A method for preparing abiraterone acetate and its intermediates

Abstract

This invention provides a method for preparing abiraterone acetate and its intermediates. The method includes step (1): in an organic solvent, in the presence of a metal catalyst, reacting the compound shown in Formula II with the compound shown in Formula III-2 to obtain abiraterone acetate or its intermediates. The method of this invention is low-cost, high-yield, simple to operate, and suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and more specifically, to a method for preparing abiraterone acetate and its intermediates. Background Technology

[0002] Prostate cancer (PCA) is an epithelial malignant tumor that occurs in the prostate gland. After lung cancer, it is the second most common malignant tumor among men worldwide and the sixth leading cause of death. Approximately one in nine men will be diagnosed with prostate cancer in their lifetime, hence its nickname "male killer." Currently, the global incidence of prostate cancer is increasing. In 2020, approximately 1.5 million new cases were reported globally, accounting for 15% of new male cancer cases. It is projected that by 2022, the number of people with prostate cancer worldwide will reach 11 million.

[0003] Abiraterone acetate is the prodrug of abiraterone, which is rapidly converted into abiraterone in the body. Abiraraterone is a selective, irreversible steroidal inhibitor of CYP17 (17α-hydroxylase and C17,20-lyase), which inhibits enzyme activity to prevent testosterone synthesis in the testes, adrenal glands, and tumors. Developed by Johnson & Johnson, this product was first approved by the FDA on April 28, 2011, for use in combination with prednisone or prednisolone to treat castration-resistant metastatic prostate cancer (mCRPC) in patients unresponsive to androgen deprivation therapy and docetaxel chemotherapy. Subsequently, on December 10, 2012, approval was granted to expand the indication to the treatment of castration-resistant advanced metastatic prostate cancer.

[0004] Currently, the main methods for preparing abiraterone acetate are as follows:

[0005] I. Synthetic method reported in WO9509178: Dehydroepiandrosterone (DHEA) is used as a raw material. First, it reacts with hydrazine hydrate to form a hydrazone under the catalysis of hydrazine sulfate. Then, it undergoes an iodination reaction with elemental iodine under the catalysis of tetramethylguanidine (TMG) to generate an alkenyl iodide. The iodide then undergoes a coupling reaction with diethyl(3-pyridyl)borane under the catalysis of bis(triphenylphosphine)palladium chloride to generate abiraterone. Finally, the hydroxyl group at the 3-position is acetylated to obtain abiraterone acetate.

[0006]

[0007] The first step of this process takes 5 days, and the third step takes 4 days, resulting in an excessively long production cycle. The overall yield is only 36.9%, and the process also requires the use of malodorous reagents such as hydrazine hydrate, iodine, and tetramethylguanidine, causing significant environmental pollution. Therefore, it is not suitable for large-scale industrial production.

[0008] II. Synthetic method reported in WO2006021777: Using dehydroepiandrosterone acetate as a raw material, its trifluoromethanesulfonyl derivative is prepared by reacting with trifluoromethanesulfonic acid anhydride under the catalysis of a base such as triethylamine. Then, it is coupled with diethyl(3-pyridyl)borane under the catalysis of bis(triphenylphosphine)palladium chloride. For purification purposes, it is then reacted with methanesulfonic acid to obtain the methanesulfonate of abiraterone acetate, yielding abiraterone acetate methanesulfonate with a purity of 96.4% and an overall yield of 32.8%. Due to the high price of trifluoromethanesulfonic acid anhydride, the production cost of this synthetic method is high. Furthermore, trifluoromethanesulfonic acid anhydride has strong hygroscopicity and corrosiveness, posing a significant risk in its use. During the reaction, 3-dehydroxyabiraterone is also generated; this impurity is difficult to remove by recrystallization and generally requires removal by column chromatography.

[0009]

[0010] CN103864878A discloses two preparation methods that do not use diethyl(3-pyridyl)borane, as shown in route 3 and route 4 below:

[0011]

[0012] The raw materials for Route 3 are the same as those for Route 2, and the trifluoromethanesulfonic anhydride used is expensive. During the reaction, 3-dehydroxyabiraterone is also generated, and this impurity is difficult to remove by recrystallization and generally requires column chromatography. The raw materials for Route 4, and the preparation of the iodinated derivative, suffer from the same drawbacks as Route 1, including long reaction times, environmental pollution, and complex production operations.

[0013] Therefore, there is still a need in the field to find new methods for preparing abiraterone acetate that are low-cost, high-yield, simple to operate, and suitable for large-scale industrial production. Summary of the Invention

[0014] To address the aforementioned problems in the existing technology, the purpose of this invention is to provide a new method for preparing abiraterone acetate that has a high yield, low cost, and is suitable for industrial production.

[0015] This invention provides a method for preparing abiraterone acetate or an intermediate thereof, the method comprising the steps of: (1) reacting the compound shown in formula II with the compound shown in formula III-2 in an organic solvent in the presence of a metal catalyst to obtain the compound shown in formula I;

[0016] The reaction formula is as follows:

[0017]

[0018] Wherein, R1 is selected from hydrogen, C1-C6 alkyl, phenyl, benzyl, C1-C6 acyl, substituted or unsubstituted benzoyl, methanesulfonyl, substituted or unsubstituted benzylsulfonyl, trialkylsilyl, or dialkylarylsilyl, wherein the alkyl group in the trialkylsilyl and dialkylarylsilyl groups is C1-C3 alkyl.

[0019] R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, methanesulfonyl, substituted or unsubstituted benzylsulfonyl, dimethylaminoacyl, diethylaminoacyl, or diphenylphosphine.

[0020] The term "substitution" refers to the independent substitution of one or more hydrogen atoms on a group by a group selected from the group consisting of:

[0021] Halogen, C1-C4 alkyl, C1-C4 haloalkyl, ether, nitro, etc.

[0022] M is magnesium, iron, zinc, copper, tin, manganese, bismuth, or indium.

[0023] X is an isocoordinate anion of fluorine, chloride, bromine, iodine, or M. Preferably, the isocoordinate anion of M is selected from pivalate or acetate.

[0024] The metal catalyst is selected from palladium salts, copper salts, iron salts, cobalt salts, nickel salts, or combinations thereof.

[0025] In another preferred embodiment, the reaction system also contains a ligand selected from phosphorus-containing ligands, amino acid ligands, nitrogen-containing ligands, or combinations thereof.

[0026] In another preferred embodiment, an auxiliary agent is also present in the reaction system, the auxiliary agent being selected from alkali metal salts.

[0027] In another preferred embodiment, the reaction system also contains a ligand and an auxiliary agent, wherein the ligand is selected from phosphorus-containing ligands, amino acid ligands, nitrogen-containing ligands, or combinations thereof, and the auxiliary agent is selected from alkali metal salts.

[0028] In another preferred embodiment, R1 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl or trialkylsilyl, wherein the alkyl group in the trialkylsilyl group is C1-C3 alkyl. In another more preferred embodiment, R1 is selected from acetyl.

[0029] In another preferred embodiment, R2 is selected from C1-C6 acyl groups, or substituted or unsubstituted benzoyl groups. In yet another more preferred embodiment, R2 is selected from acetyl groups.

[0030] In another preferred embodiment, M is magnesium, zinc, tin, or manganese.

[0031] In another preferred embodiment, X is bromine or iodine.

[0032] In another preferred embodiment, the metal catalyst is selected from palladium chloride, palladium acetate, palladium chloride, cuprous iodide, copper acetate, copper sulfate, ferric chloride, ferrous chloride, ferric acetylacetone, ferrous acetylacetone, cobalt chloride, cobalt acetate, cobalt acetylacetone, nickel chloride, nickel bromide, nickel acetate, tricyclohexylphosphine nickel chloride, or combinations thereof.

[0033] In another preferred embodiment, in step (1), the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, toluene, or a combination thereof.

[0034] In another preferred embodiment, in step (1), the molar ratio of the compound shown in Formula II to the compound shown in Formula III-2 is 1:1.0 to 4.0. In another more preferred embodiment, the molar ratio of the compound shown in Formula II to the compound shown in Formula III-2 is 1:1.0 to 2.0.

[0035] In another preferred embodiment, in step (1), the molar ratio of the compound represented by Formula II to the metal catalyst is 1:0.005 to 0.3. In another more preferred embodiment, the molar ratio of the compound represented by Formula II to the metal catalyst is 1:0.01 to 0.2.

[0036] In another preferred embodiment, in step (1), the dropping temperature of the compound shown in III-2 is -30°C to 25°C, and the reaction temperature is 0°C to 70°C. In another more preferred embodiment, in step (1), the reaction temperature is room temperature to 50°C.

[0037] In another preferred embodiment, the ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, L-proline, alanine, methionine, pyridine, 2,2-bipyridine, 1,10-phenanthroline, or derivatives thereof.

[0038] In another preferred embodiment, the molar ratio of the compound represented by Formula II to the ligand is 1:0.005 to 0.3. In another more preferred embodiment, the molar ratio of the compound represented by Formula II to the ligand is 1:0.01 to 0.2.

[0039] In another preferred embodiment, the auxiliary agent is selected from potassium chloride, potassium carbonate, potassium tert-butoxide, potassium bicarbonate, potassium phosphate, potassium acetate, sodium carbonate, sodium bicarbonate, sodium acetate, lithium chloride, lithium carbonate, or combinations thereof.

[0040] In another preferred embodiment, in step (1), the molar ratio of the compound represented by Formula II to the adjuvant is 1:0.1 to 3. In another more preferred embodiment, the molar ratio of the compound represented by Formula II to the adjuvant is 1:1 to 2.

[0041] In another preferred embodiment, in the compound shown in Formula II, R2 is an acetyl group, the compound shown in III-2 is 3-pyridine magnesium bromide, the metal catalyst is PdCl2, the ligand is triphenylphosphine, and the auxiliary is sodium acetate.

[0042] In another preferred embodiment, in the compound shown in Formula II, R2 is an acetyl group, the compound shown in III-2 is 3-pyridine zinc bromide, the metal catalyst is anhydrous ferric chloride, the ligand is tetramethylethylenediamine (TMEDA), and the auxiliary is potassium acetate.

[0043] In another preferred embodiment, in the compound shown in Formula II, R2 is p-benzenesulfonyl, the compound shown in III-2 is 3-pyridinetin bromide, the metal catalyst is nickel acetate, the ligand is tricyclohexylphosphine, and the auxiliary is sodium carbonate.

[0044] In another preferred embodiment, in the compound shown in Formula II, R2 is benzoyl, the compound shown in III-2 is 3-pyridine manganese bromide, the metal catalyst is cuprous iodide, the ligand is L-proline, and the auxiliary is anhydrous potassium phosphate.

[0045] In another preferred embodiment, the above preparation method further includes the following steps:

[0046] (1-a) The compound shown in formula IV reacts with an acylation reagent to form the compound shown in formula II;

[0047] The reaction formula is as follows:

[0048]

[0049] The acylation reagent used to generate R1 is selected from R1-halogen, R1-O-R1, or... The acylation reagent used to generate R2 is selected from R2-halogen, R2-O-R2, or...

[0050] In another preferred embodiment, the acylation agent used to generate R1 is selected from C1-C6 alkyl acyl chlorides, substituted or unsubstituted benzoic anhydride, isopropyl acetate, or trimethylchlorosilane.

[0051] In another preferred embodiment, the acylation agent used to generate R2 is selected from isopropyl acetate, or substituted or unsubstituted benzoic anhydride.

[0052] Another aspect of the present invention provides a method for preparing abiraterone, the method comprising step (2): deprotecting the compound of formula I obtained by the above-mentioned method for preparing abiraterone acetate or its intermediates to generate abiraterone, the reaction formula being as follows:

[0053]

[0054] In another aspect, the present invention provides a method for preparing abiraterone acetate, the method comprising step (3): reacting the abiraterone obtained by the above-mentioned method with acetic anhydride to obtain abiraterone acetate, the reaction formula being as follows:

[0055] Detailed Implementation

[0056] Through extensive and in-depth research, and through numerous screenings and tests, the inventors have provided a method for preparing abiraterone acetate. Compared with existing technologies, the method of this invention is low-cost, has a high yield, and is very suitable for industrial production.

[0057] the term

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0059] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed.

[0060] As used herein, the term “room temperature” or “normal temperature” refers to a temperature of 4–40°C, preferably 25 ± 5°C.

[0061] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, refers to a straight-chain or branched hydrocarbon group having a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. C1-C3 alkyl groups represent alkyl groups containing 1 to 3 carbon atoms. C1-C6 alkyl groups represent alkyl groups containing 1 to 6 carbon atoms.

[0062] Unless otherwise stated, the term "C1-C6 acyl" means C1-C6 alkyl-(C=O)-.

[0063] As used in this article, the term "halogen" includes fluorine, chlorine, bromine, and iodine.

[0064] Unless otherwise specified, the term "solution" refers to an aqueous solution. Unless otherwise specified, "solution" refers to mass concentration.

[0065] Preparation method of the compound shown in Formula I

[0066] In one specific embodiment of the present invention, the preparation method of abiraterone acetate or an intermediate thereof includes the steps of: reacting the compound shown in Formula II with the compound shown in Formula III-2 in a solvent in the presence of a metal catalyst to obtain the compound shown in Formula I.

[0067] The reaction formula is as follows:

[0068]

[0069] R1 is selected from hydrogen, C1-C6 alkyl, phenyl, benzyl, C1-C6 acyl, substituted or unsubstituted benzoyl, methanesulfonyl, substituted or unsubstituted benzylsulfonyl, trialkylsilyl, or dialkylarylsilyl, wherein the alkyl group in the trialkylsilyl and dialkylarylsilyl groups is C1-C3 alkyl; R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, methanesulfonyl, substituted or unsubstituted benzylsulfonyl, dimethylaminoacyl, diethylaminoacyl, or diphenylphosphine; M is a metal ion such as magnesium, iron, zinc, copper, tin, manganese, bismuth, or indium; R1 and R2 can be the same or different; X is a fluorine, chlorine, bromine, iodine, or an isocoordinate anion of M, preferably, the isocoordinate anion of M is selected from pivalate or acetate; the metal catalyst is selected from palladium salt, copper salt, iron salt, cobalt salt, nickel salt, or a combination thereof.

[0070] In one specific embodiment, the reaction system of the above preparation method further includes ligands and / or auxiliaries. The ligands are selected from phosphorus-containing ligands, amino acid ligands, nitrogen-containing ligands, or combinations thereof, and the auxiliaries are selected from alkali metal salts. The role of the ligands and auxiliaries is to increase the reactivity of the reaction. The compound shown in Formula II can also react with the compound shown in Formula III-2 without the addition of ligands and auxiliaries.

[0071] The molar ratio of the compound shown in Formula II to the compound shown in Formula III-2 is not particularly limited, but can be used in the conventional amounts for this type of reaction, preferably 1:1 to 4, more preferably 1:1 to 2, such as 1:1.2, 1:1.5, 1:1.8, 1:2.0. The molar ratio of the compound shown in Formula II to the metal catalyst is not particularly limited, but can be used in the conventional amounts for this type of reaction, preferably 1:0.005 to 0.3, more preferably 1:0.01 to 0.2, such as 1:0.03, 1:0.05; 1:0.07, 1:0.1. The molar ratio of the compound shown in Formula II to the ligand is not particularly limited, but can be used in the conventional amounts for such reactions, preferably 1:0.005 to 0.3; more preferably 1:0.01 to 0.2, such as 1:0.01, 1:0.02, 1:0.05, 1:0.06, 1:0.08, 0.1. The molar ratio of the compound shown in Formula II to the auxiliary is not particularly limited, but can be used in the conventional amounts for such reactions, preferably 1:0.1 to 3, more preferably 1:1 to 2, such as 1:1.2, 1:1.5, 1:1.8, 1:2.0.

[0072] The compound shown in III-2 is added at a temperature of -30°C to 25°C and reacted at a temperature of 0°C to 70°C, more preferably at a temperature of room temperature to 50°C.

[0073] The solvents used in the reaction include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, and toluene.

[0074] The "metal catalyst" that can be used in this invention is a metal salt, including but not limited to palladium salts, copper salts, iron salts, cobalt salts, and nickel salts. Palladium salts include, but are not limited to, palladium chloride, palladium acetate, palladium chloride, palladium trifluoromethanesulfonate, or combinations thereof. Copper salts include, but are not limited to, cuprous iodide, copper acetate, copper chloride, or combinations thereof. Iron salts include, but are not limited to, ferric chloride, ferrous chloride, ferric acetylacetone, and ferrous acetylacetone. Cobalt salts include, but are not limited to, cobalt chloride, cobalt sulfate, cobalt acetate, and cobalt acetylacetone. Nickel salts include, but are not limited to, nickel chloride, nickel bromide, nickel acetate, and nickel tricyclohexylphosphine chloride.

[0075] The ligands that can be used in this invention include, but are not limited to, phosphorus-containing ligands, amino acid ligands, and nitrogen-containing ligands. "Phosphorus-containing ligands" refer to ligands containing phosphorus that can form coordination catalysts with metal catalysts to increase catalyst activity. These phosphorus-containing ligands include, but are not limited to, triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, and their derivatives. "Amino acid-containing ligands" refer to ligands containing amino acids that can form coordination catalysts with metal catalysts to increase catalyst activity. These amino acid-containing ligands include, but are not limited to, L-proline, alanine, methionine, and their derivatives. "Pyridine-containing ligands" refer to ligands containing a pyridine ring that can form coordination catalysts with metal catalysts to increase catalyst activity. These pyridine-containing ligands include, but are not limited to, pyridine, 2,2-bipyridine, 1,10-phenanthroline, and their derivatives.

[0076] The adjuvants that can be used in this invention include, but are not limited to, alkali metal salts. Alkali metal salts include, but are not limited to, potassium chloride, potassium carbonate, potassium tert-butoxide, potassium bicarbonate, potassium phosphate, potassium acetate, sodium carbonate, sodium bicarbonate, sodium acetate, lithium chloride, and lithium carbonate.

[0077] Preparation method of the compound shown in Formula III-2

[0078] Typically, the compound shown in Formula III-2 can be prepared by Grignard exchange of 3-bromopyridine with isopropyl magnesium chloride, followed by transmetalation with a metal salt or metal powder to generate a pyridine metal salt. This invention does not impose any particular requirements on the preparation method of the compound shown in Formula III-2; methods commonly used in this technical field or methods referring to this invention can be used. In one specific embodiment of this invention, the reaction formula for preparing the compound shown in Formula III-2 is as follows:

[0079]

[0080] 3-Bromopyridine can be replaced by inexpensive 3-chloropyridine. The solvent is generally an ether solvent such as tetrahydrofuran. The successfully prepared pyridine metal salt solution should be used as soon as possible to prevent deterioration.

[0081] Preparation method of the compound shown in Formula II

[0082] Typically, the compound shown in Formula II can be obtained by etherification or acylation at the 3-position and acylation or sulfonation at the 17-position of dehydroepiandrosterone. The present invention does not place particular emphasis on the acylation method; methods commonly used in the art or those described herein can be used.

[0083] In one specific embodiment of the present invention, the method for preparing the compound represented by Formula II includes the following steps:

[0084] (1-a) Compound IV reacts with an acylation reagent to form compound II;

[0085] The reaction formula is as follows:

[0086]

[0087] The acylation reagent used to generate R1 can be selected from R1-halogen, R1-O-R1, etc. The acylation reagent used to generate R2 can be selected from R2-halogen, R2-O-R2, etc.

[0088] The main advantages of this invention include:

[0089] The acylation reagent used in this invention is low in cost, overcoming the shortcomings of expensive raw materials and high cost in the prior art. It provides a low-cost, high-yield method for preparing abiraterone acetate that is suitable for industrial production.

[0090] The present invention will be explained in more detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention, and the nature and scope of the present invention are not limited thereto. Unless otherwise stated, percentages and parts refer to weight percentages and weight parts.

[0091] Example 1

[0092]

[0093] 1.44 kg (5.0 mol) of dehydroepiandrosterone, 86.0 g (0.5 mol, 0.1 equiv) of p-toluenesulfonic acid, and 10.0 L of isopropyl acetate were added to a reaction flask. The reaction mixture was heated to 120 ± 5 °C and distilled at atmospheric pressure for 2 hours until the remaining material volume was approximately 3 L. Distillation was then stopped, and the mixture was kept at this temperature with stirring for another 3 hours. The mixture was cooled to 0–5 °C and stirred for 30 minutes. After filtration, the filter cake was added to 5 L of water and stirred for 30 minutes. After filtration, the filter cake was added to 3 L of ethanol and stirred at room temperature for 30 minutes. The mixture was then cooled to 0–5 °C and stirred for 30 minutes. After filtration, the filter cake was washed with a small amount of cold ethanol and dried under vacuum at 35–40 °C to obtain 1.72 kg of 17-acetate androstened-5,16-diene-3β-acetate, with a molar yield of 92.2% and an HPLC purity of 99.2%.

[0094] 3-Bromopyridine (1 equivalent, 7.5 mol, 1185 g) was added to a three-necked reaction flask with a stirrer, followed by 2.7 L of tetrahydrofuran. The reaction mixture was cooled to -20 °C, and a THF solution of isopropyl magnesium chloride and lithium chloride (1.3 M, 1.0 equivalent, 7.5 mol, 5.8 L) was slowly added dropwise. The reaction mixture was then brought to room temperature and stirred for at least 6 hours to obtain a pyridine Grignard reagent (concentration approximately 1 mol / L).

[0095] 744.0 g (2.0 mol) of 17-acetate androstenedi-5,16-diene-3β-acetate, 164 g (2.0 mol) of sodium acetate, 14.1 g (0.02 mol) of PdCl2(PPh3)2 (equivalent to PdCl2 as the metal catalyst and PPh3 as the ligand), and 8.0 L of tetrahydrofuran were added to the reaction flask. The mixture was stirred until dissolved, cooled to -30 °C, and 2.0 L (2.0 mol) of pyridine Grignard tetrahydrofuran solution was added dropwise. After the addition was complete, the reaction mixture was heated to room temperature and stirred for 5 hours. After the reaction was completed by TLC monitoring, saturated ammonium chloride solution was slowly added dropwise to quench the reaction, and the mixture was concentrated to dryness under reduced pressure. The concentrate was dissolved in dichloromethane, filtered, and the filtrate was washed successively with 2 L of 1N hydrochloric acid aqueous solution, 2 L of 1N sodium bicarbonate aqueous solution, 2 L of 1N disodium EDTA solution, and 2 L of water. The organic layer was concentrated to dryness under reduced pressure. 3 L of 90% ethanol aqueous solution was added to the concentrate, and the mixture was heated to reflux until dissolved. After two hours, the mixture was cooled to 0–5 °C to induce crystallization. The crystals were filtered and dried under vacuum to obtain 716.6 g of crude abiraterone acetate, with a molar yield of 91.6% and an HPLC purity of 98.2%, containing 0.6% abiraterone impurities. Recrystallization of the crude product from acetone yielded 667.2 g of abiraterone acetate with a purity of 99.8%.

[0096] Mass spectrometry and nuclear magnetic resonance (NMR) analysis confirmed it to be abiraterone acetate.

[0097] ESI-MS (m / z): 414 [M+Na] + ;

[0098] 1 H NMR (500MHz, CDCl3) δ (ppm): 8.93 (s, 1H), 8.82 (d, 1H), 8.64 (d, 1H), 8.07 ~ 8.04 (d d,1H), 6.56(s,1H), 5.39(d,1H), 4.48~4.42(m,1H), 2.32~2.27(m,3H), 2.14~2.0 9(m,2H), 2.04~2.01(m,1H), 1.99(s,3H), 1.86~1.77(m,2H), 1.74~1.64(m,3H), 1 .60~1.52(m,3H), 1.45~1.39(m,1H), 1.11~1.01(m,2H), 1.05(s,3H), 1.04(s,3H). 13 C NMR (125MHz, CDCl3) δ (ppm): 170.6, 151.8, 148.1, 148.0, 140.1, 133.0, 133.8, 129.3, 123.1, 122. 4, 74.0, 57.6, 50.4, 47.4, 36.9, 38.2, 37.0, 35.3, 31.9, 31.6, 30.5, 27.8, 21.5, 20.9, 19.4, 16.7.

[0099] The role of ligands and auxiliaries is to increase the reactivity. However, the reaction can still proceed without ligands and auxiliaries, but the content of the target product in the reaction solution will decrease. Using the reaction conditions of step 2 of Example 1 as a model experiment, under the same experimental conditions (the reaction substrate and its amount, the catalyst (if present in the reaction system) and its amount, the ligand (if present in the reaction system) and its amount, the auxiliaries (if present in the reaction system) and their amount, the solvent, the reaction temperature, etc. are all the same as step 2 of Example 1), the reaction results without the addition of ligands and / or auxiliaries are shown in Table 1 below.

[0100] Table 1

[0101] Example catalyst ligands Additives purity of coupling reaction solution crude product yield 1-1 <![CDATA[PdCl2]]> <![CDATA[PPh3]]> Sodium acetate 96.3％ 91.6％ 1-2 <![CDATA[PdCl2]]> / Sodium acetate 72.0％ 55.6％ 1-3 <![CDATA[PdCl2]]> <![CDATA[PPh3]]> / 84.2％ 68.9％ 1-4 / <![CDATA[PPh3]]> Sodium acetate 0 0

[0102] As shown in Table 1 above, the reaction systems of Examples 1-2 contained no ligands. After the reaction was monitored by TLC, HPLC analysis of the reaction solution showed that the content of the target product was approximately 72.0%. The reaction systems of Examples 1-3 contained no auxiliary agents. After the reaction was monitored by TLC, HPLC analysis of the reaction solution showed that the content of the target product was approximately 84.2%, significantly lower than the content of the target product in the reaction solution of Example 1-1. The reaction systems of Examples 1-4 contained no catalyst, and the coupling reaction could not occur.

[0103] Example 2

[0104]

[0105] Add 14.4 g (0.05 mol) of dehydroepiandrosterone, 100 mL of dichloromethane, and 6.1 g (0.06 mol) of triethylamine to a reaction flask, stir until dissolved, and cool the mixture to 0–5 °C. Slowly add 4.9 g (52.5 mmol) of propionyl chloride dropwise. After the addition is complete, heat the reaction mixture to room temperature and stir for 3 hours. After the reaction is complete as monitored by TLC, slowly add 50 mL of water to the reaction solution. Allow to stand, separate the layers, remove the aqueous layer, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness. Add 0.9 g (5.0 mmol) of p-toluenesulfonic acid and 100 mL of isopropyl acetate to the concentrate, heat to 120 ± 5 °C, and distill at atmospheric pressure for 1 hour. Distill until the remaining volume is approximately 50 mL, stop distillation, and continue stirring for 2 hours. The reaction mixture was cooled to 0–5 °C, stirred for 30 minutes, filtered, and the filter cake was added to 80 mL of water. The mixture was stirred for 30 minutes, filtered, and the filter cake was added to 30 mL of ethanol. The mixture was stirred at room temperature for 30 minutes, cooled to 0–5 °C, stirred for 30 minutes, filtered, and the filter cake was washed with a small amount of cold ethanol. The mixture was then dried under vacuum at 35–40 °C to obtain 17.7 g of 17-acetate androstened-5,16-diene-3β-propionate, with a molar yield of 91.5% and an HPLC purity of 99.3%.

[0106] Take 200 ml of the pyridine Grignard reagent (concentration of about 1 mol / L) prepared according to Example 1 and add it to a three-necked flask. Cool it to 0°C and add 13.0 g (0.2 mol) of zinc powder while stirring. After the addition is completed, heat it to room temperature and continue stirring for 3 hours to obtain the pyridine zinc reagent for later use.

[0107] 7.7 g (0.02 mol) of 17-acetate androstenedione-5,16-diene-3β-propionate, 50 mL of 2-methyltetrahydrofuran, 0.64 g (0.004 mol) of anhydrous ferric chloride, 2.3 g (0.02 mol) of TMEDA, and 5.88 g (0.06 mol) of potassium acetate were added to a reaction flask. 30 mL (0.03 mol) of zinc pyridine reagent was added dropwise at room temperature. The mixture was stirred vigorously, heated to 50 °C, and reacted for 5 hours. After the reaction was completed under TLC monitoring, the mixture was filtered while hot, and the filtrate was concentrated to dryness. 50 mL of ethanol and 10 mL of 30% sodium hydroxide solution were added to the concentrate, and the mixture was heated to reflux and refluxed for 3 hours. After cooling to room temperature, 100 mL of water was added, and the mixture was aged for 30 minutes. The mixture was filtered, and the filter cake was dried under vacuum to obtain 5.7 g of abiraterone, with a molar yield of 81.7%.

[0108] Mass spectrometry and proton nuclear magnetic resonance (NMR) spectroscopy confirmed it to be abiraterone.

[0109] ESI-MS (m / z): 372 [M+Na]+ .

[0110] 1 H NMR (500MHz, CDCl3) δ (ppm): 8.58 (s, 1H), 8.43 (d, 1H), 7.76 ~ 7.74 (d, 1H), 7.34 ~ 7.32 (q, 1H), 6.11 (s, 1H), 5.30 (s, 1H), 4.62 (d, 1H) ), 2.19~2.10(m,3H), 2.07~2.02(m,3H), 1.77(m,1H), 1.69~1.61(m,4H), 1.53~1.51(m,2H), 1.37~1.35(m,2H), 1.01~0.96(m,8H).

[0111] Add 5.7 g (0.016 mol) of abiraterone, 50 mL of dichloromethane, and 3.0 g (0.03 mol) of triethylamine to a reaction flask. Cool to 0–5 °C, and slowly add 3.0 g (0.03 mol) of acetic anhydride. After the addition is complete, warm the reaction mixture to room temperature and maintain the reaction for 3 hours. Filter to remove insoluble matter, and wash the filtrate successively with 20 mL of water and 20 mL of 1N sodium bicarbonate aqueous solution. Concentrate the organic layer to dryness under reduced pressure, add 20 mL of 90% ethanol aqueous solution to the concentrate, heat to reflux to dissolve the mixture, and cool to 0–5 °C for 2 hours to induce crystallization. Filter, and vacuum dry the filter cake to obtain 5.9 g of crude abiraterone acetate, with a molar yield of 92.5% and an HPLC purity of 97.8%. Recrystallize the crude product from acetone to obtain 5.1 g of abiraterone acetate with a purity of 99.5%.

[0112] Example 3

[0113]

[0114] Add 14.4 g (0.05 mol) of dehydroepiandrosterone, 100 mL of dichloromethane, and 6.1 g (0.06 mol) of triethylamine to the reaction flask, stir until dissolved, and cool the mixture to 0–5 °C. Slowly add 5.7 g (52.5 mmol) of trimethylchlorosilane dropwise. After the addition is complete, heat the mixture to room temperature and stir for 4 hours. After the reaction is complete as monitored by TLC, slowly add 50 mL of water to the reaction solution. Allow to stand, separate the layers, remove the aqueous layer, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness. Add 5.6 g (0.05 mol) of potassium tert-butoxide and 100 mL of tetrahydrofuran to the concentrate, stir for 10 minutes, cool the mixture to 0–5 °C, slowly add 16.3 g (0.05 mol) of p-toluenesulfonic anhydride, heat to 60–65 °C, and stir for 5 hours. After the reaction was completed under TLC monitoring, the reaction solution was concentrated under reduced pressure until the remaining material volume was approximately 50 mL. 80 mL of water was added, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filter cake was added to 30 mL of ethanol and stirred at room temperature for 30 minutes. The slurry was cooled to 0–5 °C, stirred for 30 minutes, filtered, and the filter cake was washed with a small amount of cold ethanol. The mixture was then vacuum dried at 35–40 °C to obtain 21.2 g of 17-p-toluenesulfonate androstened-5,16-diene-3β-trimethylsilyl ester, with a molar yield of 82.6% and an HPLC purity of 98.3%.

[0115] Take 200 ml of the pyridine Grignard reagent (concentration of about 1 mol / L) prepared according to Example 1 and add it to a three-necked flask. Cool it to 0°C and add 52.0 g (0.2 mol) of anhydrous tin chloride while stirring. After the addition is completed, heat it to room temperature and continue stirring for 3 hours to obtain the pyridine tin reagent for later use.

[0116] 10.3 g (0.02 mol) of 17-p-toluenesulfonate androst-5,16-diene-3β-trimethylsilyl ester, 0.35 g (0.002 mol) of nickel acetate, 0.56 g (0.002 mol) of tricyclohexylphosphine, 2.12 g (0.02 mol) of sodium carbonate, and 50 mL of ethylene glycol dimethyl ether were added to a reaction flask. After stirring until homogeneous, 20 mL of pyridinetin reagent was added at room temperature. The reaction mixture was heated to 40 °C and stirred for 5 hours. After the reaction was completed by TLC monitoring, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. The concentrate was added to 50 mL of ethanol and 10 mL of 30% sodium hydroxide solution, heated to reflux, and stirred for 5 hours. The mixture was cooled to room temperature, 100 mL of drinking water was added, and the mixture was aged for 30 minutes. After filtration, the filter cake was dried under vacuum to obtain 4.6 g of abiraterone, with a molar yield of 66.1%.

[0117] Add 4.6 g (0.013 mol) of abiraterone, 50 mL of dichloromethane, and 2.0 g (0.02 mol) of triethylamine to a reaction flask. Cool the mixture to 0–5 °C, and slowly add 2.0 g (0.02 mol) of acetic anhydride dropwise. After the addition is complete, raise the temperature to room temperature and maintain the reaction for 3 hours. Filter to remove insoluble matter. Wash the filtrate successively with 20 mL of water and 20 mL of 1N sodium bicarbonate aqueous solution. Concentrate the organic layer to dryness under reduced pressure. Add 20 mL of 90% ethanol-water to the concentrate and heat to reflux to dissolve the mixture. Cool to 0–5 °C for two hours to induce crystallization. Filter, and vacuum dry the filter cake to obtain 4.8 g of crude abiraterone acetate, with a molar yield of 94.4% and an HPLC purity of 98.0%. Recrystallize the crude product from acetone to obtain 4.0 g of abiraterone acetate with a purity of 99.5%.

[0118] Example 4

[0119]

[0120] Add 14.4 g (0.05 mol) of dehydroepiandrosterone, 11.2 g (0.1 mol) of potassium tert-butoxide, and 50 mL of DMF to a reaction flask. Stir for 10 minutes, cool the mixture to 0–5 °C, and slowly add 7.1 g (0.05 mol) of iodomethane. Heat the reaction mixture to 40 °C and stir overnight. Add 200 mL of water, filter, and dry the filter cake directly. Dissolve the filter cake in 100 mL of tetrahydrofuran, add 12.4 g (0.55 mol) of benzoic anhydride, and reflux the reaction mixture. Keep it warm and stir for 5 hours. After the reaction is completed under TLC monitoring, concentrate the reaction solution under reduced pressure to a remaining volume of approximately 50 mL. Add 80 mL of water and stir for 30 minutes. Filter, add the filter cake to 50 mL of water, stir for 30 minutes, filter again, add the filter cake to 30 mL of ethanol, and slurry at room temperature for 30 minutes. The slurry was cooled to 0–5°C, stirred for 30 minutes, filtered, and the filter cake was washed with a small amount of cold ethanol. It was then vacuum dried at 35–40°C to obtain 16.8 g of 17-benzoate androstened-5,16-diene-3β-methyl ether, with a molar yield of 83.0% and an HPLC purity of 97.5%.

[0121] Take 200 ml of the pyridine Grignard reagent (concentration of about 1 mol / L) prepared according to Example 1 and add it to a three-necked flask. Cool it to 0°C and add 100 ml of toluene. While stirring, add 25.2 g (0.2 mol) of anhydrous manganese chloride. After the addition is completed, heat the reaction mixture to room temperature and continue stirring for 3 hours to obtain the pyridine manganese reagent for later use.

[0122] 8.1 g (0.02 mol) of androstened 5,16-diene-3β-methyl ether (17-benzoate), 0.38 g (0.002 mol) of cuprous iodide, 0.23 g (0.002 mol) of L-proline, 6.4 g (0.03 mol) of anhydrous potassium phosphate, and 40 mL of tetrahydrofuran were added to a reaction flask. 33 mL of manganese pyridine reagent was slowly added dropwise, and the mixture was stirred vigorously. The reaction mixture was heated to 50 °C and stirred for 6 hours. After the reaction was completed under TLC monitoring, the mixture was filtered while hot, and the filtrate was concentrated to dryness and then distilled once with dichloromethane. The concentrate was dissolved in 50 mL of dichloromethane, cooled to 0 °C, and 5 mL of boron tribromide was slowly added. The mixture was stirred for 3 hours, quenched by slowly adding 10 mL of methanol, and then 100 mL of water was added. The mixture was allowed to stand, and the layers were separated. The organic layer was concentrated to dryness, crystallized from a 60% aqueous ethanol solution, filtered, and dried under vacuum to give 4.9 g of abiraterone, with a molar yield of 70.2%.

[0123] Add 4.9 g (0.014 mol) of abiraterone, 50 mL of dichloromethane, and 3.0 g (0.03 mol) of triethylamine to a reaction flask. Cool the mixture to 0–5 °C, and slowly add 3.0 g (0.03 mol) of acetic anhydride dropwise. After the addition is complete, heat to room temperature and maintain the reaction for 3 hours. Filter to remove insoluble matter. Wash the filtrate successively with 20 mL of water and 20 mL of 1N sodium bicarbonate aqueous solution. Concentrate under reduced pressure to dryness. Add the concentrate to 20 mL of 90% ethanol-water mixture and heat to reflux to dissolve completely. Cool the solution to 0–5 °C for two hours to allow crystallization. Filter and vacuum dry to obtain 5.2 g of crude abiraterone acetate, with a molar yield of 95.0% and an HPLC purity of 98.0%. Recrystallize the crude product from acetone to obtain 4.7 g of abiraterone acetate with a purity of 99.6%.

[0124] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A process for the preparation of an abiraterone intermediate characterized in that, The preparation method comprises the steps of: (1-a) reacting a compound shown in formula IV with an acylating agent to form a compound shown in formula II, The reaction formula is as follows: ， wherein the acylating agent used to generate R1is selected from R1-halogen, R1-O-R1or , the acylating agent used to generate R2is selected from R2-halogen, R2-O-R2or , R1 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, methylsulfonyl, substituted or unsubstituted benzenesulfonyl, and trialkylsilyl, wherein the alkyl in the trialkylsilyl is C1-C3 alkyl, R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, methylsulfonyl, and substituted or unsubstituted benzenesulfonyl, (1) reacting a compound shown in formula II with a compound shown in formula III-2 in an organic solvent in the presence of a metal catalyst, a ligand, and an auxiliary to obtain a compound shown in formula I; The reaction formula is as follows: ， The "substitution" means that one or more hydrogen atoms on a group are independently substituted by a group selected from the following group: halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, M is magnesium, zinc, tin, manganese, X is chlorine, bromine, iodine, The metal catalyst is selected from palladium acetate, palladium chloride, cuprous iodide, ferric chloride, ferrous chloride, iron acetylacetonate, ferrous acetylacetonate, cobalt chloride, cobalt acetate, cobalt acetylacetonate, nickel chloride, nickel bromide, nickel acetate, or a combination thereof, The ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, L-proline, alanine, methionine, pyridine, 2,2-bipyridine, or 1,10-phenanthroline, The auxiliary is selected from potassium chloride, potassium carbonate, potassium tert-butoxide, potassium bicarbonate, potassium phosphate, potassium acetate, sodium carbonate, sodium bicarbonate, sodium acetate, lithium chloride, lithium carbonate, or a combination thereof.

2. The production method according to claim 1, characterized by, R1 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, and trialkylsilyl, R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, X is chlorine or bromine.

3. The preparation method according to claim 2, characterized in that, R1 is selected from acetyl, R2 is selected from acetyl.

4. The method according to claim 1 or 2, characterized in that, Step (1) has one or more characteristics selected from the following group: The organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, toluene, or a combination thereof, The molar ratio of the compound shown in formula II to the compound shown in formula III-2 is 1:1.0-4.0, The molar ratio of the compound shown in formula II to the metal catalyst is 1:0.005-0.3, The dropping temperature of the compound shown in formula III-2 is -30°C-25°C, and the reaction temperature of the compound shown in formula II with the compound shown in formula III-2 is 0-70°C.

5. The method of claim 4, wherein, The molar ratio of the compound shown in formula II to the compound shown in formula III-2 is 1:1.0-2.0, The molar ratio of the compound shown in formula II to the metal catalyst is 1:0.01-0.2, The reaction temperature of the compound shown in formula II with the compound shown in formula III-2 is room temperature-50°C.

6. The method of claim 1, wherein, The molar ratio of the compound shown in formula II to the ligand is 1:0.005-0.3, The molar ratio of the compound shown in formula II to the auxiliary is 1:0.1-3.

7. The method of claim 6, wherein, The molar ratio of the compound shown in formula II to the ligand is 1:0.01-0.2, The molar ratio of the compound of formula II to the auxiliary agent is 1:1-2.

8. The method of claim 1, wherein, In the compound of formula II, R2 is acetyl, the compound of formula III-2 is 3-pyridyl magnesium bromide, the metal catalyst is PdCl2, the ligand is triphenylphosphine, and the auxiliary agent is sodium acetate, or In the compound of formula II, R2 is p-toluensulfonyl, the compound of formula III-2 is 3-pyridyl tin bromide, the metal catalyst is nickel acetate, the ligand is tricyclohexylphosphine, and the auxiliary agent is sodium carbonate, or In the compound of formula II, R2 is benzoyl, the compound of formula III-2 is 3-pyridyl manganese bromide, the metal catalyst is cuprous iodide, the ligand is L-proline, and the auxiliary agent is anhydrous potassium phosphate.

9. The production method according to claim 1, wherein The acylating agent for generating R1 is selected from the group consisting of C1-C6 alkyl acid chloride, substituted or unsubstituted benzoic anhydride, isopropenyl acetate, or trimethylchlorosilane, The acylating agent for generating R2 is selected from the group consisting of isopropenyl acetate or substituted or unsubstituted benzoic anhydride.

10. A process for the preparation of an abiraterone intermediate characterized in that, The preparation method comprises the following steps: (1-a) reacting the compound of formula IV with an acylating agent to form the compound of formula II, The reaction formula is as follows: ， wherein the acylating agent used to generate R1is selected from R1-halogen, R1-O-R1or , the acylating agent used to generate R2is selected from R2-halogen, R2-O-R2or , R1 is selected from the group consisting of C1-C6 acyl, substituted or unsubstituted benzoyl, methylsulfonyl, substituted or unsubstituted benzenesulfonyl, and trialkylsilyl, wherein the alkyl in the trialkylsilyl is C1-C3 alkyl, and "substituted" means that one or more hydrogen atoms in the group are independently substituted by a group selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, R2 is selected from the group consisting of acetyl, (1) reacting the compound of formula II with the compound of formula III-2 in the presence of a metal catalyst, a ligand, and an auxiliary agent in an organic solvent to obtain the compound of formula I; The reaction formula is as follows: ， M is zinc, X is bromine, The metal catalyst is selected from the group consisting of anhydrous iron chloride, The ligand is selected from the group consisting of tetramethylethylenediamine, The auxiliary agent is selected from the group consisting of potassium acetate.

11. A method of preparing abiraterone, characterized by, The preparation method comprises the following steps: (1) preparing the compound of formula I according to the preparation method in any one of claims 1 to 9; (2) deprotecting the compound of formula I obtained in step (1) to obtain abiraterone, and the reaction formula is as follows: 。 12. A process for the preparation of abiraterone acetate, characterized in that, The preparation method comprises the following steps: (1) preparing abiraterone according to the preparation method in claim 11; (2) reacting the abiraterone obtained in step (1) with acetic anhydride to obtain abiraterone acetate, and the reaction formula is as follows: 。 13. A process for the preparation of abiraterone acetate, characterized in that, The preparation method comprises the following steps: (1) reacting the compound of formula II with the compound of formula III-2 in the presence of a metal catalyst, a ligand, and an auxiliary agent in a solvent to obtain the compound of formula I, The reaction formula is as follows: ， In formula II and formula I, R1 is selected from the group consisting of acetyl, R2 is selected from the group consisting of C1-C6 acyl, substituted or unsubstituted benzoyl, methylsulfonyl, and substituted or unsubstituted benzenesulfonyl, "substituted" means that one or more hydrogen atoms in the group are independently substituted by a group selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, M is magnesium, zinc, tin, or manganese, X is chlorine, bromine, iodine, the metal catalyst is selected from palladium acetate, palladium chloride, cuprous iodide, ferric chloride, ferrous chloride, iron acetylacetonate, iron acetylacetonate, cobalt chloride, cobalt acetate, cobalt acetylacetonate, nickel chloride, nickel bromide, nickel acetate, or combinations thereof, the ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, L-proline, alanine, methionine, pyridine, 2,2-bipyridine, or 1,10-phenanthroline, the adjuvant is selected from potassium chloride, potassium carbonate, potassium tert-butoxide, potassium bicarbonate, potassium phosphate, potassium acetate, sodium carbonate, sodium bicarbonate, sodium acetate, lithium chloride, lithium carbonate, or combinations thereof.

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