Electrochemical preparation method of abiraterone and its derivatives

Abstract

The present invention provides an electrochemical preparation method for abiraterone and its derivatives, specifically involving the following steps: in a solvent, in the presence of a metal catalyst, a ligand, and an electrolyte, and under the action of a constant current, a 17-hydroxyester androsterone-5,16-diene-3β-hydroxy (ester) is reacted with a 3-halopyridine to produce an abiraterone derivative. The electrochemical preparation method of the present invention has low cost, high yield, low waste, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and in particular to an electrochemical preparation method of abiraterone and its derivatives. Background Art

[0002] Prostate cancer (PCA) is an epithelial malignancy that develops in the prostate gland. It is the second most common malignant tumor in men worldwide, after lung cancer, and ranks sixth in mortality. Approximately one in nine men will be diagnosed with prostate cancer in their lifetime, earning it the nickname "the male killer." The global incidence of prostate cancer is currently increasing. In 2020, there were approximately 1.5 million new cases worldwide, accounting for 15% of all new cancer cases in men. It is estimated that by 2022, the number of people suffering from prostate cancer worldwide will reach 11 million.

[0003] Abiraterone acetate is a prodrug of abiraterone that is rapidly converted in the body to abiraterone, a selective, irreversible steroidal inhibitor of CYP17 (17α-hydroxylase and C17,20-lyase). By inhibiting enzyme activity, it blocks testosterone synthesis in the testes, adrenal glands, and tumors. This product, developed by Johnson & Johnson, was first approved by the US FDA on April 28, 2011, for combination with prednisone or prednisolone for the treatment of castration-resistant metastatic prostate cancer (mCRPC) in patients refractory to androgen deprivation therapy and docetaxel chemotherapy. The indication was subsequently expanded on December 10, 2012, to include the treatment of advanced castration-resistant metastatic prostate cancer.

[0004] There are currently two main methods for preparing abiraterone acetate:

[0005] 1. The synthesis method reported in WO9509178: Dehydroepiandrosterone (DHEA) is used as the raw material. It is first reacted with hydrazine hydrate under the catalysis of hydrazine sulfate to form a hydrazone. Then, it undergoes an iodination reaction with elemental iodine under the catalysis of tetramethylguanidine (TMG) to form an alkenyl iodide. The iodide is then coupled with diethyl (3-pyridyl) borane under the catalysis of bistriphenylphosphine palladium chloride to produce abiraterone. Finally, the 3-hydroxyl group is acetylated to obtain abiraterone acetate.

[0006]

[0007] The first step of this route takes 5 days to react, and the third step takes 4 days to react, which makes the production cycle too long. The total yield is only 36.9%. The process also requires the use of malodorous reagents such as hydrazine hydrate, iodine, and tetramethylguanidine, which causes serious environmental pollution and is therefore not suitable for large-scale industrial production.

[0008] 2. The synthesis method reported in WO2006021777: Dehydroepiandrosterone acetate is used as a raw material, and is reacted with trifluoromethanesulfonic anhydride under the catalysis of a base such as triethylamine to prepare its trifluoromethanesulfonyl derivative, which is then coupled with diethyl (3-pyridyl) borane under the catalysis of bistriphenylphosphine palladium chloride. Then, for the purpose of purification, it is salified with methanesulfonic acid to obtain the mesylate of abiraterone acetate, and the total yield of abiraterone acetate mesylate with a purity of 96.4% is 32.8%.

[0009]

[0010] In addition to low overall yields, the two methods mentioned above also have complex reaction systems and require expensive metal catalysts for the key Suzuki coupling reaction, resulting in high production costs. The nucleophilic reagent used is diethyl(3-pyridyl)borane, which is complex to prepare, poses safety risks, has a long reaction route, and requires significant waste treatment.

[0011] Therefore, this field still needs to find a new method for preparing abiraterone acetate with low cost, less three-waste pollution and suitable for large-scale industrial production. Summary of the Invention

[0012] In response to the above-mentioned problems existing in the prior art, the present invention aims to provide a method for the electrochemical synthesis of abiraterone and its derivatives with low cost, high yield, low pollution of three wastes, and suitability for industrial production. To achieve the object of the present invention, the present invention adopts the following technical solutions:

[0013] An electrochemical preparation method for abiraterone or a derivative thereof, comprising step (1): reacting a compound represented by formula II with a compound represented by formula III in a solvent in the presence of a metal catalyst, a ligand, and an electrolyte under the action of a constant current to produce a compound represented by formula I, as shown in the following reaction formula:

[0014]

[0015] wherein R1 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, methylsulfonyl, substituted or unsubstituted phenylsulfonyl or C1-C2 trialkylsilyl;

[0016] R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, methylsulfonyl, substituted or unsubstituted benzenesulfonyl, dimethylaminoacyl, diethylaminoacyl or diphenylphosphinyl;

[0017] The term "substituted" refers to that one or more hydrogen atoms on a group are independently replaced by a group selected from the following groups:

[0018] Halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0019] X is fluorine, chlorine, bromine or iodine;

[0020] The metal catalyst is selected from: palladium salt, copper salt, cobalt salt, nickel salt, or a combination thereof; and

[0021] The ligand is selected from a phosphorus-containing ligand, an amino acid-containing ligand, a pyridine ring-containing ligand, or a combination thereof.

[0022] Preferably, R1 is acetyl, and the compound represented by Formula I is abiraterone acetate.

[0023] Preferably, the molar ratio of the compound represented by formula II to the compound represented by formula III is 1:1-4, more preferably 1:1-3, further preferably 1:1.5-2.2, such as 1:1.8 or 1:2.5;

[0024] Preferably, the molar ratio of the compound represented by formula II to the metal catalyst is 1:0.005 to 0.2, more preferably 1:0.01 to 0.1, further preferably 1:0.03 to 0.07, such as 1:0.04, 1:0.005 or 1:0.006;

[0025] Preferably, the molar ratio of the compound represented by formula II to the ligand is 1:0.005-0.3, more preferably 1:0.01-0.2, further preferably 1:0.05-0.12, such as 1:0.06, 1:0.08, and 1:0.10.

[0026] Preferably, the molar volume ratio of the electrolyte to the reaction solution is 0.1 to 0.5 mol / L.

[0027] Preferably, in step (1), the constant current is 0.05A to 1.0A, more preferably 0.1A to 0.5A.

[0028] Preferably, in step (1), the current density is 0.01 to 0.2 A / cm 2 , preferably 0.02~0.1A / cm 2 .

[0029] Preferably, in step (1), the reaction temperature is 0°C to 60°C, more preferably 10°C to 50°C.

[0030] Preferably, the metal catalyst is selected from bistriphenylphosphine palladium chloride, palladium acetate, palladium chloride, palladium trifluoromethanesulfonate, cuprous iodide, copper acetate, copper chloride, cobalt chloride, cobalt acetylacetonate, cobalt acetate, cobalt sulfate, nickel acetate, tricyclohexylphosphine nickel chloride or a combination thereof.

[0031] Preferably, the ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, L-proline, alanine, methionine, pyridine, 2,2-bipyridine, 1,10-phenanthroline, or a combination thereof.

[0032] Preferably, the electrolyte is selected from tetraethylammonium perchlorate, tetraethylammonium p-toluenesulfonate, tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, tetraethylammonium hexafluorophosphonate or a combination thereof.

[0033] Preferably, the solvent used in the reaction is selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or a combination thereof.

[0034] Preferably, the anode electrode used in the electrochemical reaction is iron, zinc, magnesium, nickel, aluminum or a combination thereof, and the cathode electrode is platinum.

[0035] Preferably, in the compound represented by formula II, R2 is acetyl, in the compound represented by formula III, X is bromine, the metal catalyst is PdCl2(PPh3)2, and the ligand is bipyridine.

[0036] Preferably, in the compound represented by formula II, R2 is acetyl, in the compound represented by formula III, X is iodine, the metal catalyst is nickel acetate, and the ligand is tricyclohexylphosphine.

[0037] Preferably, in the compound represented by formula II, R2 is p-toluenesulfonyl, in the compound represented by formula III, X is chlorine, the metal catalyst is cuprous iodide, and the ligand is L-proline, or

[0038] Preferably, in the compound represented by formula II, R2 is benzoyl, in the compound represented by formula III, X is fluorine, the metal catalyst is nickel chloride, and the ligand is 1,10-phenanthroline.

[0039] Preferably, step (1) comprises: sequentially adding a solvent, a compound represented by formula II, a compound represented by formula III, a metal catalyst, a ligand and an electrolyte into a reaction vessel, then fixing an anode electrode and a cathode electrode into the reaction vessel, turning on a power supply, and carrying out a reaction under the action of a constant current.

[0040] Preferably, the method further comprises reacting the compound represented by formula IV with an acylating agent to generate the compound represented by formula II.

[0041] The reaction formula is as follows:

[0042]

[0043] Wherein, the acylating agent for generating R1 is selected from R1-halogen, R1-O-R1 or and

[0044] The acylating agent used to generate R2 is selected from R2-halogen, R2-O-R2 or

[0045] Preferably, the acylating agent used to generate R1 is selected from C1-C6 alkyl acyl chloride, substituted or unsubstituted benzoic anhydride, isopropyl acetate or trimethylsilyl chloride.

[0046] Preferably, the acylating agent used to generate R2 is selected from isopropenyl acetate, substituted or unsubstituted benzoic anhydride or substituted or unsubstituted benzenesulfonic anhydride.

[0047] Preferably, the electrochemical preparation method further comprises step (2): deprotecting the compound represented by formula I to generate abiraterone,

[0048]

[0049] Preferably, the above-mentioned deprotection is carried out in a solvent, and the solvent is selected from alcohol.

[0050] Preferably, the alcohol is selected from methanol, ethanol, isopropanol, or a combination thereof.

[0051] Preferably, the above-mentioned deprotection is carried out in the presence of a base, and the base is selected from sodium hydroxide and / or potassium hydroxide.

[0052] Preferably, the above-mentioned deprotection is carried out at 50-100°C.

[0053] Another object of the present invention is to provide a method for preparing abiraterone acetate, which comprises step (3): reacting the abiraterone prepared by the above electrochemical preparation method with acetic anhydride to produce abiraterone acetate.

[0054]

[0055] Preferably, the solvent used in the reaction of abiraterone and acetic anhydride is selected from dichloromethane.

[0056] Preferably, the reaction of abiraterone with acetic anhydride is carried out in the presence of a base, and the base is selected from triethylamine.

[0057] Preferably, the temperature for the reaction of abiraterone and acetic anhydride is 0-40°C, more preferably 10-30°C.

[0058] Electrochemical organic synthesis uses electrons as clean redox reagents, possessing unique advantages and occupying a prominent position in the field of green chemistry. Electrochemical coupling to form new chemical bonds does not require the addition of additional oxidants or reducing agents, resulting in minimal waste pollution and significant application value. Compared to existing chemical preparation methods, the electrochemical preparation method for abiraterone and its derivatives provided by the present invention offers lower costs, reduced waste emissions, higher yields, shorter routes, and easier operation, making it more suitable for industrial production. DETAILED DESCRIPTION

[0059] The inventors of this application have addressed the shortcomings of existing methods for preparing abiraterone and its derivatives. Through extensive and in-depth research, extensive screening and testing, they have developed an electrochemical method for preparing abiraterone and its derivatives. Compared to existing methods, the present method offers low cost, high yield, and minimal pollution, making it highly suitable for industrial production. This is the basis for the present invention.

[0060] the term

[0061] Unless defined otherwise, 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 belongs.

[0062] In the description of the present invention, the term "comprising" or "including" may be open, semi-closed or closed. In other words, the term also includes "consisting essentially of" or "consisting of."

[0063] In the description of the present invention, the term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably, 25±5°C.

[0064] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon radical having the specified number of carbon atoms (e.g., C1-C6 means 1 to 6 carbon atoms, such as C1-C4). Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0065] Unless otherwise indicated, the term "acyl", used alone or as part of another group, refers to a group in which both hydrogens on the carbon closest to the point of attachment of the group are replaced with the substituent =0. "C1-C6 acyl" refers to a C1-C6 alkyl-(C=O)- group.

[0066] In the description of the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0067] The "metal catalyst" that can be used in the present invention is a metal salt, including but not limited to palladium salts, copper salts, cobalt salts, nickel salts or combinations thereof. The palladium salts that can be used in the present invention include but are not limited to bistriphenylphosphine palladium chloride, palladium acetate, palladium chloride, trifluoromethanesulfonate palladium or combinations thereof. The copper salts that can be used in the present invention include but are not limited to cuprous iodide, cupric acetate copper chloride or combinations thereof. The cobalt salts that can be used in the present invention include but are not limited to cobalt chloride, cobalt acetylacetonate or combinations thereof, cobalt acetate, cobalt sulfate. The nickel salts that can be used in the present invention include but are not limited to nickel acetate, tricyclohexylphosphine nickel chloride or combinations thereof.

[0068] In the description of the present invention, a "phosphorus-containing ligand" refers to a ligand containing phosphorus that can form a coordination catalyst with a metal catalyst to increase the activity of the catalyst. The phosphorus-containing ligand includes but is not limited to triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, or a combination thereof. An "amino acid-containing ligand" refers to a ligand containing an amino acid that can form a coordination catalyst with a metal catalyst to increase the activity of the catalyst. The amino acid-containing ligand includes but is not limited to L-proline, alanine, methionine, or a combination thereof. A "pyridine ring-containing ligand" refers to a ligand containing a pyridine ring that can form a coordination catalyst with a metal catalyst to increase the activity of the catalyst. The pyridine ring-containing ligand includes but is not limited to pyridine, 2,2-bipyridine, 1,10-phenanthroline, or a combination thereof.

[0069] In the present invention, the electrolyte is soluble in the solvent used in the electrochemical reaction and is conductive. Electrolytes that can be used in the present invention include, but are not limited to, tetraethylammonium perchlorate, tetraethylammonium p-toluenesulfonate, tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, tetraethylammonium hexafluorophosphonate, or a combination thereof.

[0070] Preparation method of the compound represented by formula I

[0071] In the description of the present invention, the compound represented by formula I is prepared by an electrochemical method, comprising step (1): in a solvent, in the presence of a metal catalyst, a ligand and an electrolyte, under the action of a constant current, the compound represented by formula II reacts with the compound represented by formula III to produce the compound represented by formula I, and the reaction formula is as follows:

[0072]

[0073] wherein R1 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, methylsulfonyl, substituted or unsubstituted phenylsulfonyl or C1-C2 trialkylsilyl;

[0074] R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, methylsulfonyl, substituted or unsubstituted benzenesulfonyl, dimethylaminoacyl, diethylaminoacyl or diphenylphosphinyl;

[0075] The term "substituted" refers to one or more hydrogen atoms on a group being independently replaced by a group selected from the following:

[0076] Halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0077] X is fluorine, chlorine, bromine or iodine;

[0078] The metal catalyst is selected from palladium salts, copper salts, cobalt salts, nickel salts or combinations thereof; and

[0079] The ligand is selected from a phosphorus-containing ligand, an amino acid-containing ligand, a pyridine ring-containing ligand or a combination thereof.

[0080] In a preferred embodiment, the molar ratio of the compound represented by formula II to the compound represented by formula III is 1:1-4, more preferably 1:1-3, further preferably 1:1.5-2.2, such as 1:1.8 or 1:2.5;

[0081] In a preferred embodiment, the molar ratio of the compound represented by Formula II to the metal catalyst is 1:0.005-0.2, more preferably 1:0.01-0.1, further preferably 1:0.03-0.07, such as 1:0.04, 1:0.005 or 1:0.006;

[0082] In a preferred embodiment, the molar ratio of the compound represented by Formula II to the ligand is 1:0.005-0.3, more preferably 1:0.01-0.2, further preferably 1:0.05-0.12, such as 1:0.06, 1:0.08, and 1:0.10.

[0083] In a preferred embodiment, the molar volume ratio of the electrolyte to the reaction solution is 0.1 to 0.5 mol / L.

[0084] In a preferred embodiment, the constant current is 0.05A to 1.0A, more preferably 0.1A to 0.5A. In a preferred embodiment, the current density is 0.01 to 0.2A / cm 2 , preferably 0.02~0.1A / cm 2 .

[0085] In a preferred embodiment, the reaction temperature is 0°C to 60°C, more preferably 10°C to 50°C.

[0086] In a preferred embodiment, the metal catalyst is selected from bistriphenylphosphine palladium chloride, palladium acetate, palladium chloride, palladium trifluoromethanesulfonate, cuprous iodide, copper acetate, copper chloride, cobalt chloride, cobalt acetylacetonate, cobalt acetate, cobalt sulfate, nickel acetate, tricyclohexylphosphine nickel chloride or a combination thereof.

[0087] In a preferred embodiment, the ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, L-proline, alanine, methionine, pyridine, 2,2-bipyridine, 1,10-phenanthroline, or a combination thereof.

[0088] In a preferred embodiment, the electrolyte is selected from tetraethylammonium perchlorate, tetraethylammonium p-toluenesulfonate, tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, tetraethylammonium hexafluorophosphonate, or a combination thereof.

[0089] In a preferred embodiment, the solvent used in the reaction is selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or a combination thereof.

[0090] In a preferred embodiment, the anode electrode is iron, zinc, magnesium, nickel, aluminum or a combination thereof, and the cathode is platinum.

[0091] In a preferred embodiment, R2 in the compound represented by formula II is acetyl, X in the compound represented by formula III is bromine, the metal catalyst is PdCl2(PPh3)2, the ligand is bipyridine, and the electrolyte is tetrabutylammonium tetrafluoroborate.

[0092] In a preferred embodiment, R2 in the compound represented by formula II is acetyl, X in the compound represented by formula III is iodine, the metal catalyst is nickel acetate, the ligand is tricyclohexylphosphine, and the electrolyte is tetraethylammonium tetrafluoroborate.

[0093] In a preferred embodiment, R2 in the compound represented by formula II is benzenesulfonyl (Ts), X in the compound represented by formula III is chlorine, the metal catalyst is cuprous iodide, the ligand is L-proline, and the electrolyte is tetrabutylammonium hexafluorophosphate.

[0094] In a preferred embodiment, R2 in the compound represented by formula II is benzoyl, X in the compound represented by formula III is fluorine, the metal catalyst is nickel chloride, the ligand is 1,10-phenanthroline, and the electrolyte is tetraethylammonium perchlorate.

[0095] During the preparation of the compound of formula I of the present invention, the completion of the reaction can be detected by conventional methods in the art, for example, the disappearance of the main raw material (ie, the compound of formula II) by TLC is the reaction endpoint.

[0096] The preparation process of the compound represented by formula I of the present invention further includes the step of treating the reaction solution after the reaction is completed to obtain the compound represented by formula I.

[0097] Preparation method of the compound represented by formula II

[0098] In the description of the present invention, the compound represented by Formula II can be obtained by acylation of dehydroepiandrosterone (compound represented by Formula IV) at positions 3 and 17. The present invention has no particular requirements for the acylation method, and the acylation can be carried out using the commonly used methods of the present invention or by referring to the methods of the present invention.

[0099] In the description of the present invention, the preparation method of the compound represented by formula II comprises reacting the compound represented by formula IV with an acylating agent to produce the compound represented by formula II;

[0100] The reaction formula is as follows:

[0101]

[0102] Wherein, the acylating agent for generating R1 is selected from R1-halogen, R1-O-R1 or and

[0103] The acylating agent used to generate R2 is selected from R2-halogen, R2-O-R2 or

[0104] In a preferred embodiment, the acylating agent used to generate R1 is selected from C1-C6 alkyl acyl chloride, substituted or unsubstituted benzoic anhydride, isopropyl acetate or trimethylsilyl chloride.

[0105] In a preferred embodiment, the acylating agent used to form R2 is selected from isopropenyl acetate, substituted or unsubstituted benzoic anhydride or substituted or unsubstituted benzenesulfonic anhydride.

[0106] During the preparation of the compound of formula II of the present invention, the completion of the reaction can be detected by conventional methods in the art, for example, by TLC, with the disappearance of the main raw material (i.e., the compound of formula IV) being the end point of the reaction.

[0107] The preparation process of the compound represented by Formula II of the present invention further includes the step of treating the reaction solution after the reaction is completed to obtain the compound represented by Formula II.

[0108] Preparation method of abiraterone

[0109] In the present invention, the preparation method of abiraterone comprises removing the protecting group of the compound represented by formula I to produce abiraterone, and the reaction formula is as follows:

[0110]

[0111] In a preferred embodiment, the deprotection is carried out in a solvent selected from methanol, ethanol, isopropanol, or a combination thereof.

[0112] In a preferred embodiment, the deprotection is carried out in the presence of a base selected from sodium hydroxide and / or potassium hydroxide;

[0113] In a preferred embodiment, the deprotection is carried out at 50-100°C.

[0114] During the preparation of abiraterone of the present invention, the completion of the reaction can be detected by conventional methods in the art, for example, by TLC detection, the disappearance of the main raw material (ie, the compound represented by Formula I) indicates the end point of the reaction.

[0115] The preparation process of Abiraterone of the present invention further comprises the step of treating the reaction solution after the reaction is completed to obtain Abiraterone.

[0116] Preparation method of abiraterone acetate

[0117] In the description of the present invention, abiraterone acetate is obtained by two methods:

[0118] (1) According to the preparation method of the compound represented by Formula I, when R1 in the compound represented by Formula I is acetyl, the compound represented by Formula I is abiraterone acetate.

[0119] (2) reacting the abiraterone prepared by the electrochemical preparation method with acetic anhydride to obtain abiraterone acetate,

[0120]

[0121] In a preferred embodiment, the solvent used in the reaction of abiraterone and acetic anhydride is selected from dichloromethane.

[0122] In a preferred embodiment, the reaction of abiraterone with acetic anhydride is carried out in the presence of a base, and the base is selected from triethylamine.

[0123] In a preferred embodiment, the temperature for the reaction of abiraterone and acetic anhydride is 0-40°C, more preferably 10-30°C.

[0124] During the preparation of abiraterone acetate of the present invention, the completion of the reaction can be detected by conventional methods in the art, for example, by TLC detection, the disappearance of the main raw material (ie, abiraterone) indicates the end point of the reaction.

[0125] The preparation process of abiraterone acetate of the present invention further comprises the step of treating the reaction liquid after the reaction is completed to obtain abiraterone acetate.

[0126] The beneficial effects of the present invention include:

[0127] The method of the present invention overcomes the defects of the prior art such as expensive raw materials, high cost, and large pollution of three wastes, and provides a method for preparing abiraterone acetate with low cost, high yield, and suitability for industrial production, thus having great application value.

[0128] The present invention will be explained in more detail below in conjunction with embodiment. The embodiment of the present invention is only used to illustrate the technical solution of the present invention, and the spirit and scope of the present invention are not limited thereto. Unless otherwise specified, percentages and parts are weight percentages and parts by weight.

[0129] Example 1

[0130]

[0131] Add 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 isopropenyl acetate to a reaction flask, heat to 120 ± 5°C, and distill under atmospheric pressure for 2 hours. Distill until the remaining volume is approximately 3 L, then stop distillation and continue stirring at this temperature for 3 hours. Cool to 0-5°C and stir for 30 minutes. Filter, add 5 L of water to the filter cake, and stir for 30 minutes. Filter, add 3 L of ethanol to the filter cake, and slurry at room temperature for 30 minutes. Cool to 0-5°C and stir for 30 minutes. Filter, rinse the filter cake with a small amount of cold ethanol (200 mL, 0-5°C), and dry under vacuum at 35-40°C to obtain 1.72 kg of 17-acetate androster-5,16-diene-3β-acetate, with a molar yield of 92.2% and a purity of 99.2% by HPLC.

[0132] Add 744.0 g (2.0 mol) of 17-acetate androsta-5,16-diene-3β-acetate, 474.0 g (3.0 mol) of 3-bromopyridine, 14.1 g (0.02 mol) of PdCl2(PPh3)2, 31.2 g (0.20 mol) of bipyridine, 5.0 L of DMF, and 658.5 g (2.0 mol) of tetrabutylammonium tetrafluoroborate to the reaction flask. Fix the electrochemical electrodes (anode: iron, cathode: platinum) in the reaction flask and conduct the reaction at a constant current of 1.0 A (current density: about 0.1 A / cm 2 ) was stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction mixture was slowly transferred to a 50L reactor containing 20L of water and stirred for 30 minutes. Filter, add 10L of dichloromethane to the filter cake to dissolve it, and wash the solution sequentially with 2L of 1N aqueous hydrochloric acid, 2L of 1N aqueous sodium bicarbonate, and 2L of water. The organic layer was concentrated to dryness under reduced pressure, and 3L of ethanol was added to the concentrate. The temperature was raised to reflux to dissolve the mixture. The temperature was uniformly lowered to 0-5°C over two hours, crystallized, filtered, and vacuum dried to obtain 678.8g of crude abiraterone acetate with a molar yield of 86.8% and an HPLC purity of 98.4%. The crude product was recrystallized from acetone to obtain 645.5g of abiraterone acetate with a purity of 99.7%.

[0133] mp: 144.8°C-146.3°C (literature data, mp: 144°C-146°C). ESI-MS (m / z): 414 [M+Na] + ; 1HNMR(400MHz, CDCl3-d1)δ(ppm):8.605(d,1H), 8.447~8.432(q,1H), 7.636~7.607(m,1H), 7.208~7.176(q,1H) ), 5.978~5.966(q,1H), 5.407~5.394(d,1H), 4.640~4.560(m,1H), 2.018(s,3H), 1.065(s,3H), 1.028(s,3H); 13 C NMR (400MHz, CDCl3-d1) δ (ppm): 170.58, 151.80, 148.06, 148.00, 140.14, 133.03, 133.75, 129.28, 123.09, 122.38 , 73.94, 57.57, 50.37, 47.43, 36.89, 38.24, 37.02, 35.32, 31.89, 31.61, 30.52, 27.84, 21.51, 20.92, 19.35, 16.67.

[0134] Example 2

[0135]

[0136] 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 and stir until the mixture becomes clear. Cool the mixture to 0-5°C and slowly add 4.9 g (52.5 mmol) of propionyl chloride dropwise to the solution. After the addition is complete, warm the mixture to room temperature and stir for 3 hours. After the reaction is complete, monitor the reaction by TLC and slowly add 50 mL of water to the reaction mixture. Separate the aqueous layer, dry the organic layer over 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 the mixture to 120±5°C, and distill under normal pressure for 1 hour. Distill until the remaining volume is approximately 50 mL, stop distillation, and continue stirring for 2 hours. Cool the mixture to 0-5°C and stir for 30 minutes. Filter the mixture, add 80 mL of water to the filter cake, and stir for 30 minutes. Filter, add the filter cake to 30 mL of ethanol, and slurry at room temperature for 30 minutes. Cool to 0-5°C and stir for 30 minutes. Filter, rinse the filter cake with a small amount of cold ethanol (5 mL, 0-5°C), and dry under vacuum at 35-40°C to obtain 17.7 g of 17-acetate androsta-5,16-diene-3β-propionate, with a molar yield of 91.5% and an HPLC purity of 99.3%.

[0137] 7.7 g (0.02 mol) of 17-acetate androsta-5,16-diene-3β-propionate, 4.1 g (0.02 mol) of 3-iodopyridine, 0.2 g (1.0 mmol) of nickel acetate, 0.3 g (1.0 mmol) of tricyclohexylphosphine, and 50 mL of acetonitrile were added to the reaction flask; 651.0 mg (3.0 mmol) of tetraethylammonium tetrafluoroborate was also added. Electrochemical electrodes (anode: zinc, cathode: platinum) were fixed in the reaction flask and the reaction was continued at a constant current of 0.05 A (current density: approximately 0.01 A / cm 2 ) was stirred at 0-10°C for 5 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated to dryness. 50 mL of ethanol and 10 mL of 30% sodium hydroxide solution were added to the concentrate, the temperature was raised to reflux, and the mixture was stirred 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 dried under vacuum to yield 5.87 g of abiraterone (a molar yield of 84.0%).

[0138] To a reaction flask, add 5.87 g (0.017 mol) of abiraterone, 50 mL of dichloromethane, and 3.0 g (0.03 mol) of triethylamine. Cool to 0-5°C, and slowly add 3.0 g (0.03 mol) of acetic anhydride dropwise. After completion of the addition, warm to room temperature and incubate for 3 hours until the abiraterone is fully reacted. Filter, and wash the organic layer with 20 mL of water, followed by 20 mL of 1N sodium bicarbonate solution. Concentrate the organic layer under reduced pressure to dryness. Add 20 mL of 90% aqueous ethanol to the concentrate and bring to reflux until the mixture becomes clear. Cool at a constant rate of 0-5°C over two hours, crystallize, filter, and vacuum dry to obtain 6.2 g of crude abiraterone acetate with a molar yield of 96.5% and an HPLC purity of 98.4%. Recrystallize the crude product from acetone to obtain 5.7 g of abiraterone acetate with a purity of 99.5%.

[0139] Example 3

[0140]

[0141] Add 14.4g (0.05mol) of dehydroepiandrosterone, 100mL of dichloromethane, and 6.1g (0.06mol) of triethylamine to a reaction flask and stir until the mixture becomes clear. Cool to 0-5°C and slowly add 5.7g (52.5mmol) of trimethylsilyl chloride dropwise. After the addition is complete, warm to room temperature and stir at this temperature for 4 hours. After the reaction is complete, monitor the reaction by TLC and slowly add 50mL of water. Separate the aqueous layer, dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness. Add 5.6g (0.05mol) of potassium tert-butoxide and 100mL of tetrahydrofuran to the concentrate and stir for 10 minutes. Cool to 0-5°C and slowly add 16.3g (0.05mol) of p-toluenesulfonic anhydride. Heat to 60-65°C and stir at this temperature for 5 hours. After the reaction is complete, monitor the reaction by TLC and concentrate under reduced pressure to a residual volume of approximately 50mL. Add 80mL of water and stir for 30 minutes. Filter, add the filter cake to 30 mL of ethanol, and slurry at room temperature for 30 minutes. Cool to 0-5°C and stir for 30 minutes. Filter, rinse the filter cake with a small amount of cold ethanol (5 mL, 0-5°C), and dry under vacuum at 35-40°C to obtain 21.2 g of 17-toluenesulfonic acid ester of androsta-5,16-diene-3β-trimethylsilyl ester, with a molar yield of 82.6% and an HPLC purity of 98.3%.

[0142] 10.3 g (0.02 mol) of 17-toluenesulfonic acid androsta-5,16-diene-3β-trimethylsilyl ester, 6.8 g (0.06 mol) of 3-chloropyridine, 0.8 g (4.0 mmol) of cuprous iodide, 0.8 g (4.0 mmol) of L-proline, 50 mL of DMSO, and 7.7 g (2.0 mmol) of tetrabutylammonium hexafluorophosphate were added to the reaction flask. Electrochemical electrodes (magnesium anode and platinum cathode) were fixed in the reaction flask and the reaction was continued at a constant current of 0.5 A (current density of about 0.1 A / cm 2 ) under the action of 50 degrees and stirred for 5 hours. After the reaction was completed by TLC monitoring, the temperature was lowered to room temperature. The reaction mixture was slowly dripped into 200mL of water and stirred for 30 minutes. Filter, add 50mL of ethanol and 10mL of 30% sodium hydroxide solution to the filter cake, heat to reflux, and stir for 5 hours. Cool to room temperature, add 100mL of water, and age for 30 minutes. Filter and dry in vacuo to obtain 6.2g of abiraterone with a molar yield of 86.2%.

[0143] To a reaction flask, add 6.2g (0.017mol) of abiraterone, 50mL of dichloromethane, and 3.0g (0.03mol) of triethylamine. Cool to 0-5°C, and slowly add 3.0g (0.03mol) of acetic anhydride dropwise. After completion of the addition, warm to room temperature and incubate for 3 hours until the abiraterone is fully reacted. Filter, and wash the organic layer with 20mL of water, followed by 20mL of 1N sodium bicarbonate solution. Concentrate the organic layer under reduced pressure to dryness. Add 20mL of 90% ethanol and bring to reflux to dissolve the mixture. Cool uniformly to 0-5°C over two hours, crystallize, filter, and vacuum dry to obtain 6.4g of crude abiraterone acetate with a molar yield of 95.1% and a purity of 98.0% by HPLC. Recrystallize the crude product from acetone to obtain 5.7g of abiraterone acetate with a purity of 99.5%.

[0144] Example 4

[0145]

[0146] Add 14.4g (0.05mol) of dehydroepiandrosterone, 11.2g (0.1mol) of potassium tert-butoxide, and 100mL of tetrahydrofuran to the reaction flask and stir for 10 minutes. Cool to 0-5°C and slowly add 22.6g (0.1mol) of benzoic anhydride. Heat to 60-65°C and stir for 3 hours. After the reaction is completed, monitor the reaction by TLC and concentrate under reduced pressure until the remaining volume is approximately 50mL. Add 80mL of water and stir for 30 minutes. Filter, add 50mL of water to the filter cake and stir for 30 minutes. Filter, add 30mL of ethanol to the filter cake and slurry at room temperature for 30 minutes. Cool to 0-5°C and stir for 30 minutes. The filter cake was filtered and rinsed with a small amount of cold ethanol (5 mL, 0-5° C.), and dried in vacuo at 35-40° C. to obtain 22.6 g of 17-benzoate androsta-5,16-diene-3β-benzoate with a molar yield of 91.2% and an HPLC purity of 98.6%.

[0147] 9.9 g (0.02 mol) of 17-benzoyl androsta-5,16-diene-3β-benzoate, 3.9 g (0.04 mol) of 3-fluoropyridine, 0.5 g (4.0 mmol) of nickel chloride, 0.7 g (4.0 mmol) of 1,10-phenanthroline, 80 mL of N,N-dimethylacetamide (DMAc), and 9.2 g (0.04 mol) of tetraethylammonium perchlorate were added to the reaction flask. Electrochemical electrodes (magnesium anode and platinum cathode) were fixed in the reaction flask and the reaction was continued at a constant current of 0.3 A (current density of about 0.06 A / cm 2) was stirred at room temperature for 6 hours. After TLC monitoring, the reaction was filtered and the filtrate was concentrated to dryness. 50 mL of ethanol and 10 mL of 30% sodium hydroxide solution were added to the concentrate, the temperature was raised to reflux, and stirred for 3 hours. Cooled to room temperature, 100 mL of water was added, and the mixture was aged for 30 minutes. Filtered and dried under vacuum to obtain 5.0 g of abiraterone, with a molar yield of 71.5%.

[0148] To a reaction flask, add 5.0 g (0.014 mol) of abiraterone, 50 mL of dichloromethane, and 3.0 g (0.03 mol) of triethylamine. Cool to 0-5°C and slowly add 3.0 g (0.03 mol) of acetic anhydride dropwise. After completion of the addition, warm to room temperature and incubate for 3 hours until the abiraterone is fully reacted. Filter, and wash the organic layer with 20 mL of water and then 20 mL of 1N sodium bicarbonate solution. Concentrate the organic layer under reduced pressure to dryness. Add 20 mL of 90% ethanol and bring to reflux to dissolve the mixture. Cool uniformly to 0-5°C over two hours, crystallize, filter, and vacuum dry to obtain 5.3 g of crude abiraterone acetate with a molar yield of 94.5% and an HPLC purity of 98.3%. Recrystallize the crude product from acetone to obtain 4.6 g of abiraterone acetate with a purity of 99.5%.

[0149] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. An electrochemical preparation method of abiraterone and its derivatives, characterized in that: The method comprises step (1): in a solvent, in the presence of a metal catalyst, a ligand and an electrolyte, and under the action of a constant current, reacting a compound represented by formula II with a compound represented by formula III to produce a compound represented by formula I, and the reaction formula is as follows: wherein R1 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, methylsulfonyl, substituted or unsubstituted phenylsulfonyl or C1-C2 trialkylsilyl; R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, methylsulfonyl, substituted or unsubstituted benzenesulfonyl, dimethylaminoacyl, diethylaminoacyl or diphenylphosphinyl; The term "substituted" refers to one or more hydrogen atoms on a group being independently replaced by a group selected from the following: Halogen, C1-C4 alkyl or C1-C4 haloalkyl; X is fluorine, chlorine, bromine or iodine; The metal catalyst is selected from palladium salts, copper salts, cobalt salts, nickel salts, or combinations thereof; as well as The ligand is selected from a phosphorus-containing ligand, an amino acid-containing ligand, a pyridine ring-containing ligand, or a combination thereof; The constant current is 0.05A to 1.0A; Current density is 0.01~0.2A / cm 2 ; The reaction temperature is 0℃~60℃.

2. The electrochemical preparation method according to claim 1, characterized in that: R1 is acetyl, and the compound represented by Formula I is abiraterone acetate.

3. The electrochemical preparation method according to claim 1, characterized in that: The step (1) has one or more characteristics selected from the following: (i) the molar ratio of the compound represented by formula II to the compound represented by formula III is 1:1 to 4; (ii) the molar ratio of the compound represented by formula II to the metal catalyst is 1:0.005 to 0.2; (iii) the molar ratio of the compound represented by formula II to the ligand is 1:0.005 to 0.3; (iv) The molar volume ratio of the electrolyte to the reaction solution is 0.1 to 0.5 mol / L.

4. The electrochemical preparation method according to claim 1, characterized in that: The step (1) has one or more characteristics selected from the following: (i) the molar ratio of the compound represented by formula II to the compound represented by formula III is 1:1 to 3; (ii) the molar ratio of the compound represented by formula II to the metal catalyst is 1:0.01 to 0.1; (iii) The molar ratio of the compound represented by formula II to the ligand is 1:0.01-0.

2.

5. The electrochemical preparation method according to claim 1, characterized in that: The step (1) has one or more characteristics selected from the following: (i) the molar ratio of the compound represented by formula II to the compound represented by formula III is 1:1.5-2.2; (ii) the molar ratio of the compound represented by formula II to the metal catalyst is 1:0.03 to 0.07; (iii) The molar ratio of the compound represented by formula II to the ligand is 1:0.05 to 0.

12.

6. The electrochemical preparation method according to claim 1, characterized in that: In the step (1), the constant current is 0.1A to 0.5A; and / or Current density is 0.02~0.1A / cm 2 and / or The reaction temperature is 10°C to 50°C.

7. The electrochemical preparation method according to claim 1, characterized in that: The step (1) has one or more characteristics selected from the following: (i) the metal catalyst is selected from bistriphenylphosphine palladium chloride, palladium acetate, palladium chloride, palladium trifluoromethanesulfonate, cuprous iodide, cupric acetate, cupric chloride, cobalt chloride, cobalt acetylacetonate, cobalt acetate, cobalt sulfate, nickel acetate, tricyclohexylphosphine nickel chloride, or a combination thereof; (ii) the ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, L-proline, alanine, methionine, pyridine, 2,2-bipyridine, 1,10-phenanthroline, or a combination thereof; (iii) the electrolyte is selected from tetraethylammonium perchlorate, tetraethylammonium p-toluenesulfonate, tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetraethylammonium tetrafluoroborate, tetraethylammonium hexafluorophosphonate, or a combination thereof; (iv) The solvent used in the reaction is selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or a combination thereof.

8. The electrochemical preparation method according to claim 1, characterized in that: In the compound represented by formula II, R2 is acetyl, in the compound represented by formula III, X is bromine, the metal catalyst is PdCl2(PPh3)2, the ligand is bipyridine, or In the compound represented by formula II, R2 is acetyl, in the compound represented by formula III, X is iodine, the metal catalyst is nickel acetate, and the ligand is tricyclohexylphosphine, or In the compound represented by formula II, R2 is p-toluenesulfonyl, in the compound represented by formula III, X is chlorine, the metal catalyst is cuprous iodide, the ligand is L-proline, or In the compound represented by formula II, R2 is a benzoyl group, in the compound represented by formula III, X is fluorine, the metal catalyst is nickel chloride, and the ligand is 1,10-phenanthroline.

9. The electrochemical preparation method according to claim 1, characterized in that: The electrochemical preparation method further comprises reacting the compound represented by formula IV with an acylating agent to generate the compound represented by formula II; The reaction formula is as follows: Wherein, the acylating agent for generating R1 is selected from R1-halogen, R1-O-R1 or The acylating agent used to generate R2 is selected from R2-halogen, R2-O-R2 or 10. The electrochemical preparation method according to claim 9, characterized in that: The acylating agent used to generate R1 is selected from C1-C6 alkyl chloride, substituted or unsubstituted benzoic anhydride, isopropyl acetate or trimethylsilyl chloride, and / or The acylating agent used to form R2 is selected from isopropenyl acetate, substituted or unsubstituted benzoic anhydride or substituted or unsubstituted benzenesulfonic anhydride.

11. The electrochemical preparation method according to claim 1, characterized in that: The electrochemical preparation method further comprises step (2): deprotecting the compound represented by formula I to generate abiraterone, and the reaction formula is as follows:

12. A method for preparing abiraterone acetate, characterized in that: The preparation method comprises step (3): reacting the abiraterone prepared by the electrochemical preparation method according to claim 11 with acetic anhydride to obtain abiraterone acetate, and the reaction formula is as follows:

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