or 35°C to 60°C or about 35°C to 50°C.
  • the compound of formula (IA) may optionally be isolated as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of formula (IA) may be taken forward for the next steps, without isolating the compound of formula (IA).
  • reaction mixture comprising the compound of formula (IA) is filtered and the filtrate comprising the compound of formula (IA) is taken forward for the next step.
  • the filtrate comprising the compound of formula (IA) is reacted with acetic anhydride in presence of triethyl amine and 4-(dimethylamino) pyridine.
  • the above reaction may be carried out at temperatures ranging from about 25°C to about 80°C or 30°C to about 75°C or 35°C to 60°C or about 35°C to 50°C.
  • the compound of formula (IA) may optionally be isolated as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of formula (IA) may be taken forward for the next steps, without isolating the compound of formula (IA).
  • reaction mixture comprising the compound of formula (IA) is treated with an activated carbon, filtered, washed with solvent used in the reaction and the filtrate comprising the compound of formula (IA) is taken forward for the next step.
  • the filtrate comprising the compound of formula (IA) is treated with water.
  • water may be added at a temperature of about 25°C to about 35°C.
  • the reaction mixture of step b) is maintained for a suitable time period to facilitate the complete formation of the abiraterone acetate.
  • the reaction mixture of step b) may be maintained at a temperature of about 25°C to about 35°C.
  • the product obtained may be isolated by techniques known in the art and optionally be dried to provide pure abiraterone acetate.
  • Another aspect of the present application provides a process for the preparation of abiraterone acetate oxalic acid salt, which comprises:
  • the starting compound abiraterone acetate may be obtained by known processes.
  • step a) The reaction of step a) is carried by treating the compound abiraterone acetate with a solvent.
  • Solvents that may be used in step a) 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, h
  • solvent that may be used in step a) includes acetone.
  • the reaction mixture containing abiraterone acetate and solvent of step a) may be maintained at a temperature of about 25°C to about 35°C.
  • the oxalic acid particle size having a particle size distribution D(90) of not less than 500 ⁇ of the present invention so far as it is the oxalic acid having an particle size distribution D(90) of not less than 500 ⁇ are preferable.
  • the average particle size thereof can be measured by using, for example, a laser diffraction/scattering particle size distribution analyzer (e.g., Mastersizer 2000, Ver. 5.22; manufactured by Malvern Instruments), an image analyzer (e.g., Luzex® AP; manufactured by Nileco) or the like, and can be calculated as the D(90) of the particle size distribution.
  • a laser diffraction/scattering particle size distribution analyzer e.g., Mastersizer 2000, Ver. 5.22; manufactured by Malvern Instruments
  • an image analyzer e.g., Luzex® AP; manufactured by Nileco
  • oxalic acid that may be used in step b) include having a particle size distribution D(90) of about 500 ⁇ to about 1500 ⁇ . In a preferred embodiment, oxalic acid that may be used in step b) include oxalic acid having a particle size distribution D(90) of about 1000 ⁇ to about 1500 ⁇ .
  • the reaction mixture of step b) is maintained for a suitable time period to facilitate the complete formation of the abiraterone acetate oxalic acid salt.
  • the reaction mixture of step b) may be maintained at a temperature of about 20°C to about 35°C.
  • the product obtained may be isolated by techniques known in the art and optionally be dried to provide of abiraterone acetate oxalic acid salt.
  • abiraterone acetate oxalic acid salt isolated in step c) may be optionally washed with hydrocarbon solvent.
  • hydrocarbon solvent that may be used for washing abiraterone acetate oxalic acid salt in step c) may be selected from cyclohexane, cycloheptane, heptane, hexane, pentane, benzene, toluene, xylene or mixtures thereof.
  • hydrocarbon solvent used is toluene.
  • abiraterone acetate oxalic acid salt obtained above may be converted to abiraterone acetate by any conventional processes known in the art.
  • the present application provides pharmaceutical compositions comprising abiraterone acetate or its oxalic acid salt obtained by the process of the present application, together with one or more pharmaceutically acceptable excipients.
  • the present application provides pharmaceutical compositions comprising crystalline abiraterone acetate obtained by the process of the present application, together with one or more pharmaceutically acceptable excipients.
  • Another aspect of the present application provides a process for the preparation of epoxide impurities of formula (M), formula (N) and isomers thereof comprising:
  • the reaction of step a) is carried out by reacting abiraterone acetate with hydrogen peroxide and acetic acid in presence of suitable solvent including but not limited to hydrocarbons such as toluene, hexane, heptane; chlorinated hydrocarbons such as chloroform, dichloromethane and the like and at a temperature of about 20 °C upto the boiling point of the solvent for a period of 5 hrs to 20 hours.
  • suitable solvent including but not limited to hydrocarbons such as toluene, hexane, heptane; chlorinated hydrocarbons such as chloroform, dichloromethane and the like and at a temperature of about 20 °C upto the boiling point of the solvent for a period of 5 hrs to 20 hours.
  • step a) is carried out by reacting abiraterone acetate with hydrogen peroxide and acetic acid in presence of chloroform at a temperature of about 30 °C to about 65 °C for a period of 14 hrs to 16 hrs.
  • Step b) may be accomplished by a technique, which is known a person skilled in the art but is not limited to coloumn chromatography, high pressure liquid chromatography, flash chromatography or the like.
  • Celite® is a flux-calcined diatomaceous earth, and Celite® is a registered trademark of World Minerals Inc.
  • alkyl includes both straight and branched chain and preferably a methyl, ethyl, propyl or isopropyl group.
  • alkoxy An analogous convention applied to the term "alkoxy”.
  • acyl group having 2 to 4 carbon atoms includes methanoyl (formyl), ethanoyl (acetyl) or propanoyl (propionyl) groups.
  • Ester solvents which may be used in the process of the present application include esters with acetic acid, such as methyl acetate, ethyl acetate and isopropyl acetate.
  • Co-solvents which may be used include an ether solvent selected from 1 ,4- dioxane, diethyl ether, tetrahydrofuran, diisopropyl ether and methyl tert-butyl ether; an alcohol solvent selected from methanol, ethanol, butanol and isopropanol; other polar aprotic solvents such as dimethylformamide.)
  • Bases that may be used in the process includes 1 ,8-diazabicycloundec-7- ene, 1 , 1 ,3,3-tetramethylguanidine, N-methyl morpholine, cesium carbonate and alkyl amine such as triethyl amine, diisopropylamine, diisopropyl ethyl amine.
  • Typical amounts of iodine that may be used are from about 1.2 to about 2.5 molar equivalents, per molar equivalent of the compound of formula (III).
  • (3-pyridyl)-substituted borane of the formula (V) which may be used in the process of step a may be selected from diethyl(3-pyridyl)borane, dimethyl(3- pyridyl)borane, 3-pyridineboronic acid and the like.
  • the palladium complex which may be used is bis(triphenylphosphine)palladium (II) chloride.
  • 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,
  • the alcohol solvent used may be selected from methanol, ethanol, butanol, n-propanol and isopropanol.
  • the organic layer was separated, diluted with ethylacetate (200 mL) and washed with aqueous saturated sodium chloride solution (100 mL).
  • the organic layer containing (33)-acetoxy- dehydroepiandrosterone -17-hydrazone was separated and kept aside.
  • EXAMPLE 5 Preparation of (3 )-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate. (33)-Androsta-5, 16-dien-3-ol, 17-iodo-, 3-acetate (50 g), isopropanol (75 mL) and water (425 mL) were charged into a round bottom flask at 25-30°C and the mixture was stirred. Diethyl(3-pyridyl)borane (16.7 g), bis(triphenylphosphine) palladium(ll) dichloride (999 mg), sodium carbonate (48.1 g) were charged in sequence to the reaction mixture and stirred.
  • the reaction mixture was heated to a temperature of 75-80°C and stirred at the same temperature for about 7 hours.
  • the reaction mixture was allowed to cool to 25-30°C, added water (500 mL) and stirred for about 90 minutes.
  • the solid obtained was filtered under vacuum, washed with water (100 mL), and dried under vacuum at 45°C.
  • reaction mixture was allowed to cool to 25-30°C, organic layer was separated and aqueous layer was extracted with ethyl acetate (2500 mL). The organic layers were combined, washed with water (2X400 mL), followed by 10% aqueous sodium chloride solution (600 mL). The organic layer was separated and concentrated completely under vacuum till no more solvent distills off to obtain crude.
  • the reaction mixture was filtered through celite bed and the filtrate was charged into a round bottom flask.
  • Citric acid 104.79 g was added to the flask and the reaction mixture was stirred at 25- 30°C for about 1 hour.
  • the solid obtained was filtered under vacuum, washed with ethylacetate and suction dried for 15 minutes.
  • EXAMPLE 8 Process for the preparation abiraterone sodium salt.
  • reaction mixture was allowed to cool to 25-30°C, stirred for 2 hours, organic layer was separated and concentrated completely under vacuum till no more solvent distill off.
  • Ethyl acetate 150 mL was charged, stirred to obtain a clear solution, washed the reaction mixture with water (60 mL) and separated the organic layer.
  • EXAMPLE 9 Process for the preparation abiraterone.
  • Tetrahydrofuran (400 mL) and the solid obtained above were charged into a round bottom flask at 25-30°C and stirred.
  • the reaction mixture was heated to a temperature of 50-55°C and maintained at the same temperature for about 30 minutes.
  • the reaction mixture was filtered and the filtrate was concentrated under vacuum to obtain a concentrated solution, cooled to 25-30°C and maintained at the same temperature for about 1 hour.
  • the solid obtained was filtered under vacuum, washed with tetrahydrofuran (50 ml), suction dried for 15 minutes and dried under vacuum at 40°c for 3 hours to obtain crystalline abiraterone.
  • the reaction mixture was allowed to cool to 25-30°C, organic layer was separated, washed with water (600 mL) and concentrated completely under vacuum till no more solvent distills off to obtain crude.
  • Toluene (1000 ml.) and the crude obtained above were charged into a round bottom flask at 25-30°C and stirred.
  • Triethylamine (127.4ml_), dimethyl amino pyridine (554 mg) and acetic anhydride (42.88 ml.) were added and the reaction mixture was stirred at 25-30°C for 2 hours.
  • Water (600 ml) was charged to the reaction mixture, stirred for 15 minutes.
  • the organic layer was separated and concentrated under vacuum.
  • Acetone (600 ml.) was charged and the reaction mass was concentrated under vacuum till no more solvent distills off to obtain a solid.
  • EXAMPLE 12 Preparation of crystalline Form-A of abiraterone acetate citric acid salt.
  • EXAMPLE 13 Preparation of crystalline Form-A of abiraterone acetate oxalic acid salt.
  • reaction mixture was allowed to cool to 25-30°C and toluene (500 mL) was added to the reaction mixture.
  • the obtained organic layer was separated and concentrated under vacuum.
  • Toluene (500 mL) was added to the concentrated mass and distilled upto 2 volumes of reaction mass and toluene (500 mL) was added to the obtained reaction mass.
  • Triethyl amine (63.8 mL), acetic anhydride (21 .5 mL) and dimethyl amino pyridine (277 mg) were added and the reaction mixture was stirred at 25- 30°C for 2 hours. Water (500 ml) was charged to the reaction mixture, stirred for 15 minutes and organic layer was separated.
  • the above suck dried compound ( ⁇ 8.3 g) and acetone (100 mL) were charged into the round bottom flask at 25-30°C.
  • the reaction mixture was heated to a temperature of 50-55°C and stirred at the same temperature for about 15 minutes.
  • the reaction mixture was filtered through 0.2 micron filter.
  • the obtained filtrate was charged into a round bottom flask and was added water slowly to the reaction mass at 25-30°C.
  • the reaction mixture was stirred at 25-30°C for 90 minutes.
  • the obtained solid was filtered, washed with water (50 mL) and dried under vacuum at 40° C for 5-6 hours to give the title compound.
  • Abiraterone acetate oxalic acid salt (15 g) and toluene (75 mL) were charged into a round bottom flask at 25-30°C.
  • Aqueous sodium bicarbonate solution (7.86 g of sodium bicarbonate dissolved in 100 mL of water) was charged into the round bottom flask at 25-30°C and stirred for 10 minutes at the same temperature.
  • Sodium bicarbonate solution (15 mL) was added to the obtained reaction mass at 25-30°C and stirred for 10 minute at the same temperature.
  • the organic layer was separated and the obtained aqueous layer was extracted with toluene (30 mL). The organic layers was combined, washed with water and passed the organic layer through celited bed.
  • the obtained filtrate was charged into round bottom flask and distilled the organic layer below 2 volumes at 45-50°C and stirred the reaction mixture for 20 minutes. Water (150 mL) was added to the obtained reaction mixture and distilled completely at 45-50°C. The obtained reaction mixture was cooled to 25-30°C and stirred for 90 minutes. The obtained solid was filtered, washed with water (30 mL), suck dried and dried under vacuum for 4 hours at 40°C under vacuum to give title compound.
  • the obtained compound and dimethyl formamide (80 mL) were charged into a round bottom flask at 25-30°C.
  • the temperature of the reaction mixture was raised to 50-60°C, stirred at the same temperature for 30 minutes and was filtered through 0.2 micron filter.
  • the obtained organic layer was charged into round bottom flask and water (80 mL) was added slowly at 25-30°C for 90 minutes.
  • the reaction mixture was stirred at 25-30°C for 2 hours.
  • the obtained solid was filtered, washed with water (40 mL), suck dried and dried under vacuum at 40°C for 4-5 hours to give the title compound.
  • the obtained compound and isopropyl alcohol 120 mL were charged into a round bottom flask at 25-30°C.
  • the temperature of the reaction mixture was raised to 50-60°C, stirred at the same temperature for 30 minutes and was filtered through 0.2 micron filter.
  • the obtained organic layer was charged into round bottom flask and stirred for 15 minutes, water (200 mL) was added slowly to the organic layer at 25-30°C for 40 minutes.
  • the reaction mixture was stirred at 25- 30°C for 90 minutes.
  • the obtained solid was filtered, washed with water (50 mL), suck dried and dried under vacuum at 40°C for 5-6 hours to give the title compound.
  • the obtained reaction mass is extracted with toluene (15 mL) and concentrated the organic layer to about 2 volumes of the reaction mass.
  • the obtained reaction mass was transferred to a round bottom flask and water was removed azeotropically.
  • the reaction mass is cooled to about 25-30°C and triethyl amine (3.15 mL) was added to it.
  • Acetic anhydride (1 .05 mL) was added slowly, followed by 4-dimethylaminopyridine (DMAP) to the reaction mass.
  • DMAP 4-dimethylaminopyridine
  • the obtained reaction mass is stirred for about 15 hours.
  • Water (25 mL) was added to the reaction mass and separated the organic layer.
  • the obtained organic layer and acetone (15 mL) was charged into a round bottom flask and stirred at 25-30°C for 10 minutes.
  • Oxalic acid dihydrate (1.57 g) was added to the reaction mixture at 25-30°C and stirred at the same temperature for about 4 hours.
  • the solid obtained was filtered, washed with toluene (50 mL).
  • the obtained solid and water (15 mL) was charged into a round bottom flask at 25- 30°C and stirred at the same temperature for about 15 minutes.
  • the pH of the reaction mass is adjusted to 7 to 8 using sodium bicarbonate solution at 25-30°C and stirred for about 2 hours.
  • the obtained solid is filtered and transferred the solid into a round bottom flask.
  • Acetone 40 mL was charged into the flask at 25- 30°C.
  • the temperature of the reaction mass was raised to 55-60°C, maintained at the same temperature for 20 minutes and filtered.
  • Water (50 mL) was added to obtained filtrate at 25-30°C and stirred at the same temperature for 2 hours.
  • the obtained solid was filtered, washed with water (10 mL), dried under vacuum to give the title compound.
  • EXAMPLE 22 Purification of (3 )-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate (Abiraterone acetate of Formula I).
  • EXAMPLE 23 Purification of (3 )-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate (Abiraterone acetate of Formula I).
  • EXAMPLE 24 Purification of (3 )-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate (Abiraterone acetate of Formula I).
  • the reaction mixture was stirred at 40-45°C for 1 -2 hours. Carbon (500 mg) was added to the reaction mass at 40-45°C and was maintained under stirring for 15 minutes. The obtained reaction mass was filtered using hyflow bed and washed the bed with acetone (10 mL). The obtained filtrate was charged into round bottom flask and was added water (75 mL) to the reaction mass at 25-30°C. The reaction mixture was stirred at 25-30°C for 1-2 hours. The precipitated solid was filtered, washed with water (50 mL) and dried under vacuum at 40° C for 4-5 hours to give the title compound. Yield: 4.35 g;
  • EXAMPLE 25 Purification of (3 )-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate (Abiraterone acetate of Formula I).
  • the reaction mixture was stirred at 40-45°C for 2-3 hours. Carbon (500 mg) was added to the reaction mass at 40-45°C and was maintained under stirring for 15 minutes.
  • the obtained reaction mass was filtered using hyflow bed and washed the bed with acetone (10 mL). The obtained filtrate was charged into round bottom flask and was added water (75 mL) to the reaction mass at 25-30°C.
  • the reaction mixture was stirred at 25-30°C for 2-3 hours.
  • the precipitated solid was filtered, washed with water (50 mL) and dried under vacuum at 40° C for 4-5 hours to give the title compound.
  • EXAMPLE 26 Purification of (3 )-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate (Abiraterone acetate of Formula I).
  • the obtained reaction mass was filtered using celite bed, washed the bed with acetone (80 mL) and obtained filtrate was further filtered using 0.22 micron filter.
  • the obtained filtrate was charged into round bottom flask and was added water (590 mL) slowly to the reaction mass at 25-30°C.
  • the reaction mixture was stirred at 25-30°C for 2-3 hours.
  • the precipitated solid was filtered, washed with water (400 mL) and dried under vacuum at 40-50°C for 5-6 hours to give the title compound.
  • EXAMPLE 27 Preparation of abiraterone acetate oxalic acid salt.
  • EXAMPLE 28 Preparation of abiraterone acetate oxalic acid salt.
  • Example 29 Preparation of epoxide impurities of abiraterone acetate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé pour la préparation de l'acétate d'abiratérone, de ses sels et de ses intermédiaires, des formes cristallines de sels d'acétate d'abiratérone et de purification de l'acétate d'abiratérone.
PCT/IB2013/060441 2012-11-28 2013-11-27 Procédé de préparation de l'acétate d'abiraterone WO2014083512A1 (fr)

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IN2606/CHE/2013 2013-06-14
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IN3455CH2013 2013-07-31
IN3814CH2013 2013-08-27
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WO2014145813A1 (fr) * 2013-03-15 2014-09-18 Iceutica Inc. Formulation d'acétate d'abiratérone
WO2015086596A1 (fr) * 2013-12-12 2015-06-18 Basf Se Forme solide d'acétate d'abiratérone
WO2015200837A1 (fr) * 2014-06-27 2015-12-30 Fl Therapeutics Llc Dérivés d'abiratérone et complexes non covalents avec l'albumine
CN105713063A (zh) * 2014-12-02 2016-06-29 重庆安格龙翔医药科技有限公司 一种阿比特龙乙酸酯的制备方法
WO2016128891A1 (fr) 2015-02-09 2016-08-18 Druggability Technologies Ip Holdco Limited Complexes d'acétate d'abiratérone, leur procédé de préparation et compositions pharmaceutiques les contenant
WO2017133360A1 (fr) * 2016-02-02 2017-08-10 深圳市塔吉瑞生物医药有限公司 Composé stéroïdien, composition le contenant, et utilisation de ce dernier
US9889144B2 (en) 2013-03-15 2018-02-13 Iceutica Inc. Abiraterone acetate formulation and methods of use
CN107840866A (zh) * 2016-09-20 2018-03-27 正大天晴药业集团股份有限公司 醋酸阿比特龙的制备方法
US10292990B2 (en) 2013-09-27 2019-05-21 Sun Pharma Global Fze Abiraterone steroid formulation

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WO1995009178A1 (fr) * 1993-09-30 1995-04-06 British Technology Group Limited Synthese de steroides a base de 17-(3-pyridyl)
CN102627681A (zh) * 2012-03-23 2012-08-08 山东新时代药业有限公司 一种醋酸阿比特龙的制备方法
CN102816200A (zh) * 2012-09-05 2012-12-12 中山大学 一种醋酸阿比特龙的制备方法

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WO1995009178A1 (fr) * 1993-09-30 1995-04-06 British Technology Group Limited Synthese de steroides a base de 17-(3-pyridyl)
CN102627681A (zh) * 2012-03-23 2012-08-08 山东新时代药业有限公司 一种醋酸阿比特龙的制备方法
CN102816200A (zh) * 2012-09-05 2012-12-12 中山大学 一种醋酸阿比特龙的制备方法

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014145813A1 (fr) * 2013-03-15 2014-09-18 Iceutica Inc. Formulation d'acétate d'abiratérone
US9889144B2 (en) 2013-03-15 2018-02-13 Iceutica Inc. Abiraterone acetate formulation and methods of use
US10292990B2 (en) 2013-09-27 2019-05-21 Sun Pharma Global Fze Abiraterone steroid formulation
WO2015086596A1 (fr) * 2013-12-12 2015-06-18 Basf Se Forme solide d'acétate d'abiratérone
US10045998B2 (en) 2013-12-12 2018-08-14 Basf Se Solid form of abiraterone acetate
WO2015200837A1 (fr) * 2014-06-27 2015-12-30 Fl Therapeutics Llc Dérivés d'abiratérone et complexes non covalents avec l'albumine
CN105713063A (zh) * 2014-12-02 2016-06-29 重庆安格龙翔医药科技有限公司 一种阿比特龙乙酸酯的制备方法
WO2016128891A1 (fr) 2015-02-09 2016-08-18 Druggability Technologies Ip Holdco Limited Complexes d'acétate d'abiratérone, leur procédé de préparation et compositions pharmaceutiques les contenant
WO2017133360A1 (fr) * 2016-02-02 2017-08-10 深圳市塔吉瑞生物医药有限公司 Composé stéroïdien, composition le contenant, et utilisation de ce dernier
CN108541255A (zh) * 2016-02-02 2018-09-14 深圳市塔吉瑞生物医药有限公司 一种甾体类化合物及包含该化合物的组合物及其用途
US10519193B2 (en) 2016-02-02 2019-12-31 Shenzhen Targetrx, Inc. Steroidal compound, composition containing the same and use thereof
CN107840866A (zh) * 2016-09-20 2018-03-27 正大天晴药业集团股份有限公司 醋酸阿比特龙的制备方法

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