A method for preparing abiraterone

Abstract

The application provides a preparation method of abiraterone and belongs to the technical field of organic synthesis. The application takes dehydroepiandrosterone 17 hydrazone as raw material, directly carries out iodination and coupling reaction to obtain abiraterone without acetylation. Since acetylation is not carried out, the 3 position of dehydroepiandrosterone 17 hydrazone is still free hydroxyl, the solubility of dehydroepiandrosterone 17 hydrazone in the second organic solvent is improved, the reactants are fully contacted in a homogeneous phase, the reaction rate is accelerated, the reaction time is shortened, the occurrence of side reactions is directly reduced, and the yield of abiraterone is improved. The solubility of abiraterone prepared by the preparation method is poor, impurities can be removed by refining, and the purity of abiraterone is improved. Then, high-yield and high-purity abiraterone acetate can be prepared through esterification. The yield of abiraterone obtained by the preparation method is more than 91%, and the purity is more than 99%.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for preparing abiraterone. Background Technology

[0002] Abiraterone acetate is an oral androgen inhibitor that inhibits the CYP450c17 enzyme in the human body, thereby suppressing androgen synthesis. Abiraterone acetate also lowers prostate-specific antigen (PSA) levels, providing a new and effective treatment option for prostate cancer patients. Abiraterone acetate is a prodrug of abiraterone, which is converted into the active ingredient abiraterone in the body to exert its effects.

[0003] Existing techniques often involve the direct synthesis of abiraterone acetate, using dehydroepiandrosterone (DHEA) as a starting material. The process begins with acetylation followed by condensation to obtain 3β-acetoxyandrost-5,16-diene-17hydrazone, which is then iodinated and coupled to yield crude abiraterone acetate, which is subsequently purified. However, this synthetic route suffers from a lengthy coupling reaction, typically requiring several days to complete. This prolonged reaction time leads to the formation of Heck-coupled dimer byproducts, which have similar structures and physicochemical properties to the target product. Conventional purification methods such as recrystallization and washing are insufficient to effectively remove these byproducts, impacting the purity of the target product. Furthermore, the long reaction time and numerous side reactions result in a low yield for the coupling step. Additionally, abiraterone acetate exhibits high solubility in solvents, leading to low yields during purification of directly synthesized abiraterone acetate and poor purification of impurities, further affecting the overall yield of the synthetic route. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing abiraterone. The preparation method provided by this invention can obtain abiraterone in high yield. High-purity abiraterone can be obtained by simple purification. Abiraterone acetate with high yield and high purity can be prepared by esterification.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing abiraterone, comprising the following steps: (1) Dehydroepiandrosterone 17hydrazone, organic base, oxidant and iodine were subjected to iodination in the first organic solvent to obtain 3β-hydroxy-17-iodo-androst-5,16-diene; (2) The 3β-hydroxy-17-iodo-androst-5,16-diene obtained in step (1) is coupled with 3-pyridylborane, an inorganic base and a catalyst in a second organic solvent to obtain abiraterone; The temperature of the coupling reaction in step (2) is 60~100℃, and the time of the coupling reaction is 2~8h; The second organic solvent in step (2) includes N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

[0006] Preferably, the organic base in step (1) includes tetramethylguanidine; the volume ratio of the organic base to the mass ratio of dehydroepiandrosterone 17hydrazone is (1.6~5) mL:1g.

[0007] Preferably, the oxidant in step (1) includes N-bromosuccinimide or N-chlorosuccinimide; the mass ratio of the oxidant to dehydroepiandrosterone 17hydrazone is (0.01~1):1.

[0008] Preferably, in step (1), the mass ratio of elemental iodine to dehydroepiandrosterone-17-hydrazone is (0.4~2):1.

[0009] Preferably, the temperature of the iodination reaction in step (1) is -20~10℃, and the time of the iodination reaction is 0.5~2h.

[0010] Preferably, in step (2), 3-pyridylborane includes dimethyl (3-pyridyl)borane, diethyl (3-pyridyl)borane, or diisopropyl (3-pyridyl)borane; the molar ratio of 3-pyridylborane to 3β-hydroxy-17-iodo-androst-5,16-diene is (1~5):1.

[0011] Preferably, the inorganic base in step (2) includes sodium carbonate, potassium carbonate or potassium phosphate; the mass ratio of the inorganic base to 3β-hydroxy-17-iodo-androst-5,16-diene is (0.2~2):1.

[0012] Preferably, the catalyst in step (2) comprises a nickel complex, wherein the ligand of the nickel complex is 1,3-bis(diphenylphosphine)propane, 1,2-bis(diphenylphosphine)ethane, 1,4-bis(diphenylphosphine)butane, 1,1'-bis(diphenylphosphine)ferrocene, xanthylphosphine, tricyclohexylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, triphenylphosphine, tri-o-methylphenylphosphine, tri-p-tolylphosphine, 2,2'-bipyridine, or phenanthroline; the mass ratio of the nickel complex to 3β-hydroxy-17-iodo-androst-5,16-diene is (0.001~0.5):1.

[0013] Preferably, the catalyst further includes a metal reducing agent, which includes zinc or manganese; the mass ratio of the metal reducing agent to 3β-hydroxy-17-iodo-androst-5,16-diene is (0.001~0.5):1.

[0014] Preferably, in step (2), the volume ratio of the second organic solvent to the mass ratio of 3β-hydroxy-17-iodo-androst-5,16-diene is (5~20) mL:1 g.

[0015] This invention provides a method for preparing abiraterone, comprising the following steps: (1) iodination of dehydroepiandrosterone 17hydrazone, organic base, oxidant and iodine in a first organic solvent to obtain 3β-hydroxy-17-iodo-androst-5,16-diene; (2) coupling reaction of the 3β-hydroxy-17-iodo-androst-5,16-diene obtained in step (1) with 3-pyridylborane, inorganic base and catalyst in a second organic solvent to obtain abiraterone; the coupling reaction temperature in step (2) is 60~100℃ and the coupling reaction time is 2~8h; the second organic solvent in step (2) includes N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide. This invention uses dehydroepiandrosterone 17-hydrazone as a raw material, and directly performs iodination and coupling reactions to obtain abiraterone without acetylation. Because acetylation is not performed, the 3-position of dehydroepiandrosterone 17-hydrazone remains a free hydroxyl group, which improves the solubility of dehydroepiandrosterone 17-hydrazone in the second organic solvent, allowing for sufficient contact of the reactants in a homogeneous phase, thereby accelerating the reaction rate, shortening the reaction time, and directly reducing the occurrence of side reactions, thus increasing the yield of abiraterone. The abiraterone prepared using the method provided by this invention can be purified by the difference in solubility of abiraterone and impurities in different solvents to remove impurities, improving the purity of abiraterone. Then, esterification can be used to prepare abiraterone acetate with high yield and high purity. Data in the examples show that the abiraterone obtained by the preparation method provided by this invention has a yield of over 91% and a purity of over 99%. Attached Figure Description

[0016] Figure 1 The liquid chromatogram of abiraterone prepared in Example 1 shows that the peak elution time is 23.771 min. Figure 2 The liquid chromatogram of abiraterone prepared in Example 2 shows that the peak elution time is 23.788 min. Detailed Implementation

[0017] This invention provides a method for preparing abiraterone, comprising the following steps: (1) Dehydroepiandrosterone 17hydrazone, organic base, oxidant and iodine were subjected to iodination in the first organic solvent to obtain 3β-hydroxy-17-iodo-androst-5,16-diene; (2) The 3β-hydroxy-17-iodo-androst-5,16-diene obtained in step (1) is coupled with 3-pyridylborane, an inorganic base and a catalyst in a second organic solvent to obtain abiraterone; The temperature of the coupling reaction in step (2) is 60~100℃, and the time of the coupling reaction is 2~8h; The second organic solvent in step (2) includes N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

[0018] In this invention, dehydroepiandrosterone 17hydrazone, an organic base, an oxidizing agent, and elemental iodine are subjected to an iodination reaction in a first organic solvent to obtain 3β-hydroxy-17-iodo-androst-5,16-diene.

[0019] In this invention, the organic base preferably comprises tetramethylguanidine; the volume ratio of the organic base to the mass ratio of dehydroepiandrosterone-17-hydrazone is preferably (1.6~5) mL:1 g, more preferably (2~5) mL:1 g. In embodiments of this invention, the volume ratio of the organic base to the mass ratio of dehydroepiandrosterone-17-hydrazone is 3 mL:1 g or 4 mL:1 g. In this invention, the organic base can activate elemental iodine to react with dehydroepiandrosterone-17-hydrazone and can neutralize the reaction byproduct hydrogen iodide.

[0020] In this invention, the oxidant preferably includes N-bromosuccinimide or N-chlorosuccinimide; the mass ratio of the oxidant to dehydroepiandrosterone-17-hydrazone is preferably (0.01~1):1, more preferably (0.1~1):1. In embodiments of this invention, the mass ratio of the oxidant to dehydroepiandrosterone-17-hydrazone is 0.6:1 or 0.7:1. By adding an oxidant to the iodination reaction, this invention can convert the iodide ions generated in the iodination reaction back into elemental iodine, which can then continue to participate in the iodination reaction, thereby reducing the amount of elemental iodine used.

[0021] In this invention, the preferred mass ratio of elemental iodine to dehydroepiandrosterone-17-hydrazone is (0.4~2):1, more preferably (0.5~1):1. In embodiments of this invention, the mass ratio of elemental iodine to dehydroepiandrosterone-17-hydrazone is 0.9:1 or 1:1.

[0022] In this invention, the first organic solvent preferably includes one or more of tetrahydrofuran, dichloromethane, and methanol; the volume ratio of the first organic solvent to the mass ratio of dehydroepiandrosterone-17-hydrazone is preferably (15~40 mL):1 g, more preferably (20~30 mL):1 g. In embodiments of this invention, the first organic solvent is tetrahydrofuran or dichloromethane, and the volume ratio of the first organic solvent to the mass ratio of dehydroepiandrosterone-17-hydrazone is 30 mL:1 g or 33 mL:1 g.

[0023] In this invention, the temperature of the iodination reaction is preferably -20~10℃, more preferably -10~5℃; the time of the iodination reaction is preferably 0.5~2h, more preferably 1~2h. In an embodiment of this invention, the temperature of the iodination reaction is -10℃ or 5℃, and the time of the iodination reaction is 1h.

[0024] In one embodiment of the present invention, the mixing of dehydroepiandrosterone 17-hydrazone, organic base, oxidant, and elemental iodine in the first organic solvent can be as follows: adding dehydroepiandrosterone 17-hydrazone and elemental iodine to a portion of the first organic solvent respectively to obtain a dehydroepiandrosterone 17-hydrazone solution and an iodine solution; adding an organic base, oxidant, and dehydroepiandrosterone 17-hydrazone solution to the iodine solution; or adding elemental iodine to the first organic solvent, followed by adding an organic base, oxidant, and dehydroepiandrosterone 17-hydrazone.

[0025] After the iodination reaction is completed, the product of the iodination reaction is preferably post-treated to obtain 3β-hydroxy-17-iodo-androst-5,16-diene. In this invention, the post-treatment includes sequential concentration, addition of water with stirring and filtration, and drying. This invention does not have special requirements for the concentration, water addition with stirring and filtration, and drying operations; any operation sufficient to purify the iodination reaction product is acceptable. In this invention, the first organic solvent is removed by concentration, then water is added to the concentrated residue, stirred, and filtered to remove water-soluble impurities. The filtered solid product is then dried to obtain 3β-hydroxy-17-iodo-androst-5,16-diene.

[0026] After obtaining 3β-hydroxy-17-iodo-androst-5,16-diene, the present invention performs a coupling reaction of the 3β-hydroxy-17-iodo-androst-5,16-diene with 3-pyridylborane, an inorganic base and a catalyst in a second organic solvent to obtain abiraterone.

[0027] In this invention, the 3-pyridylborane preferably comprises dimethyl(3-pyridyl)borane, diethyl(3-pyridyl)borane, or diisopropyl(3-pyridyl)borane; the molar ratio of the 3-pyridylborane to 3β-hydroxy-17-iodo-androst-5,16-diene is preferably (1~5):1, more preferably (1~3):1. In embodiments of this invention, the 3-pyridylborane is dimethyl(3-pyridyl)borane or diethyl(3-pyridyl)borane, and the molar ratio of the 3-pyridylborane to 3β-hydroxy-17-iodo-androst-5,16-diene is 1.08:1 or 2.34:1.

[0028] In this invention, the inorganic base preferably includes sodium carbonate, potassium carbonate, or potassium phosphate, more preferably sodium carbonate or potassium carbonate; the mass ratio of the inorganic base to 3β-hydroxy-17-iodo-androst-5,16-diene is preferably (0.2~2):1, more preferably (0.5~1):1. In embodiments of this invention, the mass ratio of the inorganic base to 3β-hydroxy-17-iodo-androst-5,16-diene is 0.8:1 or 1:1.

[0029] In this invention, the catalyst preferably comprises a nickel complex, wherein the ligands in the nickel complex are preferably 1,3-bis(diphenylphosphine)propane, 1,2-bis(diphenylphosphine)ethane, 1,4-bis(diphenylphosphine)butane, 1,1'-bis(diphenylphosphine)ferrocene, xanthylphosphine, tricyclohexylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, triphenylphosphine, tri-o-methylphenylphosphine, tri-p-tolylphosphine, 2,2'-bipyridine, or phenanthroline. In embodiments of this invention, the nickel complex is bis(triphenylphosphine)nickel chloride or bis(tricyclohexylphosphine)nickel chloride. In the catalyst of this invention, nickel atoms are isolated and dispersed in solution, avoiding the formation of large precipitates of nickel. After the ligands complex with nickel, they regulate the electron cloud density of nickel, enhance the oxidative addition capacity, control the steric hindrance of the catalyst, suppress side reactions, and improve the solubility of the catalyst.

[0030] In one embodiment of the present invention, the nickel complex can be obtained by coordination of nickel halide and ligand; the nickel halide preferably includes nickel chloride and / or nickel bromide.

[0031] In this invention, the mass ratio of the nickel complex to 3β-hydroxy-17-iodo-androst-5,16-diene is preferably (0.001~0.5):1, more preferably (0.1~0.5):1. In embodiments of this invention, the mass ratio of the nickel complex to 3β-hydroxy-17-iodo-androst-5,16-diene is 0.1:1 or 0.2:1.

[0032] In this invention, the catalyst preferably further includes a metallic reducing agent, which preferably includes zinc or manganese; the mass ratio of the metallic reducing agent to 3β-hydroxy-17-iodo-androst-5,16-diene is preferably (0.001~0.5):1, more preferably (0.1~0.5):1. In an embodiment of this invention, the metallic reducing agent is zinc powder, and the mass ratio of the metallic reducing agent to 3β-hydroxy-17-iodo-androst-5,16-diene is 0.3:1. This invention adds a reducing agent to the catalyst to reduce nickel halide to 0 valence before initiating the catalytic reaction; after the catalytic reaction begins, the nickel can be recycled.

[0033] In this invention, the second organic solvent includes N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide; the volume ratio of the second organic solvent to the mass ratio of 3β-hydroxy-17-iodo-androst-5,16-diene is preferably (5~20) mL:1 g, more preferably (10~20) mL:1 g. In embodiments of this invention, the second organic solvent is N,N-dimethylformamide or N,N-dimethylacetamide, and the volume ratio of the second organic solvent to the mass ratio of 3β-hydroxy-17-iodo-androst-5,16-diene is 10 mL:1 g or 15 mL:1 g.

[0034] In this invention, the temperature of the coupling reaction is 60~100℃, preferably 60~80℃; the time of the coupling reaction is 2~8h, preferably 2~6h. In an embodiment of this invention, the temperature of the coupling reaction is 70℃ or 80℃, and the time of the coupling reaction is 5h or 6h.

[0035] In one embodiment of the present invention, the coupling reaction is preferably carried out under a nitrogen atmosphere.

[0036] In one embodiment of the present invention, after the coupling reaction is completed, the product of the coupling reaction can be purified to obtain abiraterone.

[0037] As one embodiment of the present invention, the purification may include: cooling the product of the coupling reaction and then filtering it first, dissolving the obtained solid product and then filtering it second, and then washing, concentrating and drying the obtained liquid phase in sequence.

[0038] In this invention, the cooling temperature is preferably 5~15℃; after cooling, the product is preferably stirred and then filtered for the first time, and the stirring time is preferably 0.5~2h; the solvent for dissolving the solid product is preferably dichloromethane, and this invention does not have special requirements on the volume of the solvent used to dissolve the solid product, as long as it can completely dissolve the solid product; the number of water washings is preferably 3~5 times, and the amount of water used in each washing is preferably 100~150mL; this invention does not have special requirements on the concentration operation, as long as it can concentrate the liquid phase; the drying temperature is preferably 40~60℃, and the drying time is preferably 5~8h.

[0039] This invention involves cooling the reaction solution of the coupling reaction. The solubility of abiraterone in the second organic solvent decreases significantly with decreasing temperature, causing abiraterone to precipitate. After stirring, the mixture is filtered to separate the crude abiraterone from most impurities. The filtered solid product is dissolved in dichloromethane and filtered again. This further separation and impurity removal utilizes the property that abiraterone is soluble in dichloromethane while some inorganic salts and insoluble impurities are insoluble. The filtered liquid product is washed three times with water. Since abiraterone is essentially insoluble in water, residual inorganic salts and water-soluble impurities can be extracted from the organic phase using water. Finally, the washed solution is concentrated to dryness and then vacuum-dried to obtain abiraterone. This invention utilizes the difference in solubility of abiraterone and impurities in different solvents for stepwise purification and impurity removal, yielding high-purity abiraterone.

[0040] This invention uses dehydroepiandrosterone 17-hydrazone as a raw material and directly performs iodination and coupling reactions to obtain abiraterone without acetylation. Because acetylation is not performed, the 3-position of dehydroepiandrosterone 17-hydrazone remains a free hydroxyl group, which improves the solubility of dehydroepiandrosterone 17-hydrazone in the second organic solvent. This allows for sufficient contact of the reactants in a homogeneous phase, thereby accelerating the reaction rate, shortening the reaction time, and directly reducing the occurrence of side reactions, thus increasing the yield of abiraterone. The abiraterone prepared using the method provided by this invention can be purified by the difference in solubility of abiraterone and impurities in different solvents to remove impurities, improving the purity of abiraterone. Then, esterification can be used to prepare abiraterone acetate with high yield and high purity.

[0041] In the iodination reaction of this invention, an oxidant is used to oxidize the byproduct iodide ions in the system, causing them to regenerate into elemental iodine. This allows elemental iodine to be recycled, reducing the amount of elemental iodine used.

[0042] The coupling reaction of this invention uses a nickel-based catalyst instead of a traditional palladium catalyst, which can reduce production costs and avoid palladium residue in the product.

[0043] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0044] Example 1 A method for preparing abiraterone is as follows: Using 10g of dehydroepiandrosterone-17hydrazone as raw material, the following preparations were made: a volume ratio of tetramethylguanidine to dehydroepiandrosterone-17hydrazone of 3mL:1g, a mass ratio of N-bromosuccinimide to dehydroepiandrosterone-17hydrazone of 0.6:1, a mass ratio of elemental iodine to dehydroepiandrosterone-17hydrazone of 1:1, and a volume ratio of tetrahydrofuran to dehydroepiandrosterone-17hydrazone of 33mL:1g.

[0045] 10 g of dehydroepiandrosterone 17-hydrazone was dissolved in 180 mL of tetrahydrofuran as a reserve solution. 10 g of elemental iodine was added to 150 mL of tetrahydrofuran, and the mixture was cooled to -10 °C and maintained at this temperature. 30 mL of tetramethylguanidine (TMG) was added dropwise, followed by 6 g of N-bromosuccinimide (NBS). The reserve solution was then added dropwise, and the mixture was reacted at -10 °C for 1 hour to carry out the iodination reaction. The iodination product was concentrated to remove the tetrahydrofuran, and 200 mL of water was added. The mixture was stirred for 10 minutes, filtered, and dried at 50 °C to obtain 3β-hydroxy-17-iodo-androst-5,16-diene.

[0046] Using 10g of the obtained 3β-hydroxy-17-iodo-androst-5,16-diene as raw material, the following preparation was carried out: the molar ratio of diethyl(3-pyridyl)borane to 3β-hydroxy-17-iodo-androst-5,16-diene was 1.08:1; the mass ratio of sodium carbonate to 3β-hydroxy-17-iodo-androst-5,16-diene was 1:1; the mass ratio of bis(triphenylphosphine)nickel(II) chloride to 3β-hydroxy-17-iodo-androst-5,16-diene was 0.1:1; the mass ratio of zinc powder to 3β-hydroxy-17-iodo-androst-5,16-diene was 0.3:1; and the volume ratio of N,N-dimethylformamide to the mass ratio of 3β-hydroxy-17-iodo-androst-5,16-diene was 10mL:1g.

[0047] 10 g of 3β-hydroxy-17-iodo-androst-5,16-diene, 4 g of diethyl(3-pyridyl)borane, 1 g of bis(triphenylphosphine)nickel(II) chloride, 3 g of zinc powder, and 10 g of sodium carbonate were added to 100 mL of N,N-dimethylformamide (DMF), purged with nitrogen, and reacted at 70 °C for 6 hours for a coupling reaction. The coupling reaction product was cooled to 10 °C, stirred for 1 hour, filtered, and the filter cake was dissolved in 300 mL of dichloromethane. After filtration, the filtrate was washed three times with 100 mL of water each time. The dichloromethane solution after washing was concentrated to dryness and dried under vacuum at 50 °C for 5 hours to obtain 8.1 g of abiraterone, with a molar yield of 92.4%. The abiraterone obtained in this example was analyzed using an Agilent liquid chromatograph, and the liquid chromatogram is shown below. Figure 1 As shown, the purity of abiraterone obtained in this embodiment is 99.763%.

[0048] Example 2 A method for preparing abiraterone is as follows: Using 10g of dehydroepiandrosterone-17hydrazone as raw material, the following preparations were made: a volume ratio of tetramethylguanidine to dehydroepiandrosterone-17hydrazone of 4mL:1g, a mass ratio of N-chlorosuccinimide to dehydroepiandrosterone-17hydrazone of 0.7:1, a mass ratio of elemental iodine to dehydroepiandrosterone-17hydrazone of 0.9:1, and a volume ratio of dichloromethane to dehydroepiandrosterone-17hydrazone of 30mL:1g.

[0049] 9 g of elemental iodine was added to 300 mL of dichloromethane, cooled to 5 °C and maintained at that temperature. 40 mL of tetramethylguanidine (TMG) was added dropwise, followed by 7 g of N-chlorosuccinimide (NCS) and 10 g of dehydroepiandrosterone-17-hydrazone. The reaction was carried out at 5 °C for 1 hour to induce iodination. The iodination product was concentrated to remove the dichloromethane, and 200 mL of water was added. The mixture was stirred for 10 minutes, filtered, and dried at 50 °C to obtain 3β-hydroxy-17-iodo-androst-5,16-diene.

[0050] Using 10g of the obtained 3β-hydroxy-17-iodo-androst-5,16-diene as raw material, the following preparation was carried out: the molar ratio of dimethyl(3-pyridyl)borane to 3β-hydroxy-17-iodo-androst-5,16-diene was 2.34:1; the mass ratio of potassium carbonate to 3β-hydroxy-17-iodo-androst-5,16-diene was 0.8:1; the mass ratio of bis(tricyclohexylphosphine)nickel(II) chloride to 3β-hydroxy-17-iodo-androst-5,16-diene was 0.2:1; and the volume ratio of DMA to the mass ratio of 3β-hydroxy-17-iodo-androst-5,16-diene was 15mL:1g.

[0051] 10 g of 3β-hydroxy-17-iodo-androst-5,16-diene, 7 g of dimethyl(3-pyridyl)borane, 2 g of bis(tricyclohexylphosphine)nickel(II) chloride, and 8 g of potassium carbonate were added to 150 mL of N,N-dimethylacetamide (DMA), purged with nitrogen, and reacted at 80 °C for 5 hours for coupling reaction. The coupling reaction product was cooled to 10 °C, stirred for 1 hour, filtered, and the filter cake was dissolved in 300 mL of dichloromethane. After filtration, the filtrate was washed three times with 100 mL of water each time. The dichloromethane solution after washing was concentrated to dryness and dried under vacuum at 50 °C for 5 hours to obtain 8.0 g of abiraterone, with a molar yield of 91.2%. The abiraterone obtained in this example was analyzed using an Agilent liquid chromatograph, and the liquid chromatogram is shown below. Figure 2 As shown, the purity of abiraterone obtained in this embodiment is 99.848%.

[0052] As can be seen from the above embodiments, the preparation method of abiraterone provided by the present invention can shorten the coupling reaction time and obtain abiraterone with high purity and high yield.

[0053] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing abiraterone, characterized in that, Includes the following steps: (1) Dehydroepiandrosterone 17hydrazone, organic base, oxidant and iodine were subjected to iodination in the first organic solvent to obtain 3β-hydroxy-17-iodo-androst-5,16-diene; (2) The 3β-hydroxy-17-iodo-androst-5,16-diene obtained in step (1) is coupled with 3-pyridylborane, an inorganic base and a catalyst in a second organic solvent to obtain abiraterone; The temperature of the coupling reaction in step (2) is 60~100℃, and the time of the coupling reaction is 2~8h; The second organic solvent in step (2) includes N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

2. The preparation method according to claim 1, characterized in that, In step (1), the organic base includes tetramethylguanidine; the volume ratio of the organic base to the mass ratio of dehydroepiandrosterone 17-hydrazone is (1.6~5) mL: 1g.

3. The preparation method according to claim 1, characterized in that, The oxidant in step (1) includes N-bromosuccinimide or N-chlorosuccinimide; the mass ratio of the oxidant to dehydroepiandrosterone 17hydrazone is (0.01~1):

1.

4. The preparation method according to claim 1, characterized in that, In step (1), the mass ratio of elemental iodine to dehydroepiandrosterone-17-hydrazone is (0.4~2):

1.

5. The preparation method according to any one of claims 1 to 4, characterized in that, In step (1), the temperature of the iodination reaction is -20~10℃ and the time of the iodination reaction is 0.5~2h.

6. The preparation method according to claim 1, characterized in that, In step (2), 3-pyridylborane includes dimethyl (3-pyridyl)borane, diethyl (3-pyridyl)borane, or diisopropyl (3-pyridyl)borane; the molar ratio of 3-pyridylborane to 3β-hydroxy-17-iodo-androst-5,16-diene is (1~5):

1.

7. The preparation method according to claim 1, characterized in that, In step (2), the inorganic base includes sodium carbonate, potassium carbonate, or potassium phosphate; the mass ratio of the inorganic base to 3β-hydroxy-17-iodo-androst-5,16-diene is (0.2~2):

1.

8. The preparation method according to claim 1, characterized in that, In step (2), the catalyst includes a nickel complex, the ligands of which are 1,3-bis(diphenylphosphine)propane, 1,2-bis(diphenylphosphine)ethane, 1,4-bis(diphenylphosphine)butane, 1,1'-bis(diphenylphosphine)ferrocene, xanthylphosphine, tricyclohexylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, triphenylphosphine, tri-o-methylphenylphosphine, tri-p-tolylphosphine, 2,2'-bipyridine, or phenanthroline; the mass ratio of the nickel complex to 3β-hydroxy-17-iodo-androst-5,16-diene is (0.001~0.5):

1.

9. The preparation method according to claim 8, wherein the catalyst further comprises a metal reducing agent, wherein the metal reducing agent comprises zinc or manganese; and the mass ratio of the metal reducing agent to 3β-hydroxy-17-iodo-androst-5,16-diene is (0.001~0.5):

1.

10. The preparation method according to claim 1, characterized in that, In step (2), the volume ratio of the second organic solvent to the mass ratio of 3β-hydroxy-17-iodo-androst-5,16-diene is (5~20) mL:1g.

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