CA2890589A1 - Process for making abiraterone-3-acetate - Google Patents
Process for making abiraterone-3-acetate Download PDFInfo
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- CA2890589A1 CA2890589A1 CA2890589A CA2890589A CA2890589A1 CA 2890589 A1 CA2890589 A1 CA 2890589A1 CA 2890589 A CA2890589 A CA 2890589A CA 2890589 A CA2890589 A CA 2890589A CA 2890589 A1 CA2890589 A1 CA 2890589A1
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- esylate
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/006—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton spiro-condensed
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Abstract
The present invention relates to an improved 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 of converting the 17- triflate compound of formula (5) into abiraterone-3-acetate (1) in 2- methyl-THF as the solvent and producing a product of high purity via its acid addition salt abiraterone-3-acetate esylate (1A).
Description
Abiraterone-3-acetate (33-acetoxy-17-(3-pyridyl)androsta-5,16-diene) of formula (1) N
/
CH
CH 0*
H3C 0 (1) is a pharmaceutically active compound used for the treatment of metastatic castration-resistant prostate cancer. It is sold under 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 17-oxo group in dehydroepiandrosterone-3-acetate (DHEA
acetate) of formula (2) CH
H3C5( 0 (2) by a leaving group L, which is capable of being replaced by a 3-pyridyl group in a palladium(0) complex-catalyzed cross-coupling reaction with a 3-pyridyl (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(0) 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 (WO
95/09178) and a trifluoromethanesulfonate (triflate) group (WO 93/20097). The route employing the triflate group is shorter and thus more advantageous.
The triflate intermediate compound of formula (5) F
O-S
CH %% F
CH O.
*0 H3C 0 (5) was prepared in WO 93/20097 by contacting DHEA acetate of formula (2) with trifluoromethane sulfonic (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.
OF
CH %% F
CH Ogic 0 w (6) 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.
/
CH
CH 0*
H3C 0 (1) is a pharmaceutically active compound used for the treatment of metastatic castration-resistant prostate cancer. It is sold under 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 17-oxo group in dehydroepiandrosterone-3-acetate (DHEA
acetate) of formula (2) CH
H3C5( 0 (2) by a leaving group L, which is capable of being replaced by a 3-pyridyl group in a palladium(0) complex-catalyzed cross-coupling reaction with a 3-pyridyl (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(0) 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 (WO
95/09178) and a trifluoromethanesulfonate (triflate) group (WO 93/20097). The route employing the triflate group is shorter and thus more advantageous.
The triflate intermediate compound of formula (5) F
O-S
CH %% F
CH O.
*0 H3C 0 (5) was prepared in WO 93/20097 by contacting DHEA acetate of formula (2) with trifluoromethane sulfonic (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.
OF
CH %% F
CH Ogic 0 w (6) 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.
2 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 (1B), resp.
N
/
CH
CH 0*
(1B) Therefore column chromatography was required after both steps of the original process.
WO 2006/021776 and parallel WO 2006/021777 suggest two improvements of the original process.
In the 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, diazabicyclo-undecene). 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. N,N-diethylaniline of pKa 5.20 (and, to a certain extent, also pyridine having pKa 5.21) gave the deacetylated product of formula (3) CH
CH 0.
*0 Pi HO (3) as the major product. Bases having a pKa higher than 5.21 do not exhibit formation of the deacetylated product of formula (3).
While the amount of undesired impurities of formula (6) and (3) may be suppressed by using organic bases with pKa higher than 5.21, such bases have the disadvantage that
N
/
CH
CH 0*
(1B) Therefore column chromatography was required after both steps of the original process.
WO 2006/021776 and parallel WO 2006/021777 suggest two improvements of the original process.
In the 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, diazabicyclo-undecene). 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. N,N-diethylaniline of pKa 5.20 (and, to a certain extent, also pyridine having pKa 5.21) gave the deacetylated product of formula (3) CH
CH 0.
*0 Pi HO (3) as the major product. Bases having a pKa higher than 5.21 do not exhibit formation of the deacetylated product of formula (3).
While the amount of undesired impurities of formula (6) and (3) may be suppressed by using organic bases with pKa higher than 5.21, such bases have the disadvantage that
3
4 unreacted starting material (2) remains in the reaction mixture both after the triflation reaction and after the Suzuki coupling reaction (up to approx. 1: 3 with respect to the desired product) in the above process.
According to the second improvement suggested in WO'776 and WO'777 this starting material may be removed from the reaction mixture after performing the Suzuki coupling reaction by reacting the obtained and isolated mixed product comprising abiraterone-3-acetate of formula (1) with a suitable acid. While abiraterone-3-acetate is thereby converted into an acid addition salt, which may be isolated in solid state and, optionally, purified, the staring material of formula (2) is not able to form a salt and remains in the solution. Mesylate salt of abiraterone-3-acetate was found as the most advantageous in WO'776.
Such salt may be obtained by dissolving the isolated product of the Suzuki coupling reaction (comprising free base of the compound of formula (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, and treating the solution with methane sulfonic acid upon precipitation of the salt. Similarly, a hydrochloride, sulfate or toluyltartrate salt of compound (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 isolation and purification of the product of the Suzuki coupling reaction comprising a mixture of abiraterone-3-acetate of formula (1) and unreacted starting material dehydroepiandrosterone-3-acetate of formula (2).
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to an improved process for making abiraterone-3-acetate of formula (1).
The invention provides a process comprising reacting the compound of formula
According to the second improvement suggested in WO'776 and WO'777 this starting material may be removed from the reaction mixture after performing the Suzuki coupling reaction by reacting the obtained and isolated mixed product comprising abiraterone-3-acetate of formula (1) with a suitable acid. While abiraterone-3-acetate is thereby converted into an acid addition salt, which may be isolated in solid state and, optionally, purified, the staring material of formula (2) is not able to form a salt and remains in the solution. Mesylate salt of abiraterone-3-acetate was found as the most advantageous in WO'776.
Such salt may be obtained by dissolving the isolated product of the Suzuki coupling reaction (comprising free base of the compound of formula (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, and treating the solution with methane sulfonic acid upon precipitation of the salt. Similarly, a hydrochloride, sulfate or toluyltartrate salt of compound (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 isolation and purification of the product of the Suzuki coupling reaction comprising a mixture of abiraterone-3-acetate of formula (1) and unreacted starting material dehydroepiandrosterone-3-acetate of formula (2).
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to an improved process for making abiraterone-3-acetate of formula (1).
The invention provides a process comprising reacting the compound of formula
(5) CH o- F
CH OS
H3Cx*0 0 (5) with 3-pyridinyl diethylborane of formula (4) (BEt2 (4) in 2-methyltetrahydrofuran, under conditions of a Suzuki coupling reaction, to give abiraterone-3-acetate of formula (1) N
/
CH
CH OS
H3CI*0 0 (1), followed by adding ethane sulfonic acid to give abiraterone-3-acetate esylate of formula (1A) . CH3-CH2-S03H
CH
CH OS
H3Cx0 (1A).
In one embodiment, the compound of formula (5) comprises more than 1%, typically from 2 to 20%, and more typically from 5 to 15% of dehydroepiandrosterone-3-acetate of formula (2) CH
y( ri H 3 c o (2).
In another embodiment, compound (5) is prepared by reacting dehydroepiandrosterone-3-acetate of formula (2) with a triflating agent, preferably triflic anhydride, in an inert solvent.
The reaction with the triflating agent is carried out either in the absence of an organic base or in the presence of an inorganic base, preferably sodium or potassium carbonate.
Abiraterone-3-acetate esylate of formula (1A) is a particularly advantageous salt for purifying abiraterone-3-acetate (1).
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to an improved 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 of converting the compound of formula (5) into abiraterone-3-acetate (1) of high purity via its acid addition salt abiraterone-3-acetate esylate (1A).
As shown above, any of the prior art processes for making the compound of formula (5) comprises reaction of dehydroepiandrosterone-3-acetate (DHEA) of formula (2) with trifluoromethanesulfonic anhydride (triflic anhydride) in the presence of an organic base. In order to decrease the amount of by-products, arisen from undesired elimination and/or deacetylation reaction at position 3, relatively weak organic bases have to be used for said purpose, with a pKa of their conjugated acids higher than 5.21. However, then the reaction product comprising compound (5) also comprises a relatively high amount, in some embodiments up to 30%, of the unreacted starting material of formula (2).
CH OS
H3Cx*0 0 (5) with 3-pyridinyl diethylborane of formula (4) (BEt2 (4) in 2-methyltetrahydrofuran, under conditions of a Suzuki coupling reaction, to give abiraterone-3-acetate of formula (1) N
/
CH
CH OS
H3CI*0 0 (1), followed by adding ethane sulfonic acid to give abiraterone-3-acetate esylate of formula (1A) . CH3-CH2-S03H
CH
CH OS
H3Cx0 (1A).
In one embodiment, the compound of formula (5) comprises more than 1%, typically from 2 to 20%, and more typically from 5 to 15% of dehydroepiandrosterone-3-acetate of formula (2) CH
y( ri H 3 c o (2).
In another embodiment, compound (5) is prepared by reacting dehydroepiandrosterone-3-acetate of formula (2) with a triflating agent, preferably triflic anhydride, in an inert solvent.
The reaction with the triflating agent is carried out either in the absence of an organic base or in the presence of an inorganic base, preferably sodium or potassium carbonate.
Abiraterone-3-acetate esylate of formula (1A) is a particularly advantageous salt for purifying abiraterone-3-acetate (1).
DETAILED DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to an improved 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 of converting the compound of formula (5) into abiraterone-3-acetate (1) of high purity via its acid addition salt abiraterone-3-acetate esylate (1A).
As shown above, any of the prior art processes for making the compound of formula (5) comprises reaction of dehydroepiandrosterone-3-acetate (DHEA) of formula (2) with trifluoromethanesulfonic anhydride (triflic anhydride) in the presence of an organic base. In order to decrease the amount of by-products, arisen from undesired elimination and/or deacetylation reaction at position 3, relatively weak organic bases have to be used for said purpose, with a pKa of their conjugated acids higher than 5.21. However, then the reaction product comprising compound (5) also comprises a relatively high amount, in some embodiments up to 30%, of the unreacted starting material of formula (2).
6 Quite surprisingly, the reaction of the compound of formula (2) with triflic anhydride yields the compound of formula (5) even in the absence of an organic base. The triflation reaction may even proceed under acidic conditions, for instance when the (essentially acidic) crude reaction mixture resulting from the acetylation of dehydroepiandrosterone of formula (3) with acetic anhydride is used 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 by-products.
The advantageous process of making the triflate of formula (5) is thus characterized in that dehydroepiandrosterone-3-acetate of formula (2) reacts with a triflating agent, preferably trifluoromethanesulfonic anhydride, in an inert solvent in the absence of an organic base. The "absence of organic base" means that no organic base is present in any starting material nor is it added to the reaction mixture before, during or after the reactive contact between dehydroepiandrosterone-3-acetate and triflating agent. The absence of organic base does not preclude the presence of an inorganic base such as sodium or potassium carbonate.
Thus, typically, the crude product comprising compound (5), which is used as the starting material in the Suzuki coupling reaction, comprises more than 1%, in some embodiments from 2 to 20%, and in other embodiments from 5 to 15%, of the unreacted starting material of formula (2).
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 a reaction thereof with an acetylation agent, e.g. with acetic anhydride or an acetylhalide.
Advantageously, the acetylation reaction may be performed by acetic anhydride, which also serves as the solvent, without need of any other inert solvent and/or diluent. It should be understood that formula
The advantageous process of making the triflate of formula (5) is thus characterized in that dehydroepiandrosterone-3-acetate of formula (2) reacts with a triflating agent, preferably trifluoromethanesulfonic anhydride, in an inert solvent in the absence of an organic base. The "absence of organic base" means that no organic base is present in any starting material nor is it added to the reaction mixture before, during or after the reactive contact between dehydroepiandrosterone-3-acetate and triflating agent. The absence of organic base does not preclude the presence of an inorganic base such as sodium or potassium carbonate.
Thus, typically, the crude product comprising compound (5), which is used as the starting material in the Suzuki coupling reaction, comprises more than 1%, in some embodiments from 2 to 20%, and in other embodiments from 5 to 15%, of the unreacted starting material of formula (2).
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 a reaction thereof with an acetylation agent, e.g. with acetic anhydride or an acetylhalide.
Advantageously, the acetylation reaction may be performed by acetic anhydride, which also serves as the solvent, without need of any other inert solvent and/or diluent. It should be understood that formula
7 (2) shown in this specification represents only one of possible tautomeric forms; 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 suitable inert solvent used in the triflation reaction is typically an aprotic organic solvent and preferably comprises, without limitation, 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. 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, 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 preferably absent in the triflation process, an inorganic base such as sodium or potassium carbonate 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-3- acetate of formula (2) is used
The suitable inert solvent used in the triflation reaction is typically an aprotic organic solvent and preferably comprises, without limitation, 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. 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, 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 preferably absent in the triflation process, an inorganic base such as sodium or potassium carbonate 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-3- acetate of formula (2) is used
8 as the starting material for the triflation reaction. 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 1-5 carbon atoms, e.g. methanol or isopropanol, acetic acid, or acetic acid anhydride. In general, the crude compound of formula (5) is dissolved in the crystallization solvent at an enhanced 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.
In an advantageous embodiment, the purified reaction product comprising compound (5), which is useful in the process of the present invention, comprises less than 0.5%,
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 1-5 carbon atoms, e.g. methanol or isopropanol, acetic acid, or acetic acid anhydride. In general, the crude compound of formula (5) is dissolved in the crystallization solvent at an enhanced 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.
In an advantageous embodiment, the purified reaction product comprising compound (5), which is useful in the process of the present invention, comprises less than 0.5%,
9 preferably less than 0.2%, of both the elimination impurity of formula (1B) and the deacetylation impurity of formula (3).
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 "Suzuki coupling reaction" is a term well-known in the art and generally represents a coupling of an aryl borane compound with an aryl/vinyl halide or an analogue of halide using a palladium catalyst in presence of a base. The reaction conditions of the Suzuki coupling are well-known in the art and are disclosed in the prior art documents cited above.
In a typical embodiment of the Suzuki coupling, diethyl(3-pyridyl)borane of formula (4) is contacted with the isolated product of the triflation reaction comprising the abiraterone-triflate compound (5) in tetrahydrofuran, in the presence of 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. At first, an aqueous workup has to be performed to remove the inorganic salts and palladium compounds. As tetrahydrofuran is freely miscible with water, the reaction mixture must be partitioned between ethyl acetate and water and extracted; the organic layer comprising the product is separated and the solvent is evaporated.
The so-obtained crude abiraterone-3-acetate still comprises some unreacted starting material of formula (2) (typically less than 10%) and boron-comprising impurities (unreacted diethyl-3-pyridyl borane and products of its conversion). These impurities are removed by treating the crude product with methanol, in which they are insoluble.
Precipitated boranes are filtered off, the filtrate containing desired product is evaporated to dryness and the residue is dissolved in ethyl acetate. Ethyl acetate solution of crude abiraterone acetate is then treated with a suitable acid, wherein the formed acid addition salt precipitates from the solution, while the compound of formula (2) does not form a salt and remains in solution. The prior art documents suggest using methanesulfonic acid as the best acid for said purposes.
Last, purified abiraterone-3-acetate is liberated from the salt by treatment with a base in a biphasic system, e.g. a dichloromethane-water system. The compound is isolated from the organic phase by evaporation thereof.
The need of multiple solvent switching for isolation and purification of abiraterone-3-acetate makes the known process to be quite time consuming.
The present inventors have now discovered improvements in the process for making abiraterone-3-acetate (1) from the triflate compound of formula (5).
First, there was discovered an advantageous liquid medium, which can serve both as a reaction medium for the Suzuki coupling reaction and as a medium for subsequent purification of the reaction mixture by salt formation. Second, an advantageous acid addition salt of abiraterone acetate was found, which precipitates directly from said medium without any need of a solvent switch. Third, an advantageous solvent system for direct precipitation of abiraterone-3-acetate after liberation thereof from the corresponding acid addition salt was found.
The present invention relates to a process comprising reacting the compound of formula (5) with 3-pyridyl diethylborane of formula (4) in 2-methyltetrahydrofuran, under conditions of a Suzuki coupling reaction, to give abiraterone-3-acetate of formula (1), followed by adding ethane sulfonic acid to give abiraterone-3-acetate esylate of formula (1A). The process of the present invention may futher comprise converting the abiraterone-3-acetate esylate of formula (1A) to abiraterone-3-acetate of formula (1) by treatment with a base.
In the first step, compound (5) is subjected to a Suzuki coupling reaction with 3-pyridyl diethylborane. As already disclosed above, compound (5) generally has lower than 99%
content of the compound (5), and it typically comprises more than 1% , typically from 2 to 20%, and more typically from 5 to 15% of dehydroepiandrosterone-3-acetate of formula (2).
It may also comprise other structurally related impurities, the amounts of which depend on the production process used.
The Suzuki coupling reaction of the present invention is characterized by use of 2-methyltetrahydrofuran as the solvent. 2-Methyltetrahydrofuran has a higher boiling point compared to tetrahydrofuran enabling an increased reaction temperature that results in shortening of the reaction time. In an important difference from tetrahydrofuran, it is not miscible with water so that no other organic solvent needs to be added prior to subsequent aqueous work-up of the reaction mixture. Advantageously, the Suzuki coupling reaction may even be carried out in a 2-methyltetrahydrofuran/water mixture, which is a suitable alternative to performing the reaction in 2-methyltetrahydrofuran followed by subsequent adding of water for extractive removal of the inorganic compounds present in the reaction mixture. Moreover, 2-methyltetrahydrofuran is classified as a green solvent with negative results for genotoxicity and mutagenicity.
The Suzuki coupling reaction is typically performed by mixing the abiraterone triflate of formula (5) with diethyl(3-pyridyl)borane of formula (4) (typically 1 ¨ 2 molar equivalents), sodium carbonate (typically 1 ¨ 4 molar equivalents), and palladium catalyst (0.5 ¨ 2 molar %). Also, 2-methyltetrahydrofuran and, optionally, water are added (typically up to 5-20 wt% concentration of the compound (5)), and the resulting mixture is heated to an elevated temperature, which advantageously is reflux temperature. The progress of the reaction may be followed by a suitable method, e.g. HPLC, and the reaction may be terminated once essentially all starting material is consumed.
With respect to the palladium catalyst, not only conventional homogeneous palladium catalysts such as bis(triphenylphosphine)palladium dichloride, but also heterogeneous palladium catalysts (Pd/C, Pd/silica gel, Pd/polymer) may be employed.
Aqueous work-up is performed as the only elaboration of the reaction mixture after optional filtration and separation of the aqueous- and organic layers.
Typically, the organic phase is washed with water and/or an aqueous saturated sodium chloride solution. In an advantageous embodiment, the reaction mixture is also extracted with an aqueous solution of a sulfite compound. The sulfite compound is typically sodium sulfite, sodium hydrogen sulfite, sodium dithionite or sodium pyrosulfite, but is not limited thereto.
The sulfite compound is effective in scavenging and removing traces of palladium, which otherwise might contaminate the product to a pharmaceutically unacceptable level.
In the second step, abiraterone-3-acetate is isolated from the reaction mixture as an acid addition salt. In an important difference from the prior art procedures, there is no need to first isolate abiraterone-3-acetate as a free base, i.e. as a product still contaminated by the compound of formula (2). Instead, the present inventors have found a suitable acid addition salt of abiraterone-3-acetate, which has a very favorable solubility profile in 2-methyltetra-hydrofurane used in the first step, allowing direct precipitation of the salt from the reaction mixture after the Suzuki coupling reaction. Thus, both steps may be performed in one-pot, which is an important technological improvement over the prior art.
Thus, the process improvement in accordance with the present invention is further based on use of ethane sulfonic acid in making abiraterone-3-acetate. Ethane sulfonic acid reacts with abiraterone-3-acetate to form abiraterone-3-acetate esylate of formula (1A). In particular, the reaction mixture comprising abiraterone-3-acetate, such as that from the first step, is contacted under stirring with ethane sulfonic acid (1 ¨ 1.5 molar equivalents), typically with a solution thereof in 2-methyltetrahydrofuran. In an advantageous embodiment, the temperature of contacting is from ambient to reflux temperature, preferably between 30-60 C. A precipitate of abiraterone-3-acetate esylate of formula (1A) is easily formed, typically at ambient temperature. Advantageously, the suspension is subsequently cooled to a temperature lower than ambient temperature, typically to about 0 C, and the solid product is isolated by filtration, washed and dried. Typically, the solid esylate product is not contaminated by any boronic compounds. Also, most of the originally present impurity of the formula (2) remains in the mother liquor upon precipitation of abiraterone-3-acetate esylate of formula (1A). Thus, the present invention provides for an efficient process for purification of abiraterone-3-acetate, said process comprising precipitation of abiraterone-3-acetate esylate of formula (1A) from a solution thereof in a solvent comprising 2-methyltetrahydro-furan.
If necessary or advantageous, the esylate of formula (1A) may be recrystallized from a suitable solvent, for instance acetonitrile or an aliphatic alcohol such as isopropanol.
Typically, the esylate is obtained in a crystalline form. The purity of the esylate salt may reach at least 97% (HPLC, internal normalization), advantageously at least 98%, and in some embodiments at least 99%. The amount of the impurity of formula (2) is in some embodiments less than 3%, in other embodiments less than 2%, and yet in other embodiments less than 1%.
In the third step, pure abiraterone-3-acetate is liberated from the esylate salt by treatment of a solution thereof with a base, which advantageously is an inorganic base, followed by direct precipitation of abiraterone-3-acetate from the solution.
The treatment is advantageously performed on a solution of the esylate salt in a solvent system comprising a water-miscible organic solvent, whereby abiraterone-3-acetate precipitates from the solvent system. A suitable inorganic base is sodium- or potassium acetate, -bicarbonate or -hydroxide. The water-miscible organic solvent is not specifically limited and advantageously is a Cl-05 aliphatic alcohol, preferably methanol, ethanol or isopropanol; a water-miscible aliphatic ketone, preferably acetone, acetonitrile or acetic acid.
Advantageously, the esylate salt is first dissolved in the water-miscible organic solvent, the solution is treated (advantageously at elevated temperature) with the base, optionally filtered, and then water is added to the mixture whereby abiraterone-3-acetate precipitates.
The ratio between water and the organic solvent is not specifically limited and may be fine-tuned experimentally. In general, more water results in a higher yield, but a lesser degree of purification.
The solid abiraterone-3-acetate is separated by ordinary techniques, e.g. by filtration or centrifugation, washed and dried.
In a less preferred alternative, the esylate salt is dissolved or suspended in a solvent not miscible in water, such as in a chlorinated hydrocarbon, for instance dichloromethane, and the mixture is treated with an equivalent amount of an aqueous base, for instance with a saturated aqueous sodium carbonate or saturate aqueous sodium bicarbonate solution. The aqueous phase is then removed. Concentration of the organic phase and triturating 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.
If necessary, the process of forming the salt and liberating the compound of the formula (1) from the salt may be repeated until the desired purity is obtained.
As a result of the process of the present invention, abiraterone-3-acetate of pharmaceutical grade can be obtained The invention is further illustrated by the following examples.
EXAMPLES
Example 1 Dehydroepiandrosterone-3-acetate (2) (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 Na2CO3 (70 ml), water (100 ml) (2x 50 ml) and brine (70 ml). The combined organic layer was dried with MgSO4, filtered and concentrated to dryness to constant mass (13.43 g) giving compound (5) as an oil.
Yield: 96%, conversion 93% (HPLC).
Compound (5) (10 g, 19.26 mmol) was charged into a 100 ml three-neck flask along with 3-(diethylboryl)pyridine (2.83 g, 19.26 mmol), Pd(PPh3)2C12 (0.135 g, 0.193 mmol) and sodium carbonate (2.042 g, 19.26 mmol). The flask was filled with argon and 2-methyltetra-hydrofuran (100 ml) was added. The reaction mixture (RM) was stirred at ambient temperature until all the organics dissolved (ca. 2 min). Then water (60.0 ml) was added, the RM immersed in a preheated (80 C) oil bath and heated. The RM reached reflux temperature (70 C) in ca. 27 min. After about 1 hour and 40 min the heating was stopped.
RM was allowed to cool to RT and the aqueous layer was removed. The organic layer was washed with 100 ml of water, 50 ml of 0.25M Na2S205, 100 ml of water and 50 ml of brine, dried over MgSO4 and filtered through Celite. During the work-up the RM containing abiraterone-3-acetate (1) was diluted with a total of ca. 60 ml of 2-methyltetrahydrofuran (washings of separation funnel, filter cake, etc.) to a final volume of ca. 150 ml.
Said solution was heated to internal temperature of 49 C and ethane sulfonic acid (1.737 ml, 20.23 mmol) in 2-methyltetrahydrofuran (20.00 ml) was added dropwise over 15 min (massive crystals formation was observed when 8.25 ml of acid solution had been added). The RM was then allowed to cool to room temperature, immersed in an ice bath until internal temperature reached 1 C, and was stirred at that temperature for 15 mm. The solids were filtered off, washed with cold 2-methyltetrahydrofuran (60.0 ml), and then vacuum dried at 40 C for 1 hour affording abiraterone-3-acetate esylate (1A) (8.21 g, 16.30 mmol, 85 % yield, assay 99.6% HPLC-ES) as an off-white solid.
Example 2 Abiraterone-3-acetate esylate (1.236 g, 2.439 mmol) was dissolved in methanol (12 ml) along with sodium acetate (0.220 g, 2.68 mmol), and active charcoal (60 mg) was added. The reaction mixture (RM) was stirred for 30 mm. The suspension was then filtered and the filter cake washed with additional methanol (4 m1). The light-yellow solution was heated to 50 C
(internal temp.), and water (4.8 ml) was added dropwise (final ratio of Me0H :
water was 1:
0.3). The RM was allowed to cool to RT, rapid crystal formation was observed.
Subsequently, the RM was immersed into an ice bath for 30 mm. The precipitate was filtered, washed with a methanol/water mixture (1: 0.5 v/v, 15.00 ml), and vacuum dried at 40 C for 1 hour to give abiraterone-3-acetate (1). Yield: 0.65 g, (1.660 mmol, 68%;
purity 99.4%
HPLC-IN) as white flakes.
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 "Suzuki coupling reaction" is a term well-known in the art and generally represents a coupling of an aryl borane compound with an aryl/vinyl halide or an analogue of halide using a palladium catalyst in presence of a base. The reaction conditions of the Suzuki coupling are well-known in the art and are disclosed in the prior art documents cited above.
In a typical embodiment of the Suzuki coupling, diethyl(3-pyridyl)borane of formula (4) is contacted with the isolated product of the triflation reaction comprising the abiraterone-triflate compound (5) in tetrahydrofuran, in the presence of 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. At first, an aqueous workup has to be performed to remove the inorganic salts and palladium compounds. As tetrahydrofuran is freely miscible with water, the reaction mixture must be partitioned between ethyl acetate and water and extracted; the organic layer comprising the product is separated and the solvent is evaporated.
The so-obtained crude abiraterone-3-acetate still comprises some unreacted starting material of formula (2) (typically less than 10%) and boron-comprising impurities (unreacted diethyl-3-pyridyl borane and products of its conversion). These impurities are removed by treating the crude product with methanol, in which they are insoluble.
Precipitated boranes are filtered off, the filtrate containing desired product is evaporated to dryness and the residue is dissolved in ethyl acetate. Ethyl acetate solution of crude abiraterone acetate is then treated with a suitable acid, wherein the formed acid addition salt precipitates from the solution, while the compound of formula (2) does not form a salt and remains in solution. The prior art documents suggest using methanesulfonic acid as the best acid for said purposes.
Last, purified abiraterone-3-acetate is liberated from the salt by treatment with a base in a biphasic system, e.g. a dichloromethane-water system. The compound is isolated from the organic phase by evaporation thereof.
The need of multiple solvent switching for isolation and purification of abiraterone-3-acetate makes the known process to be quite time consuming.
The present inventors have now discovered improvements in the process for making abiraterone-3-acetate (1) from the triflate compound of formula (5).
First, there was discovered an advantageous liquid medium, which can serve both as a reaction medium for the Suzuki coupling reaction and as a medium for subsequent purification of the reaction mixture by salt formation. Second, an advantageous acid addition salt of abiraterone acetate was found, which precipitates directly from said medium without any need of a solvent switch. Third, an advantageous solvent system for direct precipitation of abiraterone-3-acetate after liberation thereof from the corresponding acid addition salt was found.
The present invention relates to a process comprising reacting the compound of formula (5) with 3-pyridyl diethylborane of formula (4) in 2-methyltetrahydrofuran, under conditions of a Suzuki coupling reaction, to give abiraterone-3-acetate of formula (1), followed by adding ethane sulfonic acid to give abiraterone-3-acetate esylate of formula (1A). The process of the present invention may futher comprise converting the abiraterone-3-acetate esylate of formula (1A) to abiraterone-3-acetate of formula (1) by treatment with a base.
In the first step, compound (5) is subjected to a Suzuki coupling reaction with 3-pyridyl diethylborane. As already disclosed above, compound (5) generally has lower than 99%
content of the compound (5), and it typically comprises more than 1% , typically from 2 to 20%, and more typically from 5 to 15% of dehydroepiandrosterone-3-acetate of formula (2).
It may also comprise other structurally related impurities, the amounts of which depend on the production process used.
The Suzuki coupling reaction of the present invention is characterized by use of 2-methyltetrahydrofuran as the solvent. 2-Methyltetrahydrofuran has a higher boiling point compared to tetrahydrofuran enabling an increased reaction temperature that results in shortening of the reaction time. In an important difference from tetrahydrofuran, it is not miscible with water so that no other organic solvent needs to be added prior to subsequent aqueous work-up of the reaction mixture. Advantageously, the Suzuki coupling reaction may even be carried out in a 2-methyltetrahydrofuran/water mixture, which is a suitable alternative to performing the reaction in 2-methyltetrahydrofuran followed by subsequent adding of water for extractive removal of the inorganic compounds present in the reaction mixture. Moreover, 2-methyltetrahydrofuran is classified as a green solvent with negative results for genotoxicity and mutagenicity.
The Suzuki coupling reaction is typically performed by mixing the abiraterone triflate of formula (5) with diethyl(3-pyridyl)borane of formula (4) (typically 1 ¨ 2 molar equivalents), sodium carbonate (typically 1 ¨ 4 molar equivalents), and palladium catalyst (0.5 ¨ 2 molar %). Also, 2-methyltetrahydrofuran and, optionally, water are added (typically up to 5-20 wt% concentration of the compound (5)), and the resulting mixture is heated to an elevated temperature, which advantageously is reflux temperature. The progress of the reaction may be followed by a suitable method, e.g. HPLC, and the reaction may be terminated once essentially all starting material is consumed.
With respect to the palladium catalyst, not only conventional homogeneous palladium catalysts such as bis(triphenylphosphine)palladium dichloride, but also heterogeneous palladium catalysts (Pd/C, Pd/silica gel, Pd/polymer) may be employed.
Aqueous work-up is performed as the only elaboration of the reaction mixture after optional filtration and separation of the aqueous- and organic layers.
Typically, the organic phase is washed with water and/or an aqueous saturated sodium chloride solution. In an advantageous embodiment, the reaction mixture is also extracted with an aqueous solution of a sulfite compound. The sulfite compound is typically sodium sulfite, sodium hydrogen sulfite, sodium dithionite or sodium pyrosulfite, but is not limited thereto.
The sulfite compound is effective in scavenging and removing traces of palladium, which otherwise might contaminate the product to a pharmaceutically unacceptable level.
In the second step, abiraterone-3-acetate is isolated from the reaction mixture as an acid addition salt. In an important difference from the prior art procedures, there is no need to first isolate abiraterone-3-acetate as a free base, i.e. as a product still contaminated by the compound of formula (2). Instead, the present inventors have found a suitable acid addition salt of abiraterone-3-acetate, which has a very favorable solubility profile in 2-methyltetra-hydrofurane used in the first step, allowing direct precipitation of the salt from the reaction mixture after the Suzuki coupling reaction. Thus, both steps may be performed in one-pot, which is an important technological improvement over the prior art.
Thus, the process improvement in accordance with the present invention is further based on use of ethane sulfonic acid in making abiraterone-3-acetate. Ethane sulfonic acid reacts with abiraterone-3-acetate to form abiraterone-3-acetate esylate of formula (1A). In particular, the reaction mixture comprising abiraterone-3-acetate, such as that from the first step, is contacted under stirring with ethane sulfonic acid (1 ¨ 1.5 molar equivalents), typically with a solution thereof in 2-methyltetrahydrofuran. In an advantageous embodiment, the temperature of contacting is from ambient to reflux temperature, preferably between 30-60 C. A precipitate of abiraterone-3-acetate esylate of formula (1A) is easily formed, typically at ambient temperature. Advantageously, the suspension is subsequently cooled to a temperature lower than ambient temperature, typically to about 0 C, and the solid product is isolated by filtration, washed and dried. Typically, the solid esylate product is not contaminated by any boronic compounds. Also, most of the originally present impurity of the formula (2) remains in the mother liquor upon precipitation of abiraterone-3-acetate esylate of formula (1A). Thus, the present invention provides for an efficient process for purification of abiraterone-3-acetate, said process comprising precipitation of abiraterone-3-acetate esylate of formula (1A) from a solution thereof in a solvent comprising 2-methyltetrahydro-furan.
If necessary or advantageous, the esylate of formula (1A) may be recrystallized from a suitable solvent, for instance acetonitrile or an aliphatic alcohol such as isopropanol.
Typically, the esylate is obtained in a crystalline form. The purity of the esylate salt may reach at least 97% (HPLC, internal normalization), advantageously at least 98%, and in some embodiments at least 99%. The amount of the impurity of formula (2) is in some embodiments less than 3%, in other embodiments less than 2%, and yet in other embodiments less than 1%.
In the third step, pure abiraterone-3-acetate is liberated from the esylate salt by treatment of a solution thereof with a base, which advantageously is an inorganic base, followed by direct precipitation of abiraterone-3-acetate from the solution.
The treatment is advantageously performed on a solution of the esylate salt in a solvent system comprising a water-miscible organic solvent, whereby abiraterone-3-acetate precipitates from the solvent system. A suitable inorganic base is sodium- or potassium acetate, -bicarbonate or -hydroxide. The water-miscible organic solvent is not specifically limited and advantageously is a Cl-05 aliphatic alcohol, preferably methanol, ethanol or isopropanol; a water-miscible aliphatic ketone, preferably acetone, acetonitrile or acetic acid.
Advantageously, the esylate salt is first dissolved in the water-miscible organic solvent, the solution is treated (advantageously at elevated temperature) with the base, optionally filtered, and then water is added to the mixture whereby abiraterone-3-acetate precipitates.
The ratio between water and the organic solvent is not specifically limited and may be fine-tuned experimentally. In general, more water results in a higher yield, but a lesser degree of purification.
The solid abiraterone-3-acetate is separated by ordinary techniques, e.g. by filtration or centrifugation, washed and dried.
In a less preferred alternative, the esylate salt is dissolved or suspended in a solvent not miscible in water, such as in a chlorinated hydrocarbon, for instance dichloromethane, and the mixture is treated with an equivalent amount of an aqueous base, for instance with a saturated aqueous sodium carbonate or saturate aqueous sodium bicarbonate solution. The aqueous phase is then removed. Concentration of the organic phase and triturating 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.
If necessary, the process of forming the salt and liberating the compound of the formula (1) from the salt may be repeated until the desired purity is obtained.
As a result of the process of the present invention, abiraterone-3-acetate of pharmaceutical grade can be obtained The invention is further illustrated by the following examples.
EXAMPLES
Example 1 Dehydroepiandrosterone-3-acetate (2) (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 Na2CO3 (70 ml), water (100 ml) (2x 50 ml) and brine (70 ml). The combined organic layer was dried with MgSO4, filtered and concentrated to dryness to constant mass (13.43 g) giving compound (5) as an oil.
Yield: 96%, conversion 93% (HPLC).
Compound (5) (10 g, 19.26 mmol) was charged into a 100 ml three-neck flask along with 3-(diethylboryl)pyridine (2.83 g, 19.26 mmol), Pd(PPh3)2C12 (0.135 g, 0.193 mmol) and sodium carbonate (2.042 g, 19.26 mmol). The flask was filled with argon and 2-methyltetra-hydrofuran (100 ml) was added. The reaction mixture (RM) was stirred at ambient temperature until all the organics dissolved (ca. 2 min). Then water (60.0 ml) was added, the RM immersed in a preheated (80 C) oil bath and heated. The RM reached reflux temperature (70 C) in ca. 27 min. After about 1 hour and 40 min the heating was stopped.
RM was allowed to cool to RT and the aqueous layer was removed. The organic layer was washed with 100 ml of water, 50 ml of 0.25M Na2S205, 100 ml of water and 50 ml of brine, dried over MgSO4 and filtered through Celite. During the work-up the RM containing abiraterone-3-acetate (1) was diluted with a total of ca. 60 ml of 2-methyltetrahydrofuran (washings of separation funnel, filter cake, etc.) to a final volume of ca. 150 ml.
Said solution was heated to internal temperature of 49 C and ethane sulfonic acid (1.737 ml, 20.23 mmol) in 2-methyltetrahydrofuran (20.00 ml) was added dropwise over 15 min (massive crystals formation was observed when 8.25 ml of acid solution had been added). The RM was then allowed to cool to room temperature, immersed in an ice bath until internal temperature reached 1 C, and was stirred at that temperature for 15 mm. The solids were filtered off, washed with cold 2-methyltetrahydrofuran (60.0 ml), and then vacuum dried at 40 C for 1 hour affording abiraterone-3-acetate esylate (1A) (8.21 g, 16.30 mmol, 85 % yield, assay 99.6% HPLC-ES) as an off-white solid.
Example 2 Abiraterone-3-acetate esylate (1.236 g, 2.439 mmol) was dissolved in methanol (12 ml) along with sodium acetate (0.220 g, 2.68 mmol), and active charcoal (60 mg) was added. The reaction mixture (RM) was stirred for 30 mm. The suspension was then filtered and the filter cake washed with additional methanol (4 m1). The light-yellow solution was heated to 50 C
(internal temp.), and water (4.8 ml) was added dropwise (final ratio of Me0H :
water was 1:
0.3). The RM was allowed to cool to RT, rapid crystal formation was observed.
Subsequently, the RM was immersed into an ice bath for 30 mm. The precipitate was filtered, washed with a methanol/water mixture (1: 0.5 v/v, 15.00 ml), and vacuum dried at 40 C for 1 hour to give abiraterone-3-acetate (1). Yield: 0.65 g, (1.660 mmol, 68%;
purity 99.4%
HPLC-IN) as white flakes.
Claims (15)
1. A process comprising reacting the compound of formula (5) with 3-pyridyl diethylborane of formula (4) in 2-methyltetrahydrofuran to give abiraterone-3-acetate of formula (1) followed by adding ethane sulfonic acid to give abiraterone-3-acetate esylate of formula (1A)
2. The process according to claim 1, further comprising converting the esylate of formula (1A) to abiraterone-3-acetate of formula (1) by treatment with a base.
3. The process according to claim 1 or 2, wherein compound (5) comprises more than 1%, typically from 2 to 20% of dehydroepiandrosterone-3-acetate of formula (2)
4. The process according to any one of claims 1-3, wherein compound (5) is prepared by reacting dehydroepiandrosterone-3-acetate of formula (2) with a triflating agent, preferably triflic anhydride, in an inert solvent.
5. The process according to claim 4, wherein the reaction with the triflating agent is carried out in the absence of an organic base or in the presence of an inorganic base, preferably sodium or potassium carbonate.
6. The process according to any of the claims 1-5, wherein the abiraterone-3-acetate esylate of formula (1A) is obtained in a crystalline form.
7. The process according to claim 6, wherein the abiraterone-3-acetate esylate comprises less than 3%, preferably less than 2%, of the compound of formula (2).
8. The process according to any one of claims 2-7, wherein the abiraterone-3-acetate esylate is treated with the base in a solvent system comprising a water-miscible organic solvent.
9. The process according to claim 8, wherein the water-miscible organic solvent is a C1-C5 aliphatic alcohol, preferably methanol, ethanol or isopropanol, a water-miscible aliphatic ketone, preferably acetone, acetonitrile or acetic acid.
10. The process according to claims 8-9, wherein the formed abiraterone-3-acetate is precipitated from the solvent system in a solid form.
11. Abiraterone-3-acetate esylate of formula (1A).
12. The abiraterone-3-acetate esylate of claim 11 in a solid, preferably crystalline, form.
13. A process of purification of abiraterone-3-acetate of formula (1) comprising precipitation of abiraterone-3-acetate esylate of formula (1A) from a solution thereof in a solvent comprising 2-methyltetrahydrofuran.
14. Use of 2-methyltetrahydrofuran in making abiraterone-3-acetate.
15. Use of ethane sulfonic acid in making abiraterone-3-acetate.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2012/072208 WO2014071984A1 (en) | 2012-11-09 | 2012-11-09 | Process for making abiraterone-3-acetate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2890589A1 true CA2890589A1 (en) | 2014-05-15 |
Family
ID=47148818
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2890589A Abandoned CA2890589A1 (en) | 2012-11-09 | 2012-11-09 | Process for making abiraterone-3-acetate |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP2917225A1 (en) |
| CA (1) | CA2890589A1 (en) |
| WO (1) | WO2014071984A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014207762A1 (en) * | 2013-06-24 | 2014-12-31 | Sun Pharmaceutical Industries Ltd. | Process for preparation of abiraterone acetate |
| US10722527B2 (en) | 2015-04-10 | 2020-07-28 | Capsugel Belgium Nv | Abiraterone acetate lipid formulations |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2742331B2 (en) | 1992-03-31 | 1998-04-22 | ブリテイツシユ・テクノロジー・グループ・リミテツド | 17-substituted steroids useful for cancer treatment |
| GB2282377B (en) | 1993-09-30 | 1997-09-03 | British Tech Group | Synthesis of 17-(3-pyridyl) steroids |
| PL1781683T3 (en) | 2004-08-24 | 2012-04-30 | Btg Int Ltd | Process for the preparation of 17-vinyl- triflates as intermediates |
| GB0418900D0 (en) | 2004-08-24 | 2004-09-29 | Btg Int Ltd | Novel salt forms |
| EP2607371A1 (en) * | 2011-12-23 | 2013-06-26 | Crystal Pharma, S.A.U. | Processes for the preparation of abiraterone and related compouds |
-
2012
- 2012-11-09 CA CA2890589A patent/CA2890589A1/en not_active Abandoned
- 2012-11-09 EP EP12784003.1A patent/EP2917225A1/en not_active Withdrawn
- 2012-11-09 WO PCT/EP2012/072208 patent/WO2014071984A1/en active Application Filing
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| EP2917225A1 (en) | 2015-09-16 |
| WO2014071984A1 (en) | 2014-05-15 |
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