EP2794633A2 - Synthèse d'abiraterone et de composés associés - Google Patents

Synthèse d'abiraterone et de composés associés

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Publication number
EP2794633A2
EP2794633A2 EP12808819.2A EP12808819A EP2794633A2 EP 2794633 A2 EP2794633 A2 EP 2794633A2 EP 12808819 A EP12808819 A EP 12808819A EP 2794633 A2 EP2794633 A2 EP 2794633A2
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
group
formula
compound
process according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12808819.2A
Other languages
German (de)
English (en)
Inventor
Alfonso PÉREZ ENCABO
José Angel TURIEL HERNANDEZ
Francisco Javier GALLO NIETO
Antonio Lorente Bonde-Larsen
Celso Miguel SANDOVAL RODRÍGUEZ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Curia Spain SA
Original Assignee
Crystal Pharma SA
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Filing date
Publication date
Application filed by Crystal Pharma SA filed Critical Crystal Pharma SA
Priority to EP12808819.2A priority Critical patent/EP2794633A2/fr
Publication of EP2794633A2 publication Critical patent/EP2794633A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07J13/005—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
    • 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
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • 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

Definitions

  • the present invention relates to a processes for obtaining abiraterone and derivatives thereof, such as abiraterone acetate, as well as to intermediates useful in said processes.
  • Abiraterone acetate [17-(3-pyridyl)-5,16-androstadien-33-acetate] is a steroid compound which inhibits selectively and efficiently the enzyme 17-ohydroxylase-C17- 20-lyase, which catalyzes the conversion of dehydroepiandrosterone and androstenedione to testosterone.
  • the inhibition of said enzyme causes a strong decrease of testosterone levels in the patient and therefore this drug is used in the treatment of certain hormone-dependent tumors resistant to chemotherapy such as prostate cancer.
  • This compound has the followin chemical formula:
  • EP 0 721 461 proposes the use of a vinyl iodide or bromide intermediate instead of the enol triflate, as depicted in the following scheme:
  • the iodo-enol is much less reactive than the triflate in the coupling with the pyridine borane, resulting in long reaction times (48 hours - 4 days) with a part of the starting material unreacted and wherein until a 5% of a dimeric impurity is obtained, which can only be removed by purification by means of reverse phase column chromatograp
  • the present invention is faced with the problem of providing a process for obtaining 17-(3-pyridyl)-5,16-androstadien-33-ol and derivatives thereof, particularly abiraterone acetate, which solves the aforementioned drawbacks existing in the different synthesis of the state of the art.
  • the present invention provides novel synthetic processes for obtaining abiraterone and derivatives thereof [encompassed under formula (I)], enabling its preparation at an industrial scale in an advantageous way with respect to the processes disclosed so far.
  • the present invention refers to a process for the preparation of compound of formula (I) or a salt or solvate thereof, which comprises reacting compound of formula (IV) with a compound of formula (III) in the presence of palladium catalyst and a base.
  • the present invention refers to a process for the preparation of a compound of general formula (I) or a salt or solvate thereof, which comprises reacting a compound of general formula (II) with a compound of general formula (III) in presence of a palladium catalyst and a base.
  • the present invention also refers to a process which further comprises transformation and/or purification of a compound of formula (I) obtained by the above process into another compound of formula (I) (especially abiraterone acetate) by any known process in the state of the art, preferably, through all or some of the following steps:
  • the present invention refers to compounds of formula (II), (IV), (V), (IX), salts or solvates thereof. In a further aspect, the present invention refers to compounds of formula (I), wherein R 1 is SiR 3 R 4 R 5 , or a salt or solvate thereof.
  • the present invention refers to a process for the preparation of a salt of a compound of formula (I), wherein R 1 is SiR 3 R 4 R 5 , by recovering the salt from a solution of the free base in any suitable solvent by treating the solution with an appropriate acid.
  • the acid is hydrochloric acid.
  • Ci-C 8 alkyl relates to a radical derived from a linear or branched alkane, with 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, butyl, etc., optionally substituted with one or more substituents independently selected from halogen, C 6 -Ci 4 aryl and CrC 8 alkyl.
  • substituted alkyl is benzyl, which may be, in turn, substituted with methoxy, nitro, cyano, halo, phenyl, etc.
  • C 3 -C 6 cycloalkyl relates to a radical derived from a cycloalkane, with 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, etc., optionally substituted with one or more substituents independently selected from halogen, C 6 -Ci 4 aryl and CrC 8 alkyl.
  • C6-Ci 4 aryl relates to a radical derived from an aromatic hydrocarbon, with 6 to 14 carbon atoms, for example, phenyl, tolyl, xylyl, naphthyl, etc., optionally substituted with one or more substituents independently selected from halogen and Ci-C 8 alkyl.
  • C C 8 alkoxy relates to an O-alkyl radical, with 1 to 8 carbon atoms, for example, methoxy, ethoxy, propoxy, butoxy, etc., optionally substituted with one or more substituents independently selected from halogen and C C 8 alkyl.
  • C 2 -C 3 alkylenedioxy is a divalent group represented by -0-R-0-, where R is an alkylene group of two or three carbon atoms optionally substituted with one or more substituents independently selected from C 6 -Ci 4 aryl and Ci-C 8 alkyl.
  • alkylenedioxy groups include -0-CH 2 -CH 2 -0-, -0-C(CH 3 ) 2 - C(CH 3 ) 2 -0-, -0-C(CH 3 ) 2 -CH(CH 3 )-0-, -0-CH 2 -CH 2 -CH 2 -0-, -0-CH 2 -C(CH 3 ) 2 -CH 2 -0- and -0-C(CH 3 ) 2 -CH 2 -CH(CH 3 )-0-.
  • C 6 aryldioxy is a divalent group represented by -O-R-
  • R is an aryl group of six carbon atoms optionally substituted with one or more substituents independently selected from Ci-C 8 alkyl. Preferably, it is benzene- 1 ,2-dioxy.
  • halogen or halo relates to fluorine, chlorine, bromine or iodine.
  • hydroxyl protecting group includes any group capable of protecting a hydroxyl group.
  • Illustrative examples of hydroxyl protecting groups have been described by Green TW et al. in "Protective Groups in Organic Synthesis", 3rd Edition (1999), Ed. John Wiley & Sons (ISBN 0-471 -16019-9). Virtually any hydroxyl protecting group can be used to put the invention into practice. Nevertheless, in a particular embodiment, the hydroxyl protecting group is an ester group or an ether group, which can be converted into a hydroxyl group under mild conditions.
  • HPGs include esters (COR), carbonates (COOR), amides (CONRR'), silyl radicals [Si(R 3 )(R 4 )(R 5 )], and ethers (R 6 ), wherein:
  • R and R' are independently selected from the group consisting of optionally substituted Ci-C 8 alkyl, optionally substituted C 3 -C 6 cycloalkyl and optionally substituted C 6 -Ci 4 aryl;
  • R 3 , R 4 and R 5 are independently selected from the group consisting of optionally substituted Ci-C 8 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 6 -Ci 4 aryl, optionally substituted Ci-C 8 alkoxy, and halogen; and R 6 is selected from the group consisting of optionally substituted Ci-C 8 alkyl, optionally substituted C 3 -C 6 cycloalkyl and optionally substituted C 6 -Ci 4 aryl.
  • Representative examples of esters and carbonates as HPGs are those wherein R is methyl or benzyl.
  • amides as HPGs are those wherein R and/or R' are independently selected from methyl and benzyl.
  • silyl groups as HPGs are those wherein R 3 , R 4 and R 5 are independently selected from C C 4 alkyl and C 6 -Ci 4 aryl; preferably are independently selected from methyl, i-propyl, t-butyl and phenyl. More preferably, the silyl group is trimethylsilyl (TMS), dimethylphenylsilyl (DMPS) or dimethyl-i-butylsilyl (TBDMS).
  • TMS trimethylsilyl
  • DMPS dimethylphenylsilyl
  • TDMS dimethyl-i-butylsilyl
  • ethers as HPGs are methyl ethers (CH 2 OR 8 ), ethyl ethers (CH 2 CH 2 OR 8 ) and benzyl ethers, wherein R 8 is CrC 8 alkyl, such as methoxymethyl, 1 -ethoxyethyl.
  • the compounds used in the process described by the present invention can be obtained in free form or in solvate form. In both cases, they are preferably obtained in crystalline form, both as free compounds or as solvates (for example, hydrates, alcoholates, etc.), both forms being included within the scope of the present invention. Solvation methods are generally well known in the state of the art.
  • the invention also provides "salts" of the compounds described in the present description.
  • said salts can be acid addition salts, base addition salts or metal salts, and can be synthesized from the parent compounds containing a basic or acid moiety by means of conventional chemical processes known by the persons skilled in the art.
  • Such salts are generally prepared, for example, by reacting the free acid or base forms of said compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of the two.
  • Nonaqueous media such as ether, ethyl acetate, ethanol, acetone, isopropanol or acetonitrile are generally preferred.
  • said acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate, etc.
  • inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.
  • organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate
  • base addition salts include inorganic base salts such as, for example, ammonium salts and organic base salts such as, for example, ethylenediamine, ethanolamine, ⁇ /,/V-dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, etc.
  • organic base salts such as, for example, ethylenediamine, ethanolamine, ⁇ /,/V-dialkylenethanolamine, triethanolamine, glutamine, amino acid basic salts, etc.
  • metal salts include, for example, sodium, potassium, calcium, magnesium, aluminum and lithium salts.
  • pharmaceutically acceptable relates to molecular entities and compositions being physiologically tolerable and normally not causing an allergic reaction or similar adverse reaction, such as gastric discomfort, dizziness and the like, when they are administered to a human being.
  • pharmaceutically acceptable means approved by a governmental regulatory agency or listed in the US pharmacopoeia or another generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • the scope of the present invention also includes salts which are not pharmaceutically acceptable as possible means for obtaining pharmaceutically acceptable salts.
  • the compounds of the invention also include compounds which differ in the presence of one or more isotopically enriched atoms.
  • compounds having the structures defined herein, with the exception of the substitution of at least one hydrogen by a deuterium or tritium, or the substitution of at least one carbon by a carbon enriched in 13 C or 14 C, or at least one nitrogen by a nitrogen enriched in 15 N are within the scope of this invention.
  • complex means a molecular structure in which neutral molecules or anions (called ligands) bond to a central metal atom (or ion) by coordinate covalent bonds.
  • catalyst is recognized in the art and means a substance that increases the rate of a reaction without modifying the overall standard Gibbs energy change in the reaction and without itself being consumed in the reaction.
  • the changing of the reaction rate by use of a catalyst is called catalysis.
  • the catalyst is used in a substoichiometric amount relative to a reactant, i. e. a catalytic amount.
  • a preferred catalytic amount is considered herein from 0.001 to 20 mol% of catalyst relative to the steroid compound to undergo coupling.
  • ligand refers to a molecule or ion that is bonded directly (i.e. covalently) to a metal center.
  • the term "about” means a slight variation of the value specified, preferably within 10 percent of the value specified. Nevertheless, the term “about” can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present invention. Further, to provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about”.
  • the present invention is directed to the preparation of a compound of formula (I) or a salt or solvate thereof, by reacting a compound of formula (IV) with a 3-substituted pyridine of formula (III) in presence of a Pd(0) or Pd(ll) cat lyst and a base
  • R 1 is selected from the group consisting of H and a hydroxyl protecting group (HPG);
  • X is halogen or OS0 2 CF 3 ;
  • Z and Z' are independently selected from the group consisting of hydroxyl, optionally substituted Ci-C 8 alkoxy and optionally substituted Ci-C 8 alkyl, or Z and Z' together form an optionally substituted C 2 -C 3 alkylenedioxy group or an optionally substituted C 6 aryldioxy group.
  • the Pd catalyst is a Pd(0) or a Pd(ll) catalyst having phosphine ligands such as Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 CI 2 , Pd(dppe) 2 CI 2 , Pd(dppf)CI 2 or Pd(dppf)CI 2 ⁇ CH 2 CI 2 . More preferably, it is Pd(PPh 3 ) 4 or Pd(dppf)CI 2 ⁇ CH 2 CI 2 .
  • the amount of the Pd catalyst is from about 0.001 % mol to about 6% mol, such as from about 0.01 % mol to about 6% mol. In some embodiments, the mount of the Pd catalyst is from about 0.2% mol to about 6% mol, preferably about 0.5-2% mol.
  • Suitable bases include alkaline and alkaline earth metal carbonates, bicarbonates, phosphates, acetates, alkoxides, hydroxides and halides.
  • the base is an alkaline metal carbonate or an alkaline earth metal carbonate. More preferably, the base is selected from sodium, cesium, potassium and calcium carbonate. Even more preferably, it is sodium carbonate, potassium carbonate or calcium carbonate.
  • reaction proceeds in the presence of water either in a homogenous system or a biphasic system.
  • this coupling reaction is carried out in the presence of an organic solvent or mixture of solvents, for example, an ether (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1 ,2-dimethoxyethane (DME), dioxane, 1 ,3-dioxolane, etc.) or an aromatic solvent (e.g., toluene, xylene, etc.) or mixtures thereof.
  • an organic solvent or mixture of solvents for example, an ether (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1 ,2-dimethoxyethane (DME), dioxane, 1 ,3-dioxolane, etc.) or an aromatic solvent (e.g., toluene, xylene, etc.) or mixtures thereof.
  • an ether e.g., tetrahydrofuran (THF), 2-methylt
  • the reaction of the compounds of formula (IV) and (I II) is carried out in a mixture of organic solvents, preferably THF and toluene, in the presence of variable amounts of water; the amount of water typically ranges from about 10% to about 100% with respect to the amount of the organic solvent/s employed. In a particular embodiment, the amount of water ranges from about 2% to about 50%, preferably from about 10% to about 30%, with respect to the amount of the organic solvent s employed. In another particular embodiment, the reaction of the compounds of formula (IV) and (I I I) is carried out in THF in the presence of water.
  • the coupling reaction is suitably carried out under heating, for example at temperatures comprised between about 40°C and about 1 10°C, preferably between about 60°C and about 90°C or at the boiling point temperature.
  • the compound of formula (I I I) is typically used in an amount ranging from about 1 .0 and about 3.0 equivalents for each equivalent of compound of formula (IV), preferably from about 1 .2 to about 1 .6 equivalents.
  • X is selected from bromo, iodo and OS0 2 CF 3 .
  • a particular and preferred example of compound of formula (I I I) is 3-bromopyridine.
  • R 1 is selected from H and a silyl protecting group of formula Si(R 3 )(R 4 )(R 5 ).
  • R 3 , R 4 and R 5 are independently selected from C C 4 alkyl and C 6 -Ci 4 aryl; more preferably are independently selected from methyl, i- propyl, t-butyl and phenyl.
  • R 1 is trimethylsilyl (TMS), dimethylphenylsilyl (DMPS) or dimethyl-i-butylsilyl (TBDMS).
  • R 1 is TBDMS.
  • R 1 is selected from the group consisting of H, COMe, SitBuMe 2 (TBDMS) and SiPhMe 2 (DMPS).
  • R 1 is TBDMS.
  • Z and Z' are OH, methoxy, ethoxy, i-propoxy or, together, form an ethylendioxy, tetramethylethylenedioxy, propylendioxy, dimethylpropylendioxy, trimethylpropylendioxy, tetramethylpropylendioxy or benzene-1 ,2-dioxy group.
  • Z and Z' are OH or ethoxy. More preferably, Z and Z' are OH.
  • radical R 1 in the compound of formula (I) can be the same or different from radical R 1 in the starting compound of formula (IV).
  • R 1 in the compound of formula (IV) is a HPG which is cleaved under coupling reaction conditions giving rise to a compound of formula (I) wherein R 1 is OH.
  • the HPG is not cleaved under coupling reaction conditions and, therefore, R 1 is a HPG in the compound of formula (IV) and in the resulting compound of formula (I).
  • R 1 is the same in the compound of formula (IV) and in the compound of formula (I) and is selected from the group consisting of H, COMe, SitBuMe 2 (TBDMS) and SiPhMe 2 (DMPS). More preferably, R 1 is TBDMS.
  • a compound of formula (I) wherein R 1 is TBDMS is obtained by reacting a compound of formula (IV) wherein R 1 is TBDMS and Z and Z' are OH with 3-bromopyridine.
  • this reaction is performed in the presence of Pd(PPh 3 ) 4 or Pd(dppf)CI 2 ⁇ CH 2 CI 2 as catalyst and Na 2 C0 3 , K 2 C0 3 or CaC0 3 as base.
  • this reaction is performed in the presence of a mixture of THF, toluene and water, or in the presence of a mixture of THF and water or in the presence of water.
  • a compound of formula (I) wherein R 1 is TBDMS is obtained by reacting a compound of formula (IV) wherein R 1 is TBDMS and Z and Z' are OH with 3-bromopyridine, in the presence of 6% mol Pd(PPh 3 ) 4 and 1 .5 equivalents of Na 2 C0 3 and a mixture of THF, toluene and water.
  • a compound of formula (I) wherein R 1 is TBDMS is obtained by reacting a compound of formula (IV) wherein R 1 is TBDMS and Z and Z' are OH with 3-bromopyridine, in the presence of Pd(dppf)CI 2 - CH 2 CI 2 and carbonate as a base and water.
  • a compound of formula (I) wherein R 1 is TBDMS is obtained by reacting a compound of formula (IV) wherein R 1 is TBDMS and Z and Z' are OH with 3-bromopyridine, in the presence of Pd(dppf)CI 2 - CH 2 CI 2 and CaC0 3 and a mixture of THF and water.
  • inorganic salts may be removed by washing with water and extracting with an organic solvent such as dichloromethane, toluene, diethyl ether, cyclopentylmethyl ether, ethyl acetate or any other suitable solvent.
  • organic solvent such as dichloromethane, toluene, diethyl ether, cyclopentylmethyl ether, ethyl acetate or any other suitable solvent.
  • the product contained in the organic phase can, depending on the nature of R 1 , be isolated by solvent removal and recrystallization of the residue in a suitable solvent, or alternatively, by precipitation in the form of a salt, such as chlorhydrate, bromhydrate, sulfate, methanesulfonate, malate, etc., or a combination of both methods.
  • Dilute solutions of acid will be preferably used when R 1 is protected with certain HPGs such as silyl radicals in order to avoid the cleavage of the protecting group.
  • the product can be isolated by solvent removal followed by addition of an HCI aqueous solution in order to precipitate the product as a hydrochloride salt and isolate it, for example, by filtration.
  • Palladium-catalyzed C-C coupling reactions usually require the presence of a component with nucleophilic character represented by an organometallic compound such as organoboron (Suzuki), organozinc (Negishi), organostannane (Stille), etc.
  • organometallic compound such as organoboron (Suzuki), organozinc (Negishi), organostannane (Stille), etc.
  • organometallic compound such as organoboron (Suzuki), organozinc (Negishi), organostannane (Stille), etc.
  • organometallic compound such as organoboron (Suzuki), organozinc (Negishi), organostannane (Stille), etc.
  • R 1 is selected from the group consisting of H and a hydroxyl protecting group
  • R 2 is S0 2 R 7 ;
  • R 7 is selected from the group consisting of optionally substituted Ci-C 8 alkyl and optionally substituted C 6 -Ci 4 aryl;
  • X is halogen or OS0 2 CF 3 .
  • the catalyst is selected from Pd 2 (dba) 3 , Pd(PPh 3 ) 4 , Pd(dppf)CI 2 ⁇ CH 2 CI 2 and PdCI 2 (CNMe) 2 , more preferably the Pd catalyst is Pd 2 (dba) 3 or Pd(dppf)CI 2 ⁇ CH 2 CI 2 .
  • the amount of the catalyst ranges from about 0.5% mol to about 10% mol, preferably from about 1 % mol to about 6% mol.
  • the ligand is a phosphine ligand.
  • Phosphine ligands are widely known by the skilled person since they are commonly used in organic catalysis.
  • suitable ligands include X-phos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), dppp (1 ,4- bis(diphenylphosphino)butane), S-phos (2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl), dppm (1 ,1 -bis(diphenylphosphino)-methane), dippe (1 ,2- bis(diisopropylphosphino)ethane, dmpe (1 ,2-Bis(dimethylphosphino)ethane, dppe (1 ,2- bis(diphenylphophino)ethane, etc.
  • the ligand is X-phos or dppp, more preferably X-phos.
  • the amount of ligand used depends on the amount of palladium catalyst. In general, the amount of the ligand ranges from about 1 % mol to about 20% mol, preferably from about 2% mol to about 12% mol.
  • the coupling is performed in basic medium.
  • Alkoxides and carbonates of alkaline and alkaline earth metals have been found particularly useful such as for example alkoxides and carbonates of Li, Na, K and Cs.
  • suitable bases for the coupling step include t-BuOLi, MeOLi, MeONa and CsC0 3 .
  • the base is t-BuOLi.
  • the amount of base preferably ranges from about 2 to about 20 eq for each equivalent of compound of formula (II), more preferably from about 4 to about 15 eq. In general, about 7.5 eq of base are suitable for the reaction occurs.
  • this coupling reaction is carried out in an organic solvent or mixture of solvents, for example, an ether (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1 ,2-dimethoxyethane (DME), dioxane, 1 ,3-dioxolane, etc.) or an aromatic solvent (e.g., toluene, xylene, etc.).
  • the reaction of the compounds of formulas (II) and (III) is carried out in dioxane.
  • the coupling reaction is suitably carried out under heating, for example at temperatures comprised between about 40°C and about 140°C, preferably between about 65°C and about 1 10°C, more preferably between about 80°C and about 1 10°C.
  • the compound of formula (III) is typically used in an amount ranging from about 1 .1 and about 3 eq for each equivalent of compound of formula (II), preferably from about 1 .3 to about 1 .6 eq.
  • a particular and preferred example of compound of formula (III) is 3-bromopyridine.
  • R 1 is selected from H and a silyl protecting group of formula Si(R 3 )(R 4 )(R 5 ).
  • R 3 , R 4 and R 5 are independently selected from C C 4 alkyl and C 6 -Ci 4 aryl; more preferably are independently selected from methyl, i- propyl, t-butyl and phenyl.
  • R 1 is trimethylsilyl (TMS), dimethylphenylsilyl (DMPS) or dimethyl-i-butylsilyl (TBDMS).
  • R 1 is TBDMS.
  • R 1 is selected from the group consisting of H, COMe, SitBuMe 2 (TBDMS) and SiMe 2 Ph (DMPS). More preferably, R 1 is TBDMS.
  • R 2 is S0 2 R 7 wherein R 7 is an optionally substituted C 6 -Ci 4 aryl, such as Ph, Tol, 2,4,6- trimethylphenyl or 2,4,6-triisopropylphenyl.
  • R 7 is an optionally substituted C 6 -Ci 4 aryl, such as Ph, Tol, 2,4,6- trimethylphenyl or 2,4,6-triisopropylphenyl.
  • the products of formula (I) obtained can be purified by column chromatography or preferably by means of industrially acceptable processes such as, for example, by means of a crystallization process, either of the product as a free base or, more preferably, through the formation of an addition salt (e.g. chlorhydrate, bromhydrate, sulfate, methanesulfonate, malate, etc).
  • an addition salt e.g. chlorhydrate, bromhydrate, sulfate, methanesulfonate, malate, etc.
  • the product is purified from all those impurities of neutral character.
  • suitable solvents for said crystallization are THF, ethyl acetate and isopropyl ether.
  • addition salts of HCI and malic acid are preferred. Dilute solutions of acid will be preferably used when R 1 is protected with certain HPGs such as silyl radicals in order to avoid the cleavage of the protecting group.
  • 3-(tert-butyldimethylsiloxy)-17-p- toluenesulfonylhydrazone-androsta-5-en is subject to reaction with 6% mol Pd 2 (dba) 3 , 12% mol X-Phos, 7.5 eq tBuOLi and 1 .5 eq 3-bromopyridine in 20-30 volume of dioxane at a temperature between 90 and 100 °C for 6-15 hours. Then, the reaction mixture is filtered and the solvent evaporated. The residue obtained is purified by re- dissolution in THF and precipitation of the product obtained as an acid addition salt of HCI (using HCI aq 1 -2 M) at room temperature.
  • the salt obtained can be used directly or can be neutralized to obtain the product in neutral form.
  • This process for obtaining chlorhydrate of 3-(tert-butyldimethylsiloxy)-17-(3-pyridyl)-androsta-5-en is depicted below:
  • the compounds of general formula (II) can be readily prepared from a ketone of general formula (VI) and a hydrazine of general formula (VII):
  • the hydrazones thus obtained can be isolated by precipitation by addition over water or by solvent evaporation and precipitation of the residue by addition of diethyl ether, toluene, heptane or any other suitable solvent, depending on the nature of R 1 .
  • the formation of the hydrazone of general formula (II) may be carried out in THF with 0.1 eq of TsOH and 1 .1 eq of p- toluenesulfonyl hydrazide at 50°C-90°C. After completion, the reaction mixture is poured into water under stirring to afford a solid, which is subsequently filtered.
  • the processes of the invention may further comprise the transformation and/or purification of the compounds of formula (I) by any known process in the state of the art, preferably through some or all of the following steps:
  • Step i) purification of a compound of formula (I) by means of crystallization and/or salt formation.
  • the compounds of formula (I) obtained can be purified by any conventional method, such as by column chromatography or, more preferably, by means of industrially acceptable processes such as, for example, by means of a crystallization process, either of the product as a free base or, more preferably, through the formation of an addition salt (e.g. chlorhydrate, bromhydrate, sulfate, methanesulfonate, malate, etc.).
  • an addition salt e.g. chlorhydrate, bromhydrate, sulfate, methanesulfonate, malate, etc.
  • the product can be purified from impurities of neutral character.
  • suitable solvents for said crystallization are THF, ethyl acetate and isopropyl ether.
  • addition salts of HCI and malic acid are preferred.
  • the salt obtained in this way may be used directly or may be neutralized.
  • Abiraterone can be prepared from a compound of formula (I) wherein R 1 is a hydroxyl protecting group by conventional methods of deprotection known by persons skilled in the art (Green TW et al. in “Protective Groups in Organic Synthesis", 3rd Edition (1999), Ed. John Wiley & Sons (ISBN 0-471 -16019-9).
  • R 1 represents an ester (COR)
  • COOR carbonate
  • CONRR' amide
  • a compound of formula (I) wherein R 1 is a silyl group, preferably TBDMS is transformed into abiraterone by treatment with tetrabutylammonium fluoride in the presence of an organic solvent.
  • R 1 TBDMS
  • the deprotection conditions are: the silyl derivative is solved in THF and tetrabutylammonium fluoride in THF (1 M) is added at room temperature. The progress of this reaction can be easily monitored by TLC. The alcohol is isolated.
  • R 1 represents an ether
  • R 6 can be easily converted into abiraterone through hydrolysis in acid media (for example, for methyl ethers (CH 2 OR 8 )), hydrogenation (for example, for benzyl ethers), oxidation (for example, for aryl ethers), etc.
  • acid media for example, for methyl ethers (CH 2 OR 8 )
  • hydrogenation for example, for benzyl ethers
  • oxidation for example, for aryl ethers
  • esterification of abiraterone into its acetate may be performed according to conventional chemical processes known by those skilled in the art. According to a particular embodiment, this esterification is carried out by using acetyl chloride as acylating agent and pyridine as solvent, or acetyl chloride as acylating agent and ethyl ether as solvent in the presence of DMAP as catalyst (EP 0721461 B, US 5,618,807 A).
  • a compound of formula (I) wherein R 1 is TBDMS is obtained by reacting a compound of formula (IV) wherein R 1 is TBDMS and Z and Z' are OH with 3-bromopyridine, which is further transformed into a compound of formula (I) wherein R 1 is H by deprotection of the hydroxyl group, preferably in the presence of a fluoride reagent such as tetrabutylammonium fluoride.
  • this process further comprises esterification of abiraterone to abiraterone acetate, preferably in the presence of acetyl chloride.
  • Purification of compounds of formula (I) can be performed at any stage of the synthesis, i.e. before and/or after transformation into abiraterone and/or before and/or after transformation into abiraterone acetate.
  • Boron derivatives of formula (IV) may be obtained from hydrazones of formula (I la) through the following sequence ⁇ J.Am.Chem.Soc, 2008, 130, 8481 -8490):
  • R 1 is as previously defined
  • Ar is an optionally substituted C 6 -Ci 4 aryl.
  • Ar is phenyl, tolyl, 2,4,6- trimethylphenyl or 2,4,6-triisopropylphenyl,
  • Z" is selected from the group consisting of hydroxyl, optionally substituted Ci-C 8 alkoxy and optionally substituted Ci-C 8 alkyl.
  • Compounds of formula (I la) may be prepared in turn from ketones of formula (VI), similarly to the compounds of formula (II) as defined above and compound of formula (lib) as defined hereinafter.
  • Enol lithium compounds of formula (V) may be prepared by Shapiro reaction, from hydrazones of formula (I la) and a lithium base, including common alkyl lithium bases such as n-BuLi, Hexyl-Li, tert-BuLi, etc. Then, the enol lithium compound is reacted with a boronic acid or boronic ester of formula (VIII) to afford a vinyl-borate of formula (IV).
  • the compound of formula (IV) may be obtained from a compound of formula (IX) by treatment with a lithium base and a compound of formula (VIII) according to the following scheme (J. Org. Chem., 1985, 50, 2438-43):
  • R 1 , Z, Z' and Z" are as previously defined, and
  • X' is bromo or iodo.
  • X' is iodo.
  • R 1 is a silyl protecting group of formula Si(R 3 )(R 4 )(R 5 ).
  • R 3 , R 4 and R 5 are independently selected from C C 4 alkyl and C 6 -Ci4 aryl; more preferably are independently selected from methyl, i-propyl, t- butyl and phenyl.
  • R 1 is trimethylsilyl (TMS), dimethylphenylsilyl (DMPS) or dimethyl-i-butylsilyl (TBDMS).
  • TMS trimethylsilyl
  • DMPS dimethylphenylsilyl
  • TDMS dimethyl-i-butylsilyl
  • R 1 is TBDMS.
  • Z, Z' and Z" are OH, methoxy, ethoxy or i-propoxy, or Z and Z' form together an ethylendioxy, tetramethylethylenedioxy, propylendioxy, dimethylpropylendioxy, trimethylpropylendioxy, tetramethylpropylendioxy or benzene- 1 ,2-dioxy group and Z" is selected from OH, methoxy, ethoxy or i-propoxy.
  • Z, Z' and Z" are OH, methoxy or ethoxy. More preferably, Z, Z' and Z" are ethoxy.
  • the lithium base can be selected from alkyl lithium bases such as n-BuLi, sec- BuLi, tert-BuLi, Hexyl-Li.
  • the lithium base is n-BuLi or Hexyl-Li.
  • Suitable solvents for the preparation of a compound of formula (IV) include organic solvents, such as acyclic or cyclic ethers (e.g. Et 2 0, iPr 2 0, dioxane, tetrahydrofuran), hydrocarbon solvents (e.g. pentane, hexane), halogenated solvents (e.g. methylene chloride), aromatic solvents (e.g. toluene, xylene), or mixtures thereof.
  • the solvent is an acyclic or cyclic ether, preferably THF.
  • the compound of formula (IV) obtained according to the above methods can be directly used in the coupling reaction with a compound of formula (III) or can be previously transformed into a different compound of formula (IV).
  • a compound of formula (IV) wherein Z and Z' are OH is obtained by reacting a compound of formula (V) with a compound of formula (VIII) wherein Z, Z' and Z" are selected from Ci-C 8 alkoxide, preferably methoxy, ethoxy or i-propoxy, followed by subsequent hydrolysis of the resulting boronic ester into the boronic acid.
  • Suitable conditions for the hydrolysis of boronic esters into the boronic acids are well known in the art.
  • said reaction is performed under acid conditions.
  • a compound of formula (IV) wherein R 1 is TBDMS and Z and Z' are ethoxy is obtained by reacting a compound of formula (IX) wherein R 1 is TBDMS and X' is I with n-BuLi and a compound of formula (VIII) wherein Z, Z' and Z" are ethoxy, preferably in the presence of THF.
  • This compound can be further hydrolyzed to give a compound of formula (IV) wherein R 1 is TBDMS and Z and Z' are OH.
  • R 1 and X' are as previously defined.
  • R 1 is selected from H and a silyl protecting group of formula Si(R 3 )(R 4 )(R 5 ) wherein R 3 , R 4 and R 5 are independently selected from C C 4 alkyl and C 6 -Ci 4 aryl; more preferably are independently selected from methyl, i-propyl, t-butyl and phenyl.
  • R 1 is selected from H, trimethylsilyl (TMS), dimethylphenylsilyl (DMPS) and dimethyl-i-butylsilyl (TBDMS).
  • TMS trimethylsilyl
  • DMPS dimethylphenylsilyl
  • TDMS dimethyl-i-butylsilyl
  • R 1 is H or TBDMS, more preferably R 1 is H.
  • X' is I.
  • Suitable basis for this reaction include non-nucleophilic bases, preferably non- nucleophilic organic bases such as non-nucleophilic amines, amidines or guanidine bases.
  • suitable bases include, for example, triethylamine, diisopropylethylamine (DIPEA), 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1 ,1 ,3,3-tetramethylguanidine (TMG), triazabicyclodecene (TBD) or dicyclohexylguanidines.
  • the base is 1 ,1 ,3,3-tetramethylguanidine (TMG).
  • Suitable solvents for the preparation of a compound of formula (IX) include organic solvents, such as acyclic or cyclic ethers (e.g. Et 2 0, iPr 2 0, dioxane, tetrahydrofuran), hydrocarbon solvents (e.g. pentane, hexane), halogenated solvents (e.g. methylene chloride), aromatic solvents (e.g. toluene, xylene), or mixtures thereof.
  • the solvent is an acyclic or cyclic ether, preferably THF.
  • a compound of formula (IX) wherein R 1 is H and X' is I is obtained by reacting a compound of formula (lib) wherein R 1 is H with l 2 and TMG, preferably, in the presence of THF. Said compound can be further protected to give a compound of formula (IX) wherein R 1 is TBDMS and X' is I.
  • compounds of formula (I la) and (lib) obtained by hydrazination of a compound of formula (VI)
  • R 1 is as previously defined, and
  • R 2 is selected from H and S0 2 Ar, wherein Ar is an optionally substituted C 6 -Ci 4 aryl.
  • Ar is phenyl, tolyl, 2,4,6-trimethylphenyl or 2,4,6- triisopropylphenyl.
  • compound of formula (VII) is hydrazine or a solvate thereof.
  • compound of formula (VII) is hydrazine hydrate or hydrazine sulfate.
  • R 1 is selected from H and a silyl protecting group of formula Si(R 3 )(R 4 )(R 5 ) wherein R 3 , R 4 and R 5 are independently selected from C C 4 alkyl and C 6 -Ci 4 aryl; more preferably are independently selected from methyl, i-propyl, t-butyl and phenyl.
  • R 1 is selected from H, trimethylsilyl (TMS), dimethylphenylsilyl (DMPS) and dimethyl-i-butylsilyl (TBDMS).
  • TMS trimethylsilyl
  • DMPS dimethylphenylsilyl
  • TDMS dimethyl-i-butylsilyl
  • R 1 is H or TBDMS; more preferably R 1 is H.
  • the reaction can be catalyzed by using a suitable acid, such as p-TsOH or hydrazine sulfate.
  • a suitable acid such as p-TsOH or hydrazine sulfate.
  • a compound of formula (II) wherein R 1 and R 2 are H is obtained by reacting a compound of formula (VI) wherein R 1 is H with hydrazine hydrate, preferably, in the presence of hydrazine sulfate and water. Said compound can be further protected to give a compound of formula (lib) wherein R 1 is TBDMS.
  • the compounds of formula (I la) and (lib) thus obtained can be optionally isolated by precipitation through addition over water or by solvent evaporation and further precipitation through addition of an organic solvent such as diethyl ether, toluene, heptane or any other suitable solvent, depending on the nature of R 1 .
  • Protection and deprotection of the hydroxyl group at position 3 can be performed at any stage of the synthesis. The most suitable stage for said protection and/or deprotection can be readily determined by those skilled in the art.
  • the hydroxyl group at position 3 is protected in a compound of formula (IX) and is deprotected in a compound of formula (I), after the coupling reaction.
  • the invention is directed to the compounds useful as intermediates in the process of the invention.
  • the invention is directed to a compound of formula (II)
  • R 1 is selected from the group consisting of H and a hydroxyl protecting group
  • R 2 is S0 2 R 7 ;
  • R 7 is selected from the group consisting of optionally substituted Ci-C 8 alkyl and optionally substituted C 6 -Ci 4 aryl;
  • R 1 is a silyl protecting group of formula Si(R 3 )(R 4 )(R 5 ).
  • R 3 , R 4 and R 5 are independently selected from C C 4 alkyl and C 6 -Ci 4 aryl; more preferably are independently selected from methyl, i-propyl, t- butyl and phenyl.
  • R 1 is trimethylsilyl (TMS), dimethylphenylsilyl (DMPS) or dimethyl-i-butylsilyl (TBDMS).
  • TMS trimethylsilyl
  • DMPS dimethylphenylsilyl
  • TDMS dimethyl-i-butylsilyl
  • R 1 is TBDMS.
  • R 1 is selected from the group consisting of H, COMe, SitBuMe 2 (TBDMS) and SiMe 2 Ph (DMPS). More preferably, R 1 is TBDMS.
  • R 2 is S0 2 R 7 wherein R 7 is an optionally substituted C 6 -Ci 4 aryl, such as Ph, Tol, 2,4,6- trimethylphenyl or 2,4,6-triisopropylphenyl.
  • R 7 is an optionally substituted C 6 -Ci 4 aryl, such as Ph, Tol, 2,4,6- trimethylphenyl or 2,4,6-triisopropylphenyl.
  • R 1 is a hydroxyl protecting group
  • X' is bromo or iodo.
  • X' is iodo.
  • R 1 is a silyl protecting group of formula Si(R 3 )(R 4 )(R 5 ).
  • R 3 , R 4 and R 5 are independently selected from C C 4 alkyl and C 6 -Ci 4 aryl; more preferably are independently selected from methyl, i-propyl, t- butyl and phenyl.
  • R 1 is trimethylsilyl (TMS), dimethylphenylsilyl (DMPS) or dimethyl-i-butylsilyl (TBDMS).
  • TMS trimethylsilyl
  • DMPS dimethylphenylsilyl
  • TDMS dimethyl-i-butylsilyl
  • R 1 is TBDMS.
  • X' is I and R 1 is TBDMS.
  • R 1 is a hydroxyl protecting group.
  • R 1 is a silyl protecting group of formula Si(R 3 )(R 4 )(R 5 ).
  • R 3 , R 4 and R 5 are independently selected from C C 4 alkyl and C 6 -Ci 4 aryl; more preferably are independently selected from methyl, i-propyl, t- butyl and phenyl.
  • R 1 is trimethylsilyl (TMS), dimethylphenylsilyl (DMPS) or dimethyl-i-butylsilyl (TBDMS).
  • TMS trimethylsilyl
  • DMPS dimethylphenylsilyl
  • TDMS dimethyl-i-butylsilyl
  • R 1 is TBDMS.
  • the invention is directed to a compound of formula (IV)
  • R 1 is selected from the group consisting of H and a hydroxyl protecting group (HPG); and Z and Z' are independently selected from the group consisting of hydroxyl, optionally substituted Ci-C 8 alkoxy and optionally substituted Ci-C 8 alkyl, or Z and Z' together form an optionally substituted C 2 -C 3 alkylenedioxy group or an optionally substituted C 6 aryldioxy.
  • HPG hydroxyl protecting group
  • R 1 is a silyl protecting group of formula
  • R 3 , R 4 and R 5 are independently selected from C C 4 alkyl and C 6 -Ci 4 aryl; more preferably are independently selected from methyl, i-propyl, t- butyl and phenyl.
  • R 1 is trimethylsilyl (TMS), dimethylphenylsilyl (DMPS) or dimethyl-i-butylsilyl (TBDMS).
  • TMS trimethylsilyl
  • DMPS dimethylphenylsilyl
  • TDMS dimethyl-i-butylsilyl
  • R 1 is TBDMS.
  • Z and Z' are OH, methoxy, ethoxy or i-propoxy, or Z and Z' form together an ethylendioxy, tetramethylethylenedioxy, propylendioxy, dimethylpropylendioxy, trimethylpropylendioxy, tetramethylpropylendioxy or benzene- 1 ,2-dioxy group.
  • Z and Z' are OH, methoxy or ethoxy. More preferably, Z and Z' are OH or ethoxy.
  • R 1 is TBDMS and Z and Z' are ethoxy.
  • R 1 is TBDMS and Z and Z' are OH.
  • the present invention refers to compounds of formula (I), wherein R 1 is SiR 3 R 4 R 5 , or a salt or solvate thereof.
  • R 1 is SiR 3 R 4 R 5 , or a salt or solvate thereof.
  • 3-((Tert- butyldimethylsilyl)oxy)abiraterone (3-TBDMS-abiraterone) and its chlorhydrate salt represent preferred compounds of the invention.
  • Salts of silyl ethers of a compound of formula (I) may be recovered from a solution of the free base in any suitable solvent, or mixture of solvents, by treating the solution with the corresponding acid.
  • suitable solvents include esters and ethers.
  • Esters which may be used include esters withy acetic acid, such as methyl acetate, ethyl acetate and isopropyl acetate.
  • Ethers which may be used include diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), and especially tetrahydrofuran (THF), which gave a particularly good recovery of the salt.
  • the acid is hydrochloric acid, such as HCI aq (1 M).
  • the chlorhydrate salt of 3-TBDMS- abiraterone is prepared by recovering the salt from a solution of the free base in any suitable solvent, more preferably THF, by treating the solution with hydrochloric acid.
  • the preferences described above for the different substituents in the intermediates and compounds of the invention as well as for the conditions of the processes for their preparation are combined.
  • the present invention is also directed to such combinations of preferred substitutions in the chemical formulae above and conditions of the processes for obtaining the same.
  • Example 14 Syntesis of 3-((tert-butyldimethylsilyl)oxy)-5-dehvdroepiandrosterone p- toluenesulfonyl hydrazone
  • Example 21 Synthesis of 3-((tert-butyldimethylsilyl)oxy)abiraterone from 3-((tert- butyldimethvsilyl)oxy)-5-dehvdroepiandrosterone p-toluenesulfonyl hydrazone
  • the reaction mixture was heated at 1 10 °C for 15 hours, and then it was cooled and filtered, washing the insoluble residue with THF (3 x 5 ml). The filtrates were combined and the solvent was evaporated under reduced pressure to afford a residue containing the desired product (43%) and a dimeric impurity resulting from two molecules of the starting material (8.5%).
  • reaction mixture was heated at 1 10 °C for 15 hours, and then it was cooled and filtered, washing the insoluble residue with THF (3 x 5 ml). The filtrates were combined and the solvent was evaporated under reduced pressure to afford a residue containing the desired product (62%) and a dimeric impurity resulting from two molecules of the starting material (15.4%).
  • reaction mixture was heated at 90 °C for 15 hours, and then it was cooled and filtered, washing the insoluble residue with THF (3 x 5 ml). The filtrates were combined and the solvent was evaporated under reduced pressure to afford a residue containing the desired product (65%) and a dimeric impurity resulting from two molecules of the starting material (6.4%).
  • reaction mixture was heated at 90 °C for 7 hours, and then it was cooled and filtered, washing the insoluble residue with THF (3 x 5 ml). The filtrates were combined and the solvent was evaporated under reduced pressure to afford a residue containing the desired product (65%) and a dimeric impurity resulting from two molecules of the starting material (6.5%).
  • Example 22 Synthesis of 3-((tert-butyldimethylsilyl)oxy)abiraterone from 3-((tert- butyldimethylsilyl)oxy)-5-dehvdroepiandrosterone 2,4,6-trimethylsulfonyl hydrazone
  • Example 23 Synthesis of 3-((tert-butyldimethylsilyl)oxy)abiraterone from 3-((tert- butyldimethylsilyl)oxy)-5-dehvdroepiandrosterone 2,4,6-tri-isopropylsulfonyl hvdrazone
  • reaction mixture was heated at 1 10 °C overnight, and then it was cooled and filtered, washing the insoluble residue with THF (3 x 5 ml). The filtrates were combined and the solvent was evaporated under reduced pressure to afford a residue containing the desired product (60%) and a dimeric impurity resulting from two molecules of the starting material of 15.6 %.
  • Example 24 Synthesis of abiraterone acetate from 3-acetyl-5-dehydroepiandrosterone toluenesulfonyl hvdrazone
  • the reaction mixture was heated at 1 10°C for 5 hours, and then it was cooled and filtered, washing the insoluble residue with THF (3 x 5 ml). The filtrates were combined and the solvent was evaporated under reduced pressure to afford a residue containing abiraterone acetate 19 (10%) and a dimeric impurity resulting from two molecules of the starting material (80%).
  • Example 25 Synthesis of abiraterone acetate from 3-acetyl-5-dehydroepiandrosterone toluenesulfon l hydrazone
  • the reaction mixture was heated at 90°C for 52 hours, and then it was cooled and filtered, washing the insoluble residue with THF (3 x 5 ml). The filtrates were combined and the solvent was evaporated under reduced pressure to afford a residue containing abiraterone acetate 19 (15%) and a dimeric impurity resulting from two molecules of the starting material (42%).
  • Example 28 Synthesis of abiraterone chlorhvdrate from 3-((tert- but ldimethylsilyl)oxy)-5-dehvdroepiandrosterone p-toluenesulfonyl hydrazine
  • the reaction mixture was heated at reflux for 5 hours, and then it was cooled and filtered.
  • Water (220 ml) and ethyl acetate (220 ml) were added over the filtrate and the two phases formed were decanted, the aqueous phase was extracted again with 100 ml of ethyl acetate and the organic phases were combined and evaporated under reduced pressure to afford a residue containing the desired product.

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Abstract

La présente invention concerne un procédé d'obtention d'abiraterone et de ses dérivés tels que l'acétate d'abiraterone, au moyen d'un couplage de Suzuki via un borate de stéroïde de formule générale (IV) ou un couplage C-C via une hydrazone de stéroïde de formule générale (II), ainsi que des intermédiaires utiles dans lesdits procédés.
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CZ2014475A3 (cs) 2014-07-09 2016-01-20 Zentiva, K.S. Způsob přípravy Abirateron acetátu o vysoké čistotě aplikovatelný v průmyslovém měřítku
CN104370991B (zh) * 2014-11-18 2016-04-27 仙居县力天化工有限公司 一种阿比特龙醋酸酯的合成方法
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