Preparation method of abiraterone acetate and its intermediate

Abstract

The present invention discloses a preparation method of abiraterone acetate and its intermediate. The preparation method includes the steps: (1) in a solvent, in the presence of a metal catalyst, a ligand and a base, 3 - protected 17 - hydroxyester androst - 5,16 - diene - 3β - hydroxy (ester) reacts with diethyl(3 - pyridyl)borane to obtain abiraterone acetate or its intermediate, and the intermediate is converted to obtain abiraterone acetate. The preparation method of the present invention has simple operation and is suitable for large - scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of abiraterone acetate and its intermediates. Background Art

[0002] Prostate cancer (PCA) refers to an epithelial malignant tumor that occurs in the prostate. It is the second most common malignant tumor among men globally after lung cancer, with a mortality rate ranking sixth. Approximately 1 / 9 of men will be diagnosed with prostate cancer during their lifetime, so it is called the "male killer". Currently, the global incidence of prostate cancer is on the rise. In 2020, about 1.5 million new cases were added globally, accounting for 15% of newly diagnosed male tumor cases. It is expected that by 2022, the number of global prostate cancer patients will reach 11 million.

[0003] Abiraterone acetate is a prodrug of abiraterone, which is rapidly converted into abiraterone in vivo. The latter is a selective and irreversible steroidal inhibitor of CYP17 (17α-hydroxylase and C17,20-lyase), which blocks the synthesis of testosterone in the testis, adrenal gland, and tumor by inhibiting the enzyme activity. This product was developed by Johnson & Johnson in the United States and was first approved by the US FDA for marketing on April 28, 2011, for the combined treatment of castration-resistant metastatic prostate cancer (mCRPC) in patients who are ineffective in androgen deprivation therapy and docetaxel chemotherapy. Subsequently, on December 10, 2012, the indication population was approved to be expanded for the treatment of castration-resistant advanced metastatic prostate cancer.

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

[0005] I. The synthesis method reported in WO9509178: Using dehydroepiandrosterone (DHEA) as a raw material, first form a hydrazone with hydrazine hydrate under the catalysis of hydrazine sulfate, then carry out an iodination reaction with iodine under the catalysis of tetramethylguanidine (TMG) to generate a vinyl iodide, and then the iodide undergoes a coupling reaction with diethyl(3-pyridyl)borane under the catalysis of bis(triphenylphosphine)palladium chloride to generate abiraterone, and finally the 3-position hydroxyl group is acetylated to obtain abiraterone acetate.

[0006]

[0007] Route 1

[0008] The first step of this route requires 5 days of reaction time, and the third step requires 4 days of reaction time. The production cycle is too long, and the total yield is only 36.9%. Malodorous reagents such as hydrazine hydrate, iodine, and tetramethylguanidine are also required in the process, resulting in large environmental pollution. Therefore, it is not suitable for large-scale industrial production.

[0009] II. Synthesis method reported in WO2006021777: Using dehydroepiandrosterone acetate as the raw material, under the catalysis of bases such as triethylamine, reacting with trifluoromethanesulfonic anhydride to prepare its trifluoromethanesulfonyl derivative, then coupling with diethyl(3-pyridyl)borane under the catalysis of bis(triphenylphosphine)palladium chloride, and then for purification purposes, forming a salt with methanesulfonic acid to obtain the methanesulfonate of abiraterone acetate, with a total yield of 32.8% for abiraterone acetate methanesulfonate with a purity of 96.4%. Due to the high price of trifluoromethanesulfonic anhydride, the production cost of this synthesis method is high, and trifluoromethanesulfonic anhydride has strong hygroscopicity and corrosiveness, with a high risk of use. During the reaction process, 3-dehydroxy abiraterone is also generated, and this impurity is difficult to remove by recrystallization and generally needs to be removed by column chromatography.

[0010]

[0011] Route 2

[0012] CN103864878A discloses the following two methods for preparing abiraterone acetate, as shown in Route 3 and Route 4:

[0013]

[0014] Route 3

[0015]

[0016] Route 4

[0017] Similar to Route 2 above, the trifluoromethanesulfonic anhydride used in Route 3 is expensive, and 3-dehydroxy abiraterone is also generated during the reaction process. This impurity is difficult to remove by recrystallization and generally needs to be removed by column chromatography. The preparation process of the raw material iodide in Route 4 is the same as that in Route 1 above, with disadvantages such as long reaction time and environmental pollution.

[0018] CN104109185A discloses a method for preparing abiraterone acetate, and the preparation route is as follows:

[0019]

[0020] This route reacts dehydroepiandrosterone acetate with p-toluenesulfonic acid to produce the compound shown in Formula VII. The compound shown in Formula VII obtained by treating the reaction solution is in an oily state. The oily compound shown in Formula VII reacts with diethyl(3-pyridyl)borane in the presence of PdCl2(PPh3)2 and Na2CO3 to obtain abiraterone acetate. The product obtained by treating the reaction solution is also in an oily state. Although this method avoids the disadvantages of high production cost, large use risk, and complex product purification process caused by the use of trifluoromethanesulfonic anhydride, the crude abiraterone acetate and its intermediate obtained by this method are both in an oily state. This oily crude product can only be purified by column chromatography and is not suitable for industrial large-scale production.

[0021] Therefore, there is still a need in the art to find a new method for preparing abiraterone acetate with low cost, high yield, simple operation, and suitable for industrial large-scale production. Summary of the Invention

[0022] In view of the above problems existing in the prior art, one aspect of the present invention provides a new method for preparing abiraterone acetate and its intermediate with simple operation, high total yield, and suitable for industrial production.

[0023] The preparation method of abiraterone acetate or its intermediate provided by the present invention includes the steps of: (1) reacting the compound shown in Formula II with the compound shown in Formula III-1 in a solvent in the presence of a metal catalyst, a ligand, and a base to obtain the compound shown in Formula I.

[0024] The reaction formula is as follows:

[0025]

[0026] Among them, R1 is selected from hydrogen, C1-C6 alkyl, phenyl, benzyl, C1-C6 acyl, substituted or unsubstituted benzoyl, trialkylsilyl or dialkylarylsilyl, and the alkyl in the trialkylsilyl and dialkylarylsilyl is C1-C3 alkyl.

[0027] R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, dimethylaminoacyl, diethylaminoacyl or diphenylphosphinyl;

[0028] The "substitution" means that one or more hydrogen atoms on the group are independently substituted by a group selected from the following group:

[0029] halogen, C1-C4 alkyl, C1-C4 haloalkyl, ether group, nitro, etc.

[0030] The metal catalyst is selected from palladium salts, copper salts, iron salts, cobalt salts, nickel salts, or a combination thereof;

[0031] The ligand is selected from phosphorus-containing ligands, amino acid ligands, nitrogen-containing ligands, or a combination thereof.

[0032] In another preferred embodiment, R1 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl or trialkylsilyl. In another more preferred embodiment, R1 is selected from acetyl.

[0033] In another preferred embodiment, R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl or dimethylaminoacyl. In another more preferred embodiment, R2 is selected from acetyl.

[0034] In another preferred embodiment, the molar ratio of the compound represented by formula II to the compound represented by formula III-1 is 1:1 to 3. In another more preferred embodiment, the molar ratio of the compound represented by formula II to the compound represented by formula III-1 is 1:1 to 1.5.

[0035] In another preferred embodiment, the molar ratio of the compound represented by formula II to the metal catalyst is 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, 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.

[0037] In another preferred embodiment, the molar ratio of the compound represented by formula II to the base is 1:1 to 3. In another more preferred embodiment, the molar ratio of the compound represented by formula II to the base is 1:1 to 2.

[0038] In another preferred embodiment, the metal catalyst is selected from palladium acetate, palladium chloride, cuprous iodide, copper acetate, ferric chloride, ferric acetylacetonate, cobalt chloride, cobalt acetylacetonate, nickel acetate, nickel chloride, or a combination thereof.

[0039] 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.

[0040] In another preferred embodiment, the base is selected from potassium carbonate, sodium carbonate, potassium phosphate, lithium tert-butoxide, sodium hydroxide, sodium bicarbonate, or a combination thereof.

[0041] In another preferred embodiment, the solvent is selected from tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, or a combination thereof.

[0042] In another preferred embodiment, in the compound represented by formula II, R2 is acetyl, the metal catalyst is palladium chloride, the ligand is triphenylphosphine, and the base is potassium carbonate.

[0043] In another preferred example, in the compound shown in formula II, R2 is propionyl, the metal catalyst is nickel acetate, the ligand is 2,2'-bipyridine, and the base is potassium phosphate.

[0044] In another preferred example, in the compound shown in formula II, R2 is N,N-dimethylformamide group, the metal catalyst is cuprous iodide, the ligand is 1,10-phenanthroline, and the base is sodium bicarbonate.

[0045] In another preferred example, in the compound shown in formula II, R2 is benzoyl, the metal catalyst is nickel chloride, the ligand is tricyclohexylphosphine, and the base is lithium tert-butoxide.

[0046] In another preferred example, the reaction temperature of step (1) is 40 - 130 °C, preferably 60 - 115 °C.

[0047] In another preferred example, the method further comprises the following steps:

[0048] (1-a) The compound shown in formula IV reacts with an acylating agent to form the compound shown in formula II; the reaction formula is as follows:

[0049]

[0050] Among them, the acylating agent for generating R1 is selected from R1-halogen, R1-O-R1 or The acylating agent for generating R2 is selected from R2-halogen, R2-O-R2 or

[0051] In another preferred example, the acylating agent for generating R1 is selected from C1-C6 alkyl acyl chloride, substituted or unsubstituted benzoic anhydride, isopropenyl acetate or trimethylchlorosilane, and the acylating agent for generating R2 is selected from isopropenyl acetate or substituted or unsubstituted benzoic anhydride.

[0052] The present invention also provides a preparation method of abiraterone, which comprises deprotecting the compound shown in formula I obtained by the above preparation method to generate abiraterone, and the reaction formula is as follows:

[0053]

[0054] The present invention also provides a preparation method of abiraterone acetate, which comprises reacting abiraterone obtained by the above preparation method with acetic anhydride to obtain abiraterone acetate, and the reaction formula is as follows:

[0055] Detailed implementation mode

[0056] After extensive and in-depth research, through a large number of screenings and tests, the present inventor provides a method for preparing abiraterone acetate. Compared with the prior art, the method of the present invention is simple to operate, has high safety, low cost, and higher yield, and is very suitable for industrial production.

[0057] 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 belongs.

[0059] As used herein, the term "comprising" or "including" can be open, semi-closed, and closed.

[0060] As used herein, the term "room temperature" or "ambient temperature" refers to a temperature of 4 - 40 °C, preferably, 25 ± 5 °C.

[0061] Unless otherwise stated, the term "alkyl" by itself or as part of another substituent refers to a straight-chain or branched-chain hydrocarbon group having the specified number of carbon atoms. Examples of alkyl 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 represents an alkyl containing 1 - 3 carbons. C1-C6 alkyl represents an alkyl containing 1 - 6 carbons.

[0062] In the description of the present invention, the term "C1-C6 acyl" represents C1-C6 alkyl-(C=O)-.

[0063] Unless otherwise specified, the term "solution" refers to an aqueous solution. Unless otherwise specified, the solution refers to the mass concentration.

[0064] Preparation method of the compound shown in Formula I

[0065] The present invention provides a method for preparing abiraterone acetate or an intermediate thereof, the preparation method comprising the steps of: in a solvent, in the presence of a metal catalyst, a ligand, and a base, reacting 3-position protected 17-hydroxyester androst-5,16-diene-3β-ol (ester) (the compound shown in Formula II) with 3-halopyridine (the compound shown in Formula III-1) to obtain abiraterone acetate or an intermediate thereof (the compound shown in Formula I), and the intermediate can be converted to abiraterone acetate.

[0066] The reaction formula is as follows:

[0067]

[0068] Wherein R1 is selected from protecting groups such as hydrogen, C1-C6 acyl group, phenyl, benzyl, C1-C6 acyl group, alkyl group, substituted or unsubstituted benzoyl group, trialkylsilyl group or diarylalkylsilyl group, etc. The alkyl group in the trialkylsilyl group and diarylalkylsilyl group is a C1-C3 alkyl group, and R2 is selected from leaving groups such as C1-C6 acyl group, substituted or unsubstituted benzoyl group, dimethylaminoacyl group, diethylaminoacyl group or diphenylphosphinyl group, etc. R1 and R2 can be the same or different. The "substitution" means that one or more hydrogen atoms on the group are independently substituted by groups selected from the following group: halogen, C1-C4 alkyl group, C1-C4 haloalkyl group, ether group, nitro group, etc.

[0069] The molar ratio of the compound shown in Formula II to the compound shown in Formula III-1 is not particularly limited and can be in accordance with the conventional dosage of such reactions. Preferably, it is 1:1 to 3, more preferably 1:1 to 1.5, such as 1:1.02, 1:1.05, 1:1.1, 1:2, 1:3, 1:4, 1:5.

[0070] The molar ratio of the compound shown in Formula II to the metal catalyst is not particularly limited and can be in accordance with the conventional dosage of such reactions. Preferably, it is 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.

[0071] The molar ratio of the compound shown in Formula II to the ligand is not particularly limited and can be in accordance with the conventional dosage of such reactions. Preferably, it is 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.

[0072] The molar ratio of the compound shown in Formula II to the base is not particularly limited and can be in accordance with the conventional dosage of such reactions. Preferably, it is 1:1 - 3; more preferably 1:1 to 2, such as 1:1, 1:1.5 or 1:2.

[0073] The "metal catalyst" that can be used in the present invention is a metal salt, including but not limited to palladium salts, copper salts, iron salts, cobalt salts, 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, iron acetylacetonate, ferrous acetylacetonate. Cobalt salts include but are not limited to cobalt chloride, cobalt sulfate, cobalt acetate, cobalt acetylacetonate. Nickel salts include but are not limited to nickel chloride, nickel bromide, nickel acetate, nickel chloride with tricyclohexylphosphine.

[0074] The ligands that can be used in the present 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 a coordination catalyst with a metal catalyst to increase the activity of the catalyst. Such 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 a coordination catalyst with a metal catalyst to increase the activity of the catalyst. Such amino acid-containing ligands include, but are not limited to, L-proline, alanine, methionine, and their derivatives. "Pyridine ring-containing ligands" refer to ligands containing a pyridine ring that can form a coordination catalyst with a metal catalyst to increase the activity of the catalyst. Such pyridine ring-containing ligands include, but are not limited to, pyridine, 2,2-bipyridine, 1,10-phenanthroline, and their derivatives.

[0075] The base that can be used in the present invention includes but is not limited to potassium carbonate, sodium carbonate, potassium phosphate, lithium tert-butoxide, sodium hydroxide, sodium bicarbonate and other inorganic bases. The role of the base is to absorb the acetate radical after the reaction as an acid binding agent to promote the reaction.

[0076] Solvents that can be used in the present invention include, but are not limited to, tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.

[0077] The reaction mechanism of the compound represented by Formula II and the compound represented by Formula III-1 is similar to the Suzuki-Miyaura coupling reaction. Taking the substrate and catalytic system of Example 1 below as an example, the possible reaction mechanism of the compound represented by Formula II and the compound represented by Formula III-1 is as follows:

[0078]

[0079] Preparation method of the compound represented by formula II

[0080] Typically, the compound represented by Formula II can be obtained by acylation of dehydroepiandrosterone 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. In a specific embodiment of the present invention, the preparation method of the compound represented by Formula II comprises the following steps:

[0081] (1-a) reacting the compound of formula IV with an acylating agent to form a compound of formula II;

[0082] The reaction formula is as follows:

[0083]

[0084] Wherein, the acylating agent for generating R1 can be selected from R1-halogen, R1-O-R1, The acylating agent for generating R2 may be selected from R2-halogen, R2-O-R2,

[0085] The main advantages of the present invention include:

[0086] Compared with the prior art, the acylating agent used in the present invention has a low cost, and the obtained abiraterone acetate or its intermediate is a solid with high purity, and it is very easy to obtain an ideal purity by recrystallization. Therefore, the preparation method of abiraterone acetate or its intermediate in the present invention is simple to operate, has a high total yield, and is suitable for industrial production.

[0087] 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 essence and scope of the present invention are not limited thereto. Unless otherwise stated, percentages and parts are weight percentages and weight parts.

[0088] Example 1

[0089]

[0090] 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 the reaction flask. Heat the reaction mixture to 120 ± 5 °C and distill at atmospheric pressure for 2 hours until the volume of the remaining material is about 3 L. Stop distillation, continue stirring while maintaining the temperature for 3 hours, cool down to 0 - 5 °C, stir for 30 minutes, filter, add the filter cake to 5 L of water, stir for 30 minutes, filter, add the filter cake to 3 L of ethanol, slurry at room temperature for 30 minutes, cool down to 0 - 5 °C, stir for 30 minutes, filter, wash the filter cake with a small amount of cold ethanol, and dry it under vacuum at 35 - 40 °C to obtain 1.72 Kg of 17-acetate androst-5,16-diene-3β-acetate. The molar yield is 92.2%, and the HPLC purity is 99.2%.

[0091] Add 744.0 g (2.0 mol) of 17-acetate androst-5,16-diene-3β-acetate, 308.7 g (2.1 mol) of diethyl(3-pyridyl)borane, 14.0 g (0.02 mol) of PdCl2(PPh3)2 (i.e., the metal catalyst is palladium chloride and the ligand is triphenylphosphine), 414.0 g (3.0 mol) of potassium carbonate, and 4.0 L of DMF into the reaction flask. After purging with nitrogen, heat the reaction mixture to 60 °C and stir for 5 hours. After monitoring the reaction by TLC until completion, cool it to room temperature. Slowly transfer the reaction mixture to a 50 L reactor containing 20 L of water, stir for 30 minutes, filter, add the filter cake to 10 L of dichloromethane to dissolve it, wash successively with 2 L of 1N hydrochloric acid aqueous solution, 2 L of 1N sodium bicarbonate aqueous solution, and 2 L of water. Concentrate the organic layer under reduced pressure to dryness. Add 3 L of 90% ethanol aqueous solution to the concentrate, heat to reflux to make it clear, cool to 0 - 5 °C in 2 hours, crystallize, filter, and dry in vacuo to obtain 736.5 g of crude abiraterone acetate. The molar yield is 94.1% and the HPLC purity is 98.9%. Recrystallize the crude product with acetone solvent to obtain 702.6 g of abiraterone acetate with a purity of 99.8%.

[0092] It was confirmed to be abiraterone acetate by mass spectrometry and nuclear magnetic resonance detection.

[0093] m.p.: 144.8 °C - 146.3 °C; ESI-MS (m / z): 414 [M+Na] + ; 1 H NMR (500 MHz, CDCl3) δ (ppm): 8.61 (d, 1H), 8.45 (q, 1H), 7.64 - 7.61 (m, 1H), 7.21 (q, 1H), 5.98 (q, 1H), 5.41 (d, 1H), 4.64 - 4.56 (m, 1H), 2.02 (s, 3H), 1.07 (s, 3H), 1.03 (s, 3H);

[0094] 13 C NMR (125 MHz, 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.

[0095] Example 2

[0096]

[0097] 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, and stir until dissolved and clear. Cool the temperature to 0 - 5 °C, and slowly add dropwise 4.9 g (52.5 mmol) of propionyl chloride. After the addition is complete, warm the reaction mixture to room temperature and stir for 3 hours while maintaining the temperature. After monitoring the reaction by TLC until it is complete, slowly add 50 mL of water. Separate 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 isopropenyl acetate to the concentrate, heat to 120 ± 5 °C, and distill at atmospheric pressure for 1 hour. Distill until the volume of the remaining material is approximately 50 mL, stop distillation, continue to stir while maintaining the temperature for 2 hours; cool to 0 - 5 °C, stir for 30 minutes; filter, add 80 mL of water to the filter cake, stir for 30 minutes; filter, add the filter cake to 30 mL of ethanol, and stir at room temperature for 30 minutes; cool to 0 - 5 °C, stir for 30 minutes; filter, wash the filter cake with a small amount of cold ethanol, and dry it under vacuum at 35 - 40 °C to obtain 17.7 g of 17-acetate androst-5,16-diene-3β-propionate, with a molar yield of 91.5% and an HPLC purity of 99.3%.

[0098] Add 7.7 g (0.02 mol) of 17-acetate androst-5,16-diene-3β-propionate, 2.94 g (0.02 mol) of diethyl(3-pyridyl)borane, 0.02 g (0.1 mmol) of nickel acetate, 0.02 g (0.1 mmol) of 2,2-bipyridine, 4.24 g (0.02 mol) of potassium phosphate, and 50 mL of toluene to the reaction flask. After purging with nitrogen, stir vigorously, heat the reaction mixture to reflux, and stir for 5 hours. After monitoring the reaction by TLC until it is complete, filter while it is hot, and concentrate the filtrate to dryness. Add the concentrate to a mixture of 50 mL of ethanol and 10 mL of 30% sodium hydroxide solution, heat to reflux, and stir for 3 hours. Cool to room temperature, add 100 mL of water, and age for 30 minutes. Filter and dry under vacuum to obtain 6.1 g of abiraterone, with a molar yield of 87.6%.

[0099] It was confirmed to be abiraterone by mass spectrometry and nuclear magnetic resonance detection.

[0100] ESI-MS (m / z): 372 [M+Na] + ; 11H NMR (500 MHz, 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).

[0101] 6.1 g (0.017 mol) of abiraterone, 50 mL of dichloromethane, and 3.0 g (0.03 mol) of triethylamine were added to a reaction flask. The temperature was lowered to 0 - 5 °C, and 3.0 g (0.03 mol) of acetic anhydride was slowly added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was filtered, and the organic layer was washed successively with 20 mL of water and 20 mL of 1N aqueous sodium bicarbonate solution. The organic layer was concentrated under reduced pressure to dryness. 20 mL of 90% aqueous ethanol was added to the concentrate, and the mixture was heated to reflux until clear. The temperature was lowered to 0 - 5 °C over 2 hours, and crystals were precipitated. The crystals were filtered and dried in vacuo to obtain 6.4 g of crude abiraterone acetate, with a molar yield of 96.8% and an HPLC purity of 98.5%. The crude product was recrystallized from acetone solvent to obtain 5.8 g of abiraterone acetate with a purity of 99.7%.

[0102] Example 3

[0103]

[0104] 14.4 g (0.05 mol) of dehydroepiandrosterone, 100 mL of dichloromethane, and 6.1 g (0.06 mol) of triethylamine were added to a reaction flask and stirred until dissolved and clear. The temperature was lowered to 0 - 5 °C, and 5.7 g (52.5 mmol) of trimethylchlorosilane was slowly added dropwise. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 4 hours while maintaining the temperature. After monitoring the reaction by TLC and determining that it was complete, 50 mL of water was slowly added. The aqueous layer was separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. 5.0 g (0.05 mol) of triethylamine and 100 mL of tetrahydrofuran were added to the concentrate, and the mixture was stirred for 10 minutes. The temperature was lowered to 0 - 5 °C, and 3.2 g (0.05 mol) of dimethylcarbamyl chloride was slowly added. The temperature was raised to reflux, and the mixture was stirred for 5 hours while maintaining the temperature. After monitoring the reaction by TLC and determining that it was complete, the mixture was concentrated under reduced pressure until the volume of the remaining material 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 slurried at room temperature for 30 minutes. The slurry was cooled to 0 - 5 °C and stirred for 30 minutes, then filtered. The filter cake was rinsed with a small amount of cold ethanol and dried in vacuo at 35 - 40 °C to obtain 18.6 g of 17-dimethylaminocarbonyl ester androst-5,16-diene-3β-trimethylsilyl ester. The molar yield was 86.5%, and the HPLC purity was 98.6%.

[0105] 8.6 g (0.02 mol) of 17-dimethylaminocarbonyl ester androst-5,16-diene-3β-trimethylsilyl ester, 4.41 g (0.03 mol) of diethyl(3-pyridyl)borane, 0.8 g (4.0 mmol) of copper(I) iodide, 0.7 g (4.0 mmol) of 1,10-phenanthroline, 2.5 g (0.03 mol) of sodium bicarbonate, and 50 mL of DMSO were added to a reaction flask. After purging with nitrogen, the mixture was stirred vigorously, and the reaction mixture was warmed to 80 °C and stirred for 3 hours. After monitoring the reaction by TLC and determining that it was complete, the reaction solution was cooled to room temperature, and 200 mL of water was slowly added dropwise, followed by stirring for 30 minutes. The mixture was filtered, and the filter cake was added to a solution formed by 50 mL of THF and 7.8 g of tetrabutylammonium fluoride and stirred at room temperature for 5 hours. 100 mL of water was added, and the mixture was aged for 30 minutes. The mixture was filtered and dried in vacuo to obtain 5.6 g of abiraterone. The molar yield was 79.2%.

[0106] Add 5.6 g (0.016 mol) of abiraterone, 50 mL of dichloromethane, and 2.0 g (0.02 mol) of triethylamine to the reaction flask. Cool the temperature 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 keep the reaction for 3 hours. Filter, and wash the organic layer successively with 20 mL of water and 20 mL of 1N sodium bicarbonate aqueous solution once, and then wash with 20 mL of 1N EDTA aqueous solution once to remove copper ions. Concentrate the organic layer under reduced pressure to dryness. Add 20 mL of 90% ethanol - water to the concentrate, heat to reflux to make it clear. Cool the temperature to 0 - 5 °C in 2 hours, crystallize, filter, and dry in vacuo to obtain 6.0 g of crude abiraterone acetate. The molar yield is 95.1%, and the HPLC purity is 97.0%. Recrystallize the crude product with acetone solvent to obtain 5.3 g of abiraterone acetate with a purity of 99.2%.

[0107] Example 4

[0108]

[0109] Add 14.4 g (0.05 mol) of dehydroepiandrosterone, 11.2 g (0.1 mol) of potassium tert - butoxide, and 100 mL of tetrahydrofuran to the reaction flask, and stir for 10 minutes. Cool the temperature to 0 - 5 °C, and slowly add 22.6 g (0.1 mol) of benzoic anhydride. Raise the temperature of the reaction mixture to 60 - 65 °C and keep stirring for 3 hours. After monitoring the reaction by TLC until it is completed, concentrate under reduced pressure until the volume of the remaining material is about 50 mL. Add 80 mL of water, stir for 30 minutes, filter, add the filter cake to 50 mL of water, stir for 30 minutes, filter, add the filter cake to 30 mL of ethanol, slurry at room temperature for 30 minutes, cool to 0 - 5 °C, stir for 30 minutes, filter, wash the filter cake with a small amount of cold ethanol, and dry in vacuo at 35 - 40 °C to obtain 22.6 g of 17 - benzoate androst - 5,16 - diene - 3β - benzoate. The molar yield is 91.2%, and the HPLC purity is 98.6%.

[0110] Add 9.9 g (0.02 mol) of 17 - benzoate androst - 5,16 - diene - 3β - benzoate, 4.41 g (0.03 mol) of diethyl(3 - pyridyl)borane, 1.38 g (2.0 mmol) of tricyclohexylphosphine nickel chloride (i.e., the metal catalyst is nickel chloride and the ligand is tricyclohexylphosphine), 2.4 g (0.03 mol) of lithium tert - butoxide, and 60 mL of acetonitrile to the reaction flask. After purging with nitrogen and stirring vigorously, raise the temperature of the reaction mixture to reflux and stir for 6 hours. After monitoring the reaction by TLC until it is completed, filter while it is hot, and concentrate the filtrate to dryness. Add the concentrate to a mixture of 50 mL of ethanol and 10 mL of 30% sodium hydroxide solution, heat to reflux, and stir for 3 hours. Cool to room temperature, add 100 mL of water, and age for 30 minutes. Filter and dry in vacuo to obtain 5.7 g of abiraterone with a molar yield of 82.9%.

[0111] Add 5.7 g (0.016 mol) of abiraterone, 50 mL of dichloromethane, and 2.0 g (0.02 mol) of triethylamine to the reaction flask. Cool the temperature to 0 - 5 °C, and slowly dropwise add 2.0 g (0.02 mol) of acetic anhydride. After the addition is complete, warm the reaction mixture to room temperature and keep the reaction for 3 hours. Filter the mixture. Wash the organic layer successively with 20 mL of water and 20 mL of 1N aqueous sodium bicarbonate solution, and then concentrate it under reduced pressure to dryness. Add the concentrate to 20 mL of 90% aqueous ethanol solution, warm it to reflux to make it clear. Cool the temperature to 0 - 5 °C in 2 hours, crystallize, filter, and dry it under vacuum to obtain 6.1 g of crude abiraterone acetate. The molar yield is 97.5%, and the HPLC purity is 99.0%. Recrystallize the crude product with acetone to obtain 5.4 g of abiraterone acetate with a purity of 99.7%.

[0112] All documents mentioned in the present invention are cited herein by reference as if each individual document was specifically and individually cited as reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A preparation method of an abiraterone intermediate, characterized in that, The method comprises the steps of: (1) reacting a compound represented by formula II with a compound represented by formula III-1 in a solvent in the presence of a metal catalyst, a ligand and a base to obtain a compound represented by formula I; The reaction formula is as follows: In Formula II and Formula I, R1 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, trialkylsilyl or dialkylarylsilyl, wherein the alkyl group in the trialkylsilyl and dialkylarylsilyl is C1-C3 alkyl, R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, dimethylaminoacyl or diethylaminoacyl; The "substituted" refers to that one or more hydrogen atoms on the group are independently replaced by a group selected from the following groups: Halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, The metal catalyst is selected from palladium salts, copper salts, nickel salts, or combinations thereof, wherein the palladium salt is selected from palladium chloride, palladium acetate, palladium trifluoromethanesulfonate, or combinations thereof, the copper salt is selected from cuprous iodide, and the nickel salt is selected from nickel chloride, nickel bromide, nickel acetate, or combinations thereof, The ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, pyridine, 2,2-bipyridine, and 1,10-phenanthroline.

2. The preparation method according to claim 1, characterized in that, R1 is selected from acetyl, and / or R2 is selected from acetyl.

3. The preparation method according to claim 1 or 2, characterized in that, Step (1) has one or more characteristics selected from the group consisting of: The molar ratio of the compound represented by formula II to the compound represented by formula III-1 is 1:1 to 3; The molar ratio of the compound represented by formula II to the metal catalyst is 1:0.005-0.3; The molar ratio of the compound represented by formula II to the ligand is 1:0.005-0.3; The molar ratio of the compound represented by formula II to the base is 1:1-3.

4. The preparation method according to claim 3, characterized in that, Step (1) has one or more characteristics selected from the group consisting of: The molar ratio of the compound represented by formula II to the compound represented by formula III-1 is 1:1 to 1.5; The molar ratio of the compound represented by formula II to the metal catalyst is 1:0.01 to 0.2; The molar ratio of the compound represented by formula II to the ligand is 1:0.01-0.2; The molar ratio of the compound represented by formula II to the base is 1:1-2.

5. The preparation method according to claim 1 or 2, characterized in that, Step (1) has one or more characteristics selected from the group consisting of: The metal catalyst is selected from palladium acetate, palladium chloride, cuprous iodide, nickel acetate, nickel chloride, or a combination thereof; the base is selected from potassium carbonate, sodium carbonate, potassium phosphate, lithium tert-butoxide, sodium hydroxide, sodium bicarbonate, or a combination thereof; The solvent is selected from tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, or a combination thereof.

6. The preparation method according to claim 1, characterized in that In the compound represented by formula II, R2 is acetyl, the metal catalyst is palladium chloride, the ligand is triphenylphosphine, and the base is potassium carbonate, or In the compound represented by formula II, R2 is propionyl, the metal catalyst is nickel acetate, the ligand is 2-bipyridine, and the base is potassium phosphate, or In the compound represented by formula II, R2 is N,N-dimethylformamide, the metal catalyst is cuprous iodide, the ligand is 1,10-phenanthroline, and the base is sodium bicarbonate, or In the compound represented by formula II, R2 is a benzoyl group, the metal catalyst is nickel chloride, the ligand is tricyclohexylphosphine, and the base is lithium tert-butoxide.

7. The preparation method according to claim 1 or 2, characterized in that, The reaction temperature of step (1) is 40-130°C.

8. The preparation method according to claim 7, characterized in that, The reaction temperature of step (1) is 60-115°C.

9. The preparation method according to claim 1, wherein The method further comprises the following steps: (1-a) reacting the compound represented by formula IV with an acylating agent to form the compound represented by formula II; The reaction formula is as follows: Among them, the acylating agent for generating R1 is selected from R1-halogen, R1-O-R1 or The acylating agent for generating R2 is selected from R2-halogen, R2-O-R2 or 10. The preparation method according to claim 9, characterized in that, 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, The acylating agent used to generate R2 is selected from isopropyl acetate or substituted or unsubstituted benzoic anhydride, 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: Halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro.

11. A preparation method of abiraterone, characterized in that, The preparation method comprises the following steps: (1) preparing the compound of formula I according to the preparation method according to any one of claims 1 to 10; (2) Deprotecting the compound of formula I obtained in step (1) to generate abiraterone, as shown in the following reaction formula:

12. A preparation method of abiraterone acetate, characterized in that, The preparation method comprises the following steps: (1) preparing abiraterone according to the preparation method of claim 11; (2) reacting the abiraterone obtained in step (1) with acetic anhydride to obtain abiraterone acetate, as shown in the following reaction formula:

13. A preparation method of abiraterone acetate, characterized in that, The preparation method comprises the following steps: (1) In a solvent, in the presence of a metal catalyst, a ligand and a base, the compound represented by formula II reacts with the compound represented by formula III-1 to obtain the compound represented by formula I. The reaction formula is as follows: In formula II and formula I, R1 is selected from acetyl, R2 is selected from C1-C6 acyl, substituted or unsubstituted benzoyl, dimethylaminoacyl or diethylaminoacyl; 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: Halogen, C1-C4 alkyl, C1-C4 haloalkyl, nitro, The metal catalyst is selected from palladium salts, copper salts, nickel salts, or combinations thereof, wherein the palladium salt is selected from palladium chloride, palladium acetate, palladium trifluoromethanesulfonate, or combinations thereof, the copper salt is selected from cuprous iodide, and the nickel salt is selected from nickel chloride, nickel bromide, nickel acetate, or combinations thereof, The ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, pyridine, 2,2-bipyridine, and 1,10-phenanthroline.

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