EP2917226A1 - Process for making the 17-triflate intermediate of abiraterone-3-acetate - Google Patents

Process for making the 17-triflate intermediate of abiraterone-3-acetate

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Publication number
EP2917226A1
EP2917226A1 EP12790830.9A EP12790830A EP2917226A1 EP 2917226 A1 EP2917226 A1 EP 2917226A1 EP 12790830 A EP12790830 A EP 12790830A EP 2917226 A1 EP2917226 A1 EP 2917226A1
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EP
European Patent Office
Prior art keywords
formula
reaction
process according
acetate
compound
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.)
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EP12790830.9A
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German (de)
French (fr)
Inventor
Bohumil Dymacek
Jakub Castulik
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Synthon BV
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Synthon BV
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • 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
    • 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

Definitions

  • the basic process for making abiraterone-3 -acetate disclosed in WO 93/20097 comprises
  • DHEA acetate replacing the enol-form of the 17-oxo group in dehydroepiandrosterone- 3 -acetate (DHEA acetate) of formula (2)
  • a leaving group L which is capable of being replaced by a 3-pyridyl group in a palladium(O) complex-catalyzed cross-coupling reaction with a 3-pyridinyl (dialkyl/ dialkoxy) -boron compound (so called Suzuki coupling reaction)
  • the palladium complex in Suzuki coupling reaction is preferably a palladium(O) complex such as tetrakis(triphenylphosphine)palladium(0) or a complex reducible in situ to such palladium(0)phosphine species.
  • the leaving groups L actually used in prior art documents were an iodo group and a trifluoromethanesulfonate (triflate) group.
  • the 3-acetate group may be introduced only after introducing the 17-(3-pyridyl)- group, thus the actual starting material is not the compound of formula (2) but dehydroepiandrosterone (DHEA) of formula (3).
  • DHEA dehydroepiandrosterone
  • the compound of formula (3) is converted to the corresponding iodo-compound of formula (4) in two steps; subsequently, after performing the Suzuki coupling reaction on compound (4), abiraterone of formula (1A) is obtained.
  • abiraterone (1A) is acetylated to the desired abiraterone-3 -acetate.
  • the second known route employing the triflate leaving group L is two steps shorter and thus more advantageous.
  • diethyl(3-pyridyl)borane was added to the isolated triflate compound of formula (5) in THF containing a catalytic amount of
  • WO 2006/021776 and WO 2006/021777 suggest two improvements in the original process.
  • the triflating step is advantageously conducted in the presence of an organic base comprising a tertiary or heterocyclic amine having a pKa value of the conjugate acid at 25°C within the range of 5.21 (i.e. pyridine) to 12 (i.e DBU, a diazabicycloundecene).
  • an organic base comprising a tertiary or heterocyclic amine having a pKa value of the conjugate acid at 25°C within the range of 5.21 (i.e. pyridine) to 12 (i.e DBU, a diazabicycloundecene).
  • DBU diazabicycloundecene
  • this starting material may be removed from the reaction mixture by converting the product (1) to an acid addition salt, separating the salt in solid state and recrystallizing the salt.
  • the mesylate salt of (1) was described to be the most advantageous salt in WO'776.
  • Such salt may be obtained from a solution of the free base of (1) in a suitable solvent, e.g.
  • the present invention relates to an improved process for making the compound 3 ⁇ - acetoxy-androsta-5,16-dien-17-yl trifluoromethanesulfonate of formula (5), which is an important intermediate in making abiraterone-3 -acetate of formula (1).
  • the invention provides a process for making the compound of formula (5)
  • a inflating agent preferably trifluoromethanesulfonic anhydride, in an inert solvent in the absence of an organic base.
  • the inert solvent comprises an aliphatic acid ester, preferably having 2 to 10 carbon atoms, an aliphatic or aromatic hydrocarbon, preferably having 5 to 8 carbon atoms or a chlorinated aliphatic or aromatic hydrocarbon, preferably having 1 to 8 carbon atoms, and mixtures thereof.
  • concentration of the compound (2) in the solvent is higher than 0.3M, preferably higher than 1.5M.
  • reaction temperature is lower than 0°C, preferably from -5 to -30°C, most preferably from -10 to -20°C.
  • the dehydroepiandrosterone-3 -acetate of formula (2) is prepared by reaction of dehydroepiandrosterone of formula (3) with acetic anhydride, and the so-obtained crude reaction mixture is used as the starting material for the reaction with the triflating agent.
  • the reaction is carried out either in the absence of a base or in the presence of an inorganic base, preferably sodium or potassium carbonate.
  • the triflate of formula (5) may be advantageously isolated from the reaction mixture, and the crude triflate may be purified by crystallization from a suitable solvent.
  • a suitable crystallization solvent is an aliphatic alcohol, e.g. methanol or isopropanol, acetic acid, acetic anhydride or any mixture thereof with water.
  • the invention provides a process for purification of the compound of formula (5), comprising crystallizing the compound of formula (5) from a solvent comprising an aliphatic alcohol, acetic acid or acetic anhydride or any mixture thereof with water.
  • the triflate compound of formula (5) prepared by the above process is converted to crude abiraterone-3 -acetate of formula (1) under conditions of Suzuki coupling reaction, preferably by reaction with a dialkyl(3-pyridyl)borane in an inert solvent in the presence of a catalytic amount of bis(triphenylphosphine)palladium(II)chloride.
  • the present invention relates to a process for making abiraterone-3 -acetate of formula (1) starting from dehydroepiandrosterone-3-acetate (DHEA) of formula (2).
  • DHEA dehydroepiandrosterone-3-acetate
  • Any of the known processes for making the compound of formula (5) comprises reaction of dehydroepiandrosterone-3 -acetate (DHEA) of formula (2) with a triflating agent such as trifluoromethanesulfonic anhydride in the presence of an organic base.
  • the reaction of the compound of formula (2) with a triflating agent may proceed even without a base or in the presence of an inorganic base.
  • the triflation reaction may even proceed under acidic conditions, e.g. in the presence of formic acid, acetic acid or acetanhydride.
  • the reaction of compound (2) with triflic anhydride in the absence of an organic base often exhibits a high degree of conversion without considerable formation of the elimination and deacetylation byproducts.
  • the present invention accordingly provides an improved process for making abiraterone-3 -acetate of formula (1), which includes a process for making the triflate compound of formula (5) in which dehydroepiandrosterone- 3 -acetate (DHEA- 3 -acetate) of formula (2) reacts with a triflating agent, preferably trifluoromethanesulfonic anhydride.
  • a triflating agent preferably trifluoromethanesulfonic anhydride
  • absence of an organic base means that no organic base is present in any starting material nor is added to the reaction mixture before, during or after the reactive contact between dehydroepiandrosterone-3 -acetate and triflating agent. The absence of an organic base does not preclude the presence of an inorganic base.
  • the starting material dehydroepiandrosterone- 3 -acetate of formula (2) is commercially available or may be produced by processes known in the art.
  • the compound of formula (2) may be prepared from dehydroepiandrosterone of formula (3) by reaction thereof with an acetylation agent, e.g. with acetic anhydride or an acetyl halide.
  • an acetylation agent e.g. with acetic anhydride or an acetyl halide.
  • the acetylation reaction may be performed using acetic anhydride, which also serves as the solvent, without need of any other inert solvent and/or diluent.
  • the compound of formula (2) does not need to be purified after acetylation of dehydroepiandrosterone of formula (3) with acetic anhydride, but may advantageously be used as a crude reaction mixture in the triflation process in accordance with the present invention.
  • a suitable inert solvent to be used in accordance with the process of the present invention typically is an aprotic organic solvent and preferably comprises, without limitation, an aliphatic acid ester, preferably having 2 to 10 carbon atoms; an aliphatic or aromatic hydrocarbon, preferably having 5 to 8 carbon atoms; or a chlorinated aliphatic or aromatic hydrocarbon, preferably having 1 to 8 carbon atoms, and mixtures thereof.
  • Suitable solvents include ethyl acetate, isopropyl acetate, dichloromethane, 1 ,2-dichloroethane, toluene, and mixtures thereof.
  • the preferred triflating agent is trifluoromethanesulfonic anhydride (triflic anhydride), which is commercially available. Preferably, it is used in a molar excess (5-150 molar excess) with respect to the compound of formula (2).
  • the concentration of the compound of formula (2) in the inert solvent is preferably higher than 0.3M, more preferably higher than 0.4M, and most preferably higher than 1.5M.
  • the triflation reaction typically proceeds at a lower than ambient temperature.
  • the reaction temperature is lower than 0°C, more preferably from -5 to -30°C, most preferably from -10 to -20°C.
  • the triflating agent is advantageously added slowly, e.g. portionwise, under temperature control, to the well-stirred mixture comprising the compound (2) in the inert solvent to avoid local overheating.
  • the course of reaction may be monitored by a suitable analytical technique, for instance by HPLC.
  • an inorganic base such as sodium or potassium carbonate or sodium or potassium acetate
  • an inorganic base may optionally be added to the reaction mixture, before and/or during the triflation reaction, in particular in the case when the above (crude) acidic reaction mixture comprising DHEA-3acetate is used as the starting material for the triflation reaction.
  • an inorganic base may react with the acetic acid or triflic acid arising from the reaction and neutralize the acid, it does neither react with the starting material nor with the desired end-product.
  • the relative molar amount of the inorganic base is advantageously at least equivalent to the molar amount of the acidic components in the reaction mixture such as acetate or trifluoromethanesulfonate moieties.
  • the reaction mixture is advantageously elaborated with the aim to remove side-products, particularly the resulting triflic acid.
  • the mixture is extracted with water, which may be optionally alkalinized, and the traces of water are removed by drying the organic phase.
  • the extractions may be performed at ambient or lower than ambient temperature.
  • the so-obtained solution of the crude triflate compound of formula (5) may be used in the next step as such if desired, or advantageously the triflate may be isolated therefrom by evaporation of the solvent.
  • the obtained triflate compound of formula (5) may be purified.
  • the purification is performed without using chromatographic separation.
  • the inert organic solvent is removed by evaporation and the residual material is crystallized from a suitable solvent, which may be an aliphatic alcohol having from 1 to 5 carbon atoms, e.g. methanol or, preferably, isopropanol, acetic acid, or acetic anhydride.
  • a suitable solvent which may be an aliphatic alcohol having from 1 to 5 carbon atoms, e.g. methanol or, preferably, isopropanol, acetic acid, or acetic anhydride.
  • the crude compound of formula (5) is dissolved in the crystallization solvent at an elevated temperature, which advantageously is a temperature from 40°C up to the boiling point of the solvent, the solution is optionally treated with a surface active material and/or filtered, and the hot solution is cooled to ambient or lower than ambient temperature.
  • seed crystals of compound (5) may be added.
  • an anti-solvent may be added to decrease the solubility of the product.
  • the obtained solid, typically crystalline triflate is isolated by filtration or centrifugation, and optionally dried.
  • the triflate compound of formula (5) or a solution comprising it is used in the next step without delay; otherwise it may be stored for certain time in a closed container protected from light and, preferably, at a temperature well below 0°C.
  • the triflate compound of formula (5) prepared by the above process is converted into crude abiraterone-3 -acetate of formula (1) under conditions of the Suzuki coupling reaction.
  • the conditions of the Suzuki coupling reaction on the compound of formula (5) are well- known in the art and were disclosed in the prior art documents cited above.
  • diethyl(3-pyridyl)borane is added to the isolated triflate compound (5) in a suitable solvent, e.g. in tetrahydrofuran, containing a catalytic amount of bis(triphenylphosphine)- palladium(II) dichloride and sodium carbonate as a nucleophilic activator.
  • the reaction proceeds by stirring the mixture at an elevated temperature (typically at 60-90°C) and may be followed by a suitable analytical technique, for instance by HPLC. After termination of the reaction, the reaction mixture is worked-up with the aim to isolate crude abiraterone-3 - acetate. Typically, the mixture is partitioned between ethyl acetate and water; the organic layer is separated, and the solvent is evaporated.
  • an elevated temperature typically at 60-90°C
  • HPLC HPLC
  • the resulting crude abiraterone-3 -acetate still comprises some unreacted starting material (typically less than 10%) and traces of other impurities. It may be purified by converting it to an acid addition salt. While the prior art documents suggest using methanesulfonic acid as the best acid for said purposes, in the context of the present invention the use of ethanesulfonic (esylic) acid is preferred. This acid forms the esylate salt of abiraterone-3 -acetate in a good yield and superior purity. Such salt is insoluble in non-polar or low polar organic solvents and may be easily separated by precipitation and filtration.
  • the salt of abiraterone-3 -acetate with ethanesulfonic acid is obtained in an isolated, solid state.
  • Impurities, which do not comprise the pyridine moiety, such as the starting material or the intermediate, unreacted triflate, remain dissolved.
  • the crude abiraterone-3 -acetate is dissolved in a suitable solvent, which preferably is an aliphatic ester, such as ethyl acetate, an ether, such as methyl tert-butyl ether, and mixtures thereof.
  • a suitable solvent which preferably is an aliphatic ester, such as ethyl acetate, an ether, such as methyl tert-butyl ether, and mixtures thereof.
  • ethanesulfonic acid is added upon stirring, typically at ambient temperature.
  • the ethanesulfonate (esylate) salt precipitates from the solution and may be easily isolated by filtration.
  • the esylate salt may be recrystallized from a suitable solvent, for instance from acetonitrile or an aliphatic alcohol, such as isopropanol.
  • the purity of the esylate salt may reach at least 97% (HPLC, internal normalization (IN)), advantageously at least 98%, and in some embodiments at least 99%.
  • pure abiraterone- 3 -acetate is made starting from the esylate salt.
  • the esylate salt is dissolved or suspended in a solvent which is not miscible with water, such as a chlorinated hydrocarbon, for instance
  • aqueous base for instance saturated aqueous sodium carbonate or saturated aqueous sodium acetate.
  • aqueous phase is then removed.
  • Concentration of the organic phase and triturating the residue with a useful liquid vehicle such as with an aliphatic hydrocarbon, for instance a hexane or a heptane, or with an ethanol/water mixture, gives a suspension of the desired product.
  • the solid is separated by ordinary techniques, e.g. by filtration or centrifugation, washed, and dried.
  • the process of forming the salt and liberating the compound (1) from the salt may be repeated until the desired purity is obtained.
  • reaction mixture was diluted with dichloromethane (100 ml) and was extracted two times with 1M aqueous solution of sodium carbonate (2x 200 ml). The reaction mixture was allowed to heat to ambient temperature during extractions.
  • Trifluoromethanesulfonic anhydride (0.544 ml, 3.78 mmol) was added portionwise to the reaction mixture over 20 minutes at -15°C. The mixture was stirred at -15°C for 1.5 hours, and then diluted with 2 ml of dichloromethane. The mixture was extracted with 2 x 7 ml of 1M sodium carbonate, 2x 10 ml of wate,r and 10 ml of brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated to dryness on rotavap to constant weight. Yield: 1.35 g (85%), conversion 86% (HPLC).
  • Dehydroepiandrosterone-3-acetate (10 g, 30.3 mmol) was diluted with toluene (40 ml) and benzene (1 ml). Potassium carbonate (8.36 g, 60.5 mmol) was added, and the mixture was stirred for 0.5 h at 25°C. The mixture was cooled to -15°C, trifluoromethanesulfonic anhydride (7.17 ml, 42.4 mmol) was dosed over 20 min, and the whole mixture was stirred at -15 to -18°C for 20 h. The reaction mixture was diluted with water (70 ml), and then with toluene (40 ml).
  • Dehydroepiandrosterone-3-acetate (1 g, 3.03 mmol) was diluted with dichloromethane (8 ml) and toluene (0.1 ml). Potassium carbonate (1.673 g, 12.10 mmol) and acetic acid (0.207 ml, 3.63 mmol) were added, and the mixture was stirred for 0.5 h at 25°C. The mixture was cooled to -15°C and trifluoromethanesulfonic anhydride (1.739 ml, 10.3 mmol) was added in 3 portions. The mixture was stirred at -15 to -18°C for 11 h. The reaction mixture was diluted with water (7 ml), and then with toluene (7 ml).
  • Dehydroepiandrosterone-3-acetate (1 g, 3.03 mmol) was diluted with dichloromethane (6 ml) and toluene (0.1 ml). Potassium carbonate (1.673 g, 12.10 mmol) and acetic anhydride (0.286 ml, 3.03 mmol) were added, and the mixture was stirred for 0.5 h at 25°C. The mixture was cooled to -15°C and trifluoromethanesulfonic anhydride (1.739 ml, 10.3 mmol) was added in 3 portions. The mixture was stirred at -15 to -18°C for 11 h. The reaction mixture was diluted with water (7 ml) and then with toluene (7 ml).

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Abstract

The present invention relates to a process for making the compound 3β-acetoxy- androsta-5,16-dien-17-yl trifluoromethanesulfonate of formula (5) and is characterized in that dehydroepiandrosterone-3-acetate of formula (2) is reacted with a triflating agent, preferably trifluoromethanesulfonic anhydride, in an inert solvent in the absence of an organic base.

Description

PROCESS FOR MAKING THE 17-TRIFLATE INTERMEDIATE OF
ABIRATERONE-3-ACETATE
Abiraterone-3 -acetate (3P-acetoxy-17-(3-pyridyl)androsta-5,16-diene) of formula (1)
is a pharmaceutically active compound used for the treatment of metastatic castration- resistant prostate cancer. It is sold under the trade name Zytiga by Johnson and Johnson.
The compound was discovered in 1990 at the Institute of Cancer Research UK and is disclosed in WO 93/20097.
The basic process for making abiraterone-3 -acetate disclosed in WO 93/20097 comprises
= replacing the enol-form of the 17-oxo group in dehydroepiandrosterone- 3 -acetate (DHEA acetate) of formula (2)
by a leaving group L, which is capable of being replaced by a 3-pyridyl group in a palladium(O) complex-catalyzed cross-coupling reaction with a 3-pyridinyl (dialkyl/ dialkoxy) -boron compound (so called Suzuki coupling reaction)
= carrying out said Suzuki coupling reaction. The palladium complex in Suzuki coupling reaction is preferably a palladium(O) complex such as tetrakis(triphenylphosphine)palladium(0) or a complex reducible in situ to such palladium(0)phosphine species.
The leaving groups L actually used in prior art documents were an iodo group and a trifluoromethanesulfonate (triflate) group.
The first known route employing the iodo-leaving group has been elaborated in WO 95/09178 and is shown in the Scheme below. In an important aspect, the 3-acetate group may be introduced only after introducing the 17-(3-pyridyl)- group, thus the actual starting material is not the compound of formula (2) but dehydroepiandrosterone (DHEA) of formula (3). The compound of formula (3) is converted to the corresponding iodo-compound of formula (4) in two steps; subsequently, after performing the Suzuki coupling reaction on compound (4), abiraterone of formula (1A) is obtained. In the final step, abiraterone (1A) is acetylated to the desired abiraterone-3 -acetate.
The second known route employing the triflate leaving group L is two steps shorter and thus more advantageous. The triflate intermediate compound of formula (5)
was prepared in WO 93/20097 by contacting DHEA acetate of formula (2) with trifluoromethanesulfonic (triflic) anhydride in dichloromethane in the presence of a molar amount of the organic base 2,6-di-t-butyl-4-methylpyridine. The reaction gave, after chromatographic separation, the desired triflate product of formula (5) in 58% yield, and also de-acetylated product of elimination of formula (6) in 10% yield.
In the second step, diethyl(3-pyridyl)borane was added to the isolated triflate compound of formula (5) in THF containing a catalytic amount of
bis(triphenylphosphine)palladium(II) chloride and sodium carbonate as a nucleophilic activator. After extraction and chromatography, the desired compound of formula (1) was obtained as a free base in 84% yield and was recrystallized from hexane.
As disclosed in WO 2006/021776, the elimination byproducts cannot be removed by recrystallization in either step, i.e. both as the originally formed triflate by-product of formula (6) and as subsequently formed dehydroabiraterone of formula (IB), resp.
Therefore column chromatography was required after both steps of the original process.
WO 2006/021776 and WO 2006/021777 suggest two improvements in the original process. In a first improvement, the triflating step is advantageously conducted in the presence of an organic base comprising a tertiary or heterocyclic amine having a pKa value of the conjugate acid at 25°C within the range of 5.21 (i.e. pyridine) to 12 (i.e DBU, a diazabicycloundecene). By using such base, the amount of the elimination by-product of formula (6) is minimized to an acceptable level. Furthermore, it was found that if the base had a relatively low pKa, it gave bad results because of a competing deacetylation reaction. E.g. Ν,Ν-diethylaniline having pKa 5.20 (and, to certain extent, also pyridine having pKa 5.21) gave the deacetylated product of formula (3) as the major product.
Instead of the undesired impurities of formula (6) and (3), resp., some unreacted starting material (2) remains in the reaction mixture both after the triflation reaction and after the Suzuki coupling reaction (approx. 1:3 in respect to the desired product) in the above process of WO'776 and WO'777, resp. In a second improvement, this starting material may be removed from the reaction mixture by converting the product (1) to an acid addition salt, separating the salt in solid state and recrystallizing the salt. The mesylate salt of (1) was described to be the most advantageous salt in WO'776. Such salt may be obtained from a solution of the free base of (1) in a suitable solvent, e.g. in an ester and/or an ether solvent, preferably in ethyl acetate and/or methyl t-butyl ether, by treatment with methanesulfonic acid. Similarly, a hydrochloride, sulfate or toluyltartrate salt of (1) may be prepared. The salts may be converted to the free base almost quantitatively.
While several processes of making abiraterone-3 -acetate are known in prior art documents, an improvement in the matter is still desirable. In particular, it is desired to improve the process of making the key triflate intermediate of formula (5). BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to an improved process for making the compound 3β- acetoxy-androsta-5,16-dien-17-yl trifluoromethanesulfonate of formula (5), which is an important intermediate in making abiraterone-3 -acetate of formula (1).
In the main aspect, the invention provides a process for making the compound of formula (5)
comprising reacting dehydroepiandrosterone-3 -acetate of formula (2)
with a inflating agent, preferably trifluoromethanesulfonic anhydride, in an inert solvent in the absence of an organic base.
In an advantageous embodiment, the inert solvent comprises an aliphatic acid ester, preferably having 2 to 10 carbon atoms, an aliphatic or aromatic hydrocarbon, preferably having 5 to 8 carbon atoms or a chlorinated aliphatic or aromatic hydrocarbon, preferably having 1 to 8 carbon atoms, and mixtures thereof. In particular, the concentration of the compound (2) in the solvent is higher than 0.3M, preferably higher than 1.5M.
In particular, the reaction temperature is lower than 0°C, preferably from -5 to -30°C, most preferably from -10 to -20°C.
In an advantageous aspect, the dehydroepiandrosterone-3 -acetate of formula (2) is prepared by reaction of dehydroepiandrosterone of formula (3) with acetic anhydride, and the so-obtained crude reaction mixture is used as the starting material for the reaction with the triflating agent.
The reaction is carried out either in the absence of a base or in the presence of an inorganic base, preferably sodium or potassium carbonate.
The triflate of formula (5) may be advantageously isolated from the reaction mixture, and the crude triflate may be purified by crystallization from a suitable solvent. A suitable crystallization solvent is an aliphatic alcohol, e.g. methanol or isopropanol, acetic acid, acetic anhydride or any mixture thereof with water.
Thus, in a second aspect, the invention provides a process for purification of the compound of formula (5), comprising crystallizing the compound of formula (5) from a solvent comprising an aliphatic alcohol, acetic acid or acetic anhydride or any mixture thereof with water.
The triflate compound of formula (5) prepared by the above process is converted to crude abiraterone-3 -acetate of formula (1) under conditions of Suzuki coupling reaction, preferably by reaction with a dialkyl(3-pyridyl)borane in an inert solvent in the presence of a catalytic amount of bis(triphenylphosphine)palladium(II)chloride.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a process for making abiraterone-3 -acetate of formula (1) starting from dehydroepiandrosterone-3-acetate (DHEA) of formula (2). In particular, it relates to an improved process for making the key intermediate in said process, the compound 3 -acetoxy-androsta-5,16-dien-17-yl trifluoromethanesulfonate of formula (5). Any of the known processes for making the compound of formula (5) comprises reaction of dehydroepiandrosterone-3 -acetate (DHEA) of formula (2) with a triflating agent such as trifluoromethanesulfonic anhydride in the presence of an organic base. It has been taught in prior art documents that the presence of the relatively strong organic base 2,6-di-t- butyl-4-methylpyridine (pK 4.41) in said process is associated with the formation of a considerable amount of the by-product of formula (6), caused by an elimination reaction of the 3-acetoxy group. In a later improvement, the formation of the elimination by-product was suppressed by using relatively weak organic bases for said purpose, with pKa of their conjugated acids higher than 5.21; instead, however, the reaction mixture comprised a relatively high amount of the unreacted starting material of formula (2). When repeating the known triflation reaction using triethylamine (pKa of 10.8), which was considered as the most preferred organic base in the prior art, it was found that the reaction product comprised 7.4% of unreacted starting material and only 67.2% of the desired triflate. As this starting material of formula (2) can be removed from the desired product in a later purification step, such modification based on the use of relatively weak organic bases may be considered as being advantageous over the original process. However, incomplete conversion of the relatively expensive starting material, associated with accordingly lower yield of the desired product, still represents an economical disadvantage.
The present inventors found, with surprise, that the reaction of the compound of formula (2) with a triflating agent, typically with triflic anhydride, may proceed even without a base or in the presence of an inorganic base. Moreover, the triflation reaction may even proceed under acidic conditions, e.g. in the presence of formic acid, acetic acid or acetanhydride. Notably, it is possible and advantageous to use the crude reaction mixture comprising the compound of formula (2), i.e. an essentially acidic reaction mixture resulting from acetylation of dehydroepiandrosterone of formula (3) with acetic anhydride, as the starting material for the triflation reaction. The reaction of compound (2) with triflic anhydride in the absence of an organic base often exhibits a high degree of conversion without considerable formation of the elimination and deacetylation byproducts.
Furthermore, a prolonged stirring of the reaction mixture does not cause a drop in the yield of the triflate product, which is typically observed when the reaction is performed in the presence of an organic base.
The present invention accordingly provides an improved process for making abiraterone-3 -acetate of formula (1), which includes a process for making the triflate compound of formula (5) in which dehydroepiandrosterone- 3 -acetate (DHEA- 3 -acetate) of formula (2) reacts with a triflating agent, preferably trifluoromethanesulfonic anhydride. The invented process for making the compound of formula (5) is characterized in that dehydroepiandrosterone-3-acetate of formula (2) is reacted with a triflating agent, preferably trifluoromethanesulfonic anhydride, in an inert solvent in the absence of an organic base.
The term "absence of an organic base" means that no organic base is present in any starting material nor is added to the reaction mixture before, during or after the reactive contact between dehydroepiandrosterone-3 -acetate and triflating agent. The absence of an organic base does not preclude the presence of an inorganic base.
It should be understood that the structure of the compound of formula (2) shown in this specification represents only one of two possible tautomeric forms with respect to the 17-oxo group; the compound dehydroepiandrosterone- 3 -acetate may also exist as an enol. It is to be understood that the invention is not limited merely to one tautomeric form which is illustrated.
The starting material dehydroepiandrosterone- 3 -acetate of formula (2) is commercially available or may be produced by processes known in the art. For instance, the compound of formula (2) may be prepared from dehydroepiandrosterone of formula (3) by reaction thereof with an acetylation agent, e.g. with acetic anhydride or an acetyl halide. Advantageously, the acetylation reaction may be performed using acetic anhydride, which also serves as the solvent, without need of any other inert solvent and/or diluent.
In a specific aspect of the present invention, the compound of formula (2) does not need to be purified after acetylation of dehydroepiandrosterone of formula (3) with acetic anhydride, but may advantageously be used as a crude reaction mixture in the triflation process in accordance with the present invention.
A suitable inert solvent to be used in accordance with the process of the present invention typically is an aprotic organic solvent and preferably comprises, without limitation, an aliphatic acid ester, preferably having 2 to 10 carbon atoms; an aliphatic or aromatic hydrocarbon, preferably having 5 to 8 carbon atoms; or a chlorinated aliphatic or aromatic hydrocarbon, preferably having 1 to 8 carbon atoms, and mixtures thereof. Suitable solvents include ethyl acetate, isopropyl acetate, dichloromethane, 1 ,2-dichloroethane, toluene, and mixtures thereof.
The preferred triflating agent is trifluoromethanesulfonic anhydride (triflic anhydride), which is commercially available. Preferably, it is used in a molar excess (5-150 molar excess) with respect to the compound of formula (2).
The concentration of the compound of formula (2) in the inert solvent is preferably higher than 0.3M, more preferably higher than 0.4M, and most preferably higher than 1.5M.
The triflation reaction typically proceeds at a lower than ambient temperature.
Preferably, the reaction temperature is lower than 0°C, more preferably from -5 to -30°C, most preferably from -10 to -20°C. The triflating agent is advantageously added slowly, e.g. portionwise, under temperature control, to the well-stirred mixture comprising the compound (2) in the inert solvent to avoid local overheating. Advantageously, the course of reaction may be monitored by a suitable analytical technique, for instance by HPLC.
While an organic base is absent in the process of the present invention, an inorganic base, such as sodium or potassium carbonate or sodium or potassium acetate, may optionally be added to the reaction mixture, before and/or during the triflation reaction, in particular in the case when the above (crude) acidic reaction mixture comprising DHEA-3acetate is used as the starting material for the triflation reaction. While such inorganic base may react with the acetic acid or triflic acid arising from the reaction and neutralize the acid, it does neither react with the starting material nor with the desired end-product. The relative molar amount of the inorganic base is advantageously at least equivalent to the molar amount of the acidic components in the reaction mixture such as acetate or trifluoromethanesulfonate moieties.
After termination of the triflation reaction, the reaction mixture is advantageously elaborated with the aim to remove side-products, particularly the resulting triflic acid.
Typically, the mixture is extracted with water, which may be optionally alkalinized, and the traces of water are removed by drying the organic phase. The extractions may be performed at ambient or lower than ambient temperature.
The so-obtained solution of the crude triflate compound of formula (5) may be used in the next step as such if desired, or advantageously the triflate may be isolated therefrom by evaporation of the solvent.
The obtained triflate compound of formula (5) may be purified. Advantageously, the purification is performed without using chromatographic separation. In a suitable arrangement, the inert organic solvent is removed by evaporation and the residual material is crystallized from a suitable solvent, which may be an aliphatic alcohol having from 1 to 5 carbon atoms, e.g. methanol or, preferably, isopropanol, acetic acid, or acetic anhydride. In general, the crude compound of formula (5) is dissolved in the crystallization solvent at an elevated temperature, which advantageously is a temperature from 40°C up to the boiling point of the solvent, the solution is optionally treated with a surface active material and/or filtered, and the hot solution is cooled to ambient or lower than ambient temperature.
Optionally, seed crystals of compound (5) may be added. Yet optionally, an anti-solvent may be added to decrease the solubility of the product. The obtained solid, typically crystalline triflate is isolated by filtration or centrifugation, and optionally dried.
Until now, the only useful process for purification of the compound (5) was by means of chromatographic separation. The crystallization process in accordance with the present invention is simpler and may be easily performed on a large batch industrial scale. The above-mentioned crystallization solvents allow for an effective removal of both the products of undesired elimination and deacetylation at position 3, which are the most common and undesired impurities in the crude triflate product (as both of them can cause formation of difficultly removable side-products in the next stage).
It should be understood that the use of the above-mentioned crystallization process is not limited to the crude product prepared by the above triflation reaction process. It may be employed for purification of crude compound (5) prepared by any prior art procedure.
It is advantageous that the triflate compound of formula (5) or a solution comprising it, is used in the next step without delay; otherwise it may be stored for certain time in a closed container protected from light and, preferably, at a temperature well below 0°C.
The triflate compound of formula (5) prepared by the above process is converted into crude abiraterone-3 -acetate of formula (1) under conditions of the Suzuki coupling reaction. The conditions of the Suzuki coupling reaction on the compound of formula (5) are well- known in the art and were disclosed in the prior art documents cited above. Typically, diethyl(3-pyridyl)borane is added to the isolated triflate compound (5) in a suitable solvent, e.g. in tetrahydrofuran, containing a catalytic amount of bis(triphenylphosphine)- palladium(II) dichloride and sodium carbonate as a nucleophilic activator. The reaction proceeds by stirring the mixture at an elevated temperature (typically at 60-90°C) and may be followed by a suitable analytical technique, for instance by HPLC. After termination of the reaction, the reaction mixture is worked-up with the aim to isolate crude abiraterone-3 - acetate. Typically, the mixture is partitioned between ethyl acetate and water; the organic layer is separated, and the solvent is evaporated.
The resulting crude abiraterone-3 -acetate still comprises some unreacted starting material (typically less than 10%) and traces of other impurities. It may be purified by converting it to an acid addition salt. While the prior art documents suggest using methanesulfonic acid as the best acid for said purposes, in the context of the present invention the use of ethanesulfonic (esylic) acid is preferred. This acid forms the esylate salt of abiraterone-3 -acetate in a good yield and superior purity. Such salt is insoluble in non-polar or low polar organic solvents and may be easily separated by precipitation and filtration. Thereby, the salt of abiraterone-3 -acetate with ethanesulfonic acid is obtained in an isolated, solid state. Impurities, which do not comprise the pyridine moiety, such as the starting material or the intermediate, unreacted triflate, remain dissolved.
Thus, the crude abiraterone-3 -acetate is dissolved in a suitable solvent, which preferably is an aliphatic ester, such as ethyl acetate, an ether, such as methyl tert-butyl ether, and mixtures thereof. To the solution, ethanesulfonic acid is added upon stirring, typically at ambient temperature. The ethanesulfonate (esylate) salt precipitates from the solution and may be easily isolated by filtration. If necessary or advantageous, the esylate salt may be recrystallized from a suitable solvent, for instance from acetonitrile or an aliphatic alcohol, such as isopropanol.
Typically, the purity of the esylate salt may reach at least 97% (HPLC, internal normalization (IN)), advantageously at least 98%, and in some embodiments at least 99%. In the last step, pure abiraterone- 3 -acetate is made starting from the esylate salt.
In a less preferred alternative, the esylate salt is dissolved or suspended in a solvent which is not miscible with water, such as a chlorinated hydrocarbon, for instance
dichloromethane, and the mixture is treated with an equivalent amount of an aqueous base, for instance saturated aqueous sodium carbonate or saturated aqueous sodium acetate. The aqueous phase is then removed. Concentration of the organic phase and triturating the residue with a useful liquid vehicle, such as with an aliphatic hydrocarbon, for instance a hexane or a heptane, or with an ethanol/water mixture, gives a suspension of the desired product.
The solid is separated by ordinary techniques, e.g. by filtration or centrifugation, washed, and dried.
If necessary, the process of forming the salt and liberating the compound (1) from the salt may be repeated until the desired purity is obtained.
The invention is further illustrated by the following examples.
EXAMPLES
Example 1
A suspension of dehydroepiandrosterone (10 g, 34.3 mmol) and acetic anhydride (6.48 ml, 68.6 mmol) was heated under mechanical stirring under argon to 105°C to give a solution. The stirring was continued at a temperature of 105-110°C for 2 h. Then, the reaction mixture was diluted with water (50 ml), and the suspension was cooled to 25 °C, and filtered. The filter cake was washed with water (50 ml), and dried in a drier (40°C, 130 mbar, N2 bleed, 20 hours). Yield 11.0 g (97%), conversion 99% (HPLC), purity 99.14% (LC IN).
A solution of dehydroepiandrosterone-3-acetate (50 g, 151 mmol), dichloromethane (100 ml) and toluene (5.00 ml used as internal standard (IS)) was cooled under mechanical stirring under argon to -15°C. Trifluoromethanesulfonic anhydride (47.0 g, 166 mmol) was added dropwise during 20 min at -15 to -13°C. Stirring was continued at -15 to -13°C for 3.5 h with analytical control (HPLC IS).
The reaction mixture was diluted with dichloromethane (100 ml) and was extracted two times with 1M aqueous solution of sodium carbonate (2x 200 ml). The reaction mixture was allowed to heat to ambient temperature during extractions.
The combined aqueous layers were extracted with dichloromethane (100 ml).
Combined organic layers were washed with water (2 x 300 ml), followed with brine (100 ml), and dried with sodium sulphate. The volatiles were removed in vacuo (-10 mbar; 50°C) to afford 65.7 g of dark red oil. The oil was diluted with n-heptane (250 ml), the mixture was filtered and the filter cake was washed with n-heptane (80 ml). The combined solution was concentrated to constant weight (-10 mbar; 50°C). Yield: 63 g (90%), conversion 92% (HPLC).
Example 2
A suspension of dehydroepiandrosterone (lg, 3.43 mmol) and acetic anhydride (0.648 ml, 5.86 mmol) was heated (105-110°C) with stirring for 2 hours under argon atmosphere. The reaction mixture was subsequently cooled to 25 °C and diluted with dichloromethane (2 ml) and toluene (0.1 ml). Resulting solution was then cooled to -15°C under stirring.
Trifluoromethanesulfonic anhydride (0.544 ml, 3.78 mmol) was added portionwise to the reaction mixture over 20 minutes at -15°C. The mixture was stirred at -15°C for 1.5 hours, and then diluted with 2 ml of dichloromethane. The mixture was extracted with 2 x 7 ml of 1M sodium carbonate, 2x 10 ml of wate,r and 10 ml of brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated to dryness on rotavap to constant weight. Yield: 1.35 g (85%), conversion 86% (HPLC). Example 3
Dehydroepiandrosterone-3-acetate (10 g, 30.3 mmol) was diluted with toluene (40 ml) and benzene (1 ml). Potassium carbonate (8.36 g, 60.5 mmol) was added, and the mixture was stirred for 0.5 h at 25°C. The mixture was cooled to -15°C, trifluoromethanesulfonic anhydride (7.17 ml, 42.4 mmol) was dosed over 20 min, and the whole mixture was stirred at -15 to -18°C for 20 h. The reaction mixture was diluted with water (70 ml), and then with toluene (40 ml). The organic phase was separated, washed with 1M Na2CC>3 (70 ml), water (2x 50 ml), and brine (70 ml). The combined organic layer was dried with MgS04, filtered, and concentrated to dryness to constant mass (13.43 g) giving an oil. Yield: 96%, conversion 93% (HPLC).
Example 4
Dehydroepiandrosterone-3-acetate (1 g, 3.03 mmol) was diluted with dichloromethane (8 ml) and toluene (0.1 ml). Potassium carbonate (1.673 g, 12.10 mmol) and acetic acid (0.207 ml, 3.63 mmol) were added, and the mixture was stirred for 0.5 h at 25°C. The mixture was cooled to -15°C and trifluoromethanesulfonic anhydride (1.739 ml, 10.3 mmol) was added in 3 portions. The mixture was stirred at -15 to -18°C for 11 h. The reaction mixture was diluted with water (7 ml), and then with toluene (7 ml). The separated organic phase was washed with 1M Na2C03 (7 ml), water (7 ml), brine (10 ml), dried with MgS04, filtered, and concentrated to dryness (1.32 g). Yield: 94%, conversion 97% (HPLC).
Example 5
Dehydroepiandrosterone-3-acetate (1 g, 3.03 mmol) was diluted with dichloromethane (6 ml) and toluene (0.1 ml). Potassium carbonate (1.673 g, 12.10 mmol) and acetic anhydride (0.286 ml, 3.03 mmol) were added, and the mixture was stirred for 0.5 h at 25°C. The mixture was cooled to -15°C and trifluoromethanesulfonic anhydride (1.739 ml, 10.3 mmol) was added in 3 portions. The mixture was stirred at -15 to -18°C for 11 h. The reaction mixture was diluted with water (7 ml) and then with toluene (7 ml). The separated organic phase was washed with 1M Na2CC>3 (7 ml), water (7 ml), brine (10 ml), dried with MgS04, filtered, and concentrated to dryness (1.25 g) giving a brown oil, which completely crystallised within 0.5 h. Yield: 88%, conversion 94% (HPLC).
Example 6
A suspension of dehydroepiandrosterone (1 g, 3.43 mmol) and acetic anhydride (0.648 ml, 6.86 mmol) was heated (105-120°C) with stirring for 2 h under argon atmosphere. The reaction mixture was then cooled to 25°C, and diluted with dichloromethane (3 ml) and toluene (0.1 ml). Potassium carbonate (0.956 g, 6.92 mmol) was added and the mixture was stirred for 0.5 h at 25°C, and then cooled to -15°C. Trifluoromethanesulfonic anhydride (0.844 ml, 4.98 mmol) was added in 2 portions. The mixture was stirred at -15°C for 6 h. The mixture was then diluted with dichloromethane (20 ml) and extracted with 1M Na2C03 (2x 7 ml), water (2x 10 ml), and brine (10 ml). The organic layer was dried with MgS04, filtered, and concentrated to dryness on rotavap to constant weight (1.37 g). Yield: 86%, conversion 95% (HPLC).
Example 7
Crude compound (5) (7.290 g, 13.00 mmol, 82.5% assay (HPLC)) was charged in a 50 ml round-bottomed flask equipped with a magnetic stirring bar, and 2-propanol (21 ml) was added. The reaction mixture was heated to 50°C under stirring, and was cooled to 25 °C overnight. The crystalline slurry was filtered, washed with 3 ml of MeOH, and dried in a drier (40°C, 130 mbar, N2 bleed, 3 hours). Yield: 3.03 g.
The mother liquor was concentrated to dryness on rotavap (-100 mbar; 50°C) to give 4.247 g. The residue was diluted with 2-propanol (21 ml), heated to dissolution (~ 40°C), and cooled to -15°C. The crystalline slurry was filtered, washed with 3 ml pre-cooled 2-propanol, and dried in a drier (40 °C, 130 mbar, N2 bleed, 3 hours). Yield: 2,351 g.
Combined crop was analysed by HPLC. Content of the elimination by-product was less than 0.1 %, content of the deacetylation by-product was less than 0.1 %, largest unknown impurity was 0.2% (HPLC IN).

Claims

1. A process for making the compound 3P-acetoxy-androsta-5,16-dien-17-yl
trifluoromethanesulfonate of formula (5)
comprising reacting dehydroepiandrosterone-3 -acetate of formula (2)
with a triflating agent, preferably trifluoromethanesulfonic anhydride, in an inert solvent in the absence of an organic base.
2. The process according to claim 1 , wherein the inert solvent comprises an aliphatic acid ester, preferably having from 2 to 10 carbon atoms, an aliphatic or aromatic hydrocarbon, preferably having from 5 to 8 carbon atoms, or a chlorinated aliphatic or aromatic hydrocarbon, preferably having from 1 to 8 carbon atoms, and mixtures thereof.
3. The process according to claim 1 or 2, wherein the concentration of the compound of formula (2) in the inert solvent is higher than 0.3M, preferably higher than 0.4M.
4. The process according to any one of claims 1-3, wherein the reaction temperature is lower than 0°C, preferably from -5 to -30°C.
5. The process according to any one of claims 1-4, wherein the triflating agent is added portionwise to the stirred reaction mixture.
6. The process according to any one of claims 1-5, wherein the dehydroepiandrosterone-3- acetate of formula (2) is prepared by a reaction of dehydroepiandrosterone of formula (3) with acetic anhydride, and the crude reaction mixture is used as the starting material for the reaction with the triflating agent.
7. The process according to any one of claims 1-6, wherein an inorganic base, preferably sodium or potassium carbonate is used during the triflation reaction.
8. The process according to any one of claims 1-7, wherein the triflation reaction is
carried out under acidic conditions, in the presence of formic acid, acetic acid or acetanhydride.
9. The process according to any one of claims 1-8, wherein the triflate of formula (5) is isolated from the reaction mixture by crystallization from a suitable solvent.
10. The process according to claim 9, wherein the crystallization solvent comprises an aliphatic alcohol having from 1 to 5 carbon atoms, acetic acid, acetic anhydride, or mixtures thereof.
11. A process for the purification of 3 -acetoxy-androsta-5,16-dien-17-yl trifluoromethane- sulfonate of formula (5) comprising crystallizing the compound of formula (5) from a solvent comprising, alone or in combination, an aliphatic alcohol having from 1 to 5 carbon atoms, acetic acid or acetanhydride.
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