阅读说明：本技术 一种醋酸阿比特龙的合成方法及其中间体 (Synthetic method of abiraterone acetate and intermediate thereof ) 是由 高杰 陈梦婷 蒋澄宇 顾向忠 郭晔堃 钟静芬 于 2019-11-15 设计创作，主要内容包括：本发明公开了一种醋酸阿比特龙的合成方法及其中间体。本发明的合成方法包括如下步骤：在溶剂中,在碱的存在下,将化合物I与三氟甲磺酸酐进行如下所示的酯化反应得到化合物II即可。本发明的合成方法所用原料廉价易得,不存在三氟乙酰中间体,中间体和最终产品纯度有显著提高,总收率高。(The invention discloses a synthetic method of abiraterone acetate and an intermediate thereof. The synthesis method comprises the following steps: in a solvent, in the presence of alkali, the compound I and trifluoromethanesulfonic anhydride are subjected to esterification reaction as shown below to obtain a compound II. The synthesis method has the advantages of cheap and easily-obtained raw materials, no trifluoroacetyl intermediate, obviously improved purity of the intermediate and the final product, and high total yield.)

1. A method for synthesizing a compound II is characterized by comprising the following steps: in a solvent, in the presence of alkali, carrying out esterification reaction on a compound I and trifluoromethanesulfonic anhydride as shown in the specification to obtain a compound II;

wherein R is phenyl or phenyl substituted by halogen.

2. The method of synthesis according to claim 1,

the halogen is fluorine, chlorine, bromine or iodine;

and/or said substitution is monosubstituted;

and/or, in the esterification reaction, the solvent is a halogenated hydrocarbon solvent;

and/or, in the esterification reaction, the volume mol ratio of the solvent to the compound I is 5.0L/mol to 10.0L/mol;

and/or, in the esterification reaction, the alkali is inorganic alkali;

and/or in the esterification reaction, the molar ratio of the alkali to the compound I is 1.5-3.0;

and/or in the esterification reaction, the molar ratio of the trifluoromethanesulfonic anhydride to the compound I is 1.0-2.0;

and/or, in the esterification reaction, the esterification reaction is carried out in the atmosphere of protective gas;

and/or, in the esterification reaction, the reaction temperature of the esterification reaction is-10 ℃ to 0 ℃.

3. The method of synthesis according to claim 2,

r is phenyl,

And/or, in the esterification reaction, the solvent is dichloromethane;

and/or, in the esterification reaction, the inorganic base is an alkali metal carbonate, preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate;

and/or, in the esterification reaction, the protective gas is nitrogen and/or helium.

4. The method of synthesis of claim 1, further comprising the steps of: reacting dehydroepiandrosterone with a catalyst in a solvent in the presence of a catalystCarrying out the substitution reaction shown as the following to obtain the compound I;

5. a method for synthesizing a compound III, which is characterized by comprising the following steps: in a solvent, in the presence of alkali and a palladium catalyst, carrying out a coupling reaction shown in the specification on a compound II and diethyl-3-pyridine borane to obtain a compound III;

wherein R is as defined in any one of claims 1 to 3.

6. The method of synthesizing the compound III according to claim 5,

the synthesis method of the compound III further comprises the following steps: according to the synthesis method of the compound II as claimed in any one of claims 1 to 4, the compound II is obtained;

and/or, in the coupling reaction, the solvent is a mixed solvent of an ether solvent and water; the volume ratio of the ether solvent to water is preferably 1.0-10.0; the ether solvent is preferably tetrahydrofuran;

and/or, in the coupling reaction, the volume mol ratio of the solvent to the compound II is 6.0L/mol-12.0L/mol;

and/or, in the coupling reaction, the alkali is carbonate of alkali metal, preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate;

and/or, in the coupling reaction, the molar ratio of the alkali to the compound II is 2.0-5.0;

and/or, in the coupling reaction, the palladium catalyst is Pd (PPh)₃)₄、PdCl₂(PPh₃)₂And PdCl₂(dppf);

and/or in the coupling reaction, the molar ratio of the palladium catalyst to the compound II is 0.005-0.05;

and/or in the coupling reaction, the molar ratio of the diethyl-3-pyridine borane to the compound II is 1.0-1.5;

and/or, in the coupling reaction, the reaction temperature of the coupling reaction is the reflux temperature of the solvent.

7. A synthetic method of abiraterone is characterized by comprising the following steps:

in a solvent, carrying out hydrolysis reaction on the compound III and alkali as shown in the specification to obtain a compound IV;

wherein R is as defined in any one of claims 1 to 3.

8. The method of synthesis according to claim 7,

the synthesis method of the abiraterone further comprises the following steps: according to the synthesis method of the compound III as claimed in any one of claims 1 to 6, obtaining the compound III;

and/or, in the hydrolysis reaction, the solvent is a mixed solvent of an organic solvent and water; the organic solvent is preferably an alcohol solvent and/or an ether solvent; the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol; the ether solvent is preferably tetrahydrofuran; in the mixed solvent, the volume ratio of the organic solvent to water is preferably 10.0-50.0;

and/or, in the hydrolysis reaction, the volume molar ratio of the solvent to the compound III is 2.0L/mol to 15L/mol, preferably 4.0L/mol to 9.0L/mol;

and/or, in the hydrolysis reaction, the alkali is hydroxide of alkali metal, preferably sodium hydroxide and/or potassium hydroxide;

and/or in the hydrolysis reaction, the molar ratio of the alkali to the compound III is 1.5-3.0;

and/or, in the hydrolysis reaction, the alkali and the water in the solvent participate in the reaction together in the form of an aqueous alkali solution; the mass fraction of the alkali aqueous solution is preferably 20-50%;

and/or, in the hydrolysis reaction, the temperature of the reaction is room temperature.

9. A synthetic method of abiraterone acetate is characterized by comprising the following steps:

(1) obtaining abiraterone according to the synthesis method of abiraterone of any one of claims 1-8;

(2) in a solvent, under the action of a catalyst, carrying out the reaction shown in the following on the abiraterone synthesized in the step (1) and acetic anhydride to obtain abiraterone acetate;

10. one of the compounds II or III is,

wherein R is as defined in any one of claims 1 to 3;

said compound II is preferably

Said compound III is preferably

Technical Field

The invention relates to a synthetic method of abiraterone acetate and an intermediate thereof.

Background

Abiraterone acetate is an irreversible inhibitor of 17 alpha-hydroxylase/C17, 20-lyase co-developed by Cougar biopharmaceuticals and Johnson in the United states, and is clinically used for treating metastatic castration-resistant prostate cancer and high-risk metastatic endocrine therapy-sensitive prostate cancer.

In the research process of the synthesis process of abiraterone acetate, the original research patent US5604213 finds that dehydroepiandrosterone acetate is used as a starting material, firstly, the dehydroepiandrosterone acetate reacts with trifluoromethanesulfonic anhydride under the catalysis of a large-steric-hindrance organic base 2, 6-di-tert-butyl-4-methylpyridine to generate a 17-site activated vinyl trifluoromethanesulfonate intermediate, and the intermediate reacts with diethyl-3-pyridineborane under the catalysis of triphenylphosphine palladium dichloride and sodium carbonate to generate abiraterone acetate through Suzuki coupling reaction, wherein the total yield is 48.72%, and the purity is not reported. The main problems in the route are that expensive trifluoromethanesulfonic anhydride and 2, 6-di-tert-butyl-4-methylpyridine are used in the first step, the reaction purity is low, a small amount of raw materials are remained, an elimination product with the concentration of about 10% can be generated, and the post-treatment needs to be subjected to column chromatography purification and hexane recrystallization to be put into the next step of reaction. The second step of reaction needs short silica gel column, column chromatography purification and hexane recrystallization.

The original route is as follows:

in patents WO2006021776 and WO2006021777, the problems of the first step described above are addressed: (1)2, 6-di-tert-butyl-4-methylpyridine is expensive (2) and the catalytic elimination of the by-product generation proposes to replace the organic base with large steric hindrance by other organic bases. The patent mainly reports the reaction results of three organic bases (2, 6-lutidine, triethylamine and diisopropylethylamine), and although the three organic bases well avoid the generation of elimination byproducts, the highest conversion rate is only 85%, and the purity is not reported.

Since organic base catalysis tends to cause problems with low conversion of the feedstock, this patent also describes how to remove unreacted feedstock. As follows, taking triethylamine as an example, unreacted raw materials are carried to the second step, and finally, the unreacted raw materials can be separated from abiraterone acetate mesylate under the acidic condition of methanesulfonic acid because the unreacted raw materials do not have alkalinity because the unreacted raw materials cannot construct a pyridine ring connected with 17-position C-C.

However, even if the purification is carried out by way of salt formation and then dissociation, the total yield is only 21%, and the purity is 96.4%, and the solid obtained in one step of salt formation is reported to be extremely viscous and not easy to filter, so that other cheap organic bases cannot be used for obtaining satisfactory results.

Patent WO2015015246 reports the use of PhN (Tf)₂The aromatic bis (trifluoromethanesulfonimide) and KHMDS or LiHMDS and other bases replace the original trifluoromethanesulfonic anhydride and organic bases to avoid the generation of elimination by-products, but the conversion rate of raw materials is only 75% (the ratio of the raw materials to the target product in the crude product is 1:3), and the fluorination reagents and the bases are expensive and the reaction needs to be carried out at-78 ℃. The crude product obtained in the second step is neutralized with hydrochloric acid in isopropanol to form salt, and then abiraterone acetate is separated out by sodium carbonate, the purity is only 99.04%, and the yield is 52.19%.

Patent CN103864878 reports that the original diethyl (3-pyridyl) borane is replaced by 3-pyridinylbromide/magnesium/indium lithium chloride reagent because diethyl (3-pyridyl) borane is expensive. According to the patent, isopropyl chloride and magnesium are firstly prepared into a Grignard reagent, 3-bromopyridine and isopropyl magnesium chloride are subjected to halogen-magnesium exchange reaction to prepare pyridine magnesium chloride, and then the pyridine magnesium chloride is reacted with diethyl methoxyborane to obtain a metal bromide reagent. However, 3-pyridine zinc bromide/magnesium/indium lithium chloride reagent is not available in the market and needs to be synthesized by itself. The coupling yield of the second step is different from 75 to 85 percent.

The patent US2016347786 uses trifluoroacetyl protecting group method, the procedure is shorter, and the total yield of continuous batch is 43%.

Patent CN 104066744A adopts a formate protecting group, the procedure is equivalent to that of patent US2016347786, the total mass yield is 43% -46.5%, the total molar yield is 30%, and a certain amount of triene impurities are generated.

Disclosure of Invention

The invention provides a synthetic method of abiraterone acetate and an intermediate thereof, aiming at the defects of expensive reagents, high cost, genotoxicity risk of the intermediate, low total yield and the like existing in the synthetic method of the abiraterone acetate in the prior art. The synthesis method disclosed by the invention has the advantages that the raw materials are cheap and easy to obtain, intermediates containing genotoxicity warning structures such as trifluoroacetyl and aldehyde groups do not exist, the purity of the intermediates and final products is obviously improved, and the total yield is high.

The invention provides a synthesis method of a compound II, which comprises the following steps: in a solvent, in the presence of alkali, carrying out esterification reaction on a compound I and trifluoromethanesulfonic anhydride as shown in the specification to obtain a compound II;

wherein R is phenyl or phenyl substituted by halogen.

The halogen is preferably fluorine, chlorine, bromine or iodine.

The substitution is preferably monosubstituted.

R is preferably phenyl,

In the esterification reaction, the solvent may be a conventional solvent in the art for performing such a reaction, preferably a halogenated hydrocarbon solvent, more preferably dichloromethane. The amount of the solvent may be an amount conventionally used in carrying out such a reaction in the art, and is preferably in a volume molar ratio to the compound I of 5.0L/mol to 10.0L/mol, for example, 7.85L/mol.

In the esterification reaction, the base may be a conventional base used in the art for carrying out such a reaction, and is preferably an inorganic base. The inorganic base is preferably an alkali metal carbonate, more preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate. The amount of the base can be the amount conventionally used in the art for carrying out such reactions, and is preferably 1.5 to 3.0, e.g., 2.5, molar ratio to the compound I.

In the esterification reaction, the trifluoromethanesulfonic anhydride can be used in an amount which is conventional in the art for carrying out such a reaction, and preferably, the molar ratio of the trifluoromethanesulfonic anhydride to the compound I is 1.0-2.0, for example, 1.5.

In the esterification reaction, the esterification reaction is preferably performed under an atmosphere of a protective gas. The protective gas can be nitrogen and/or helium.

In the esterification reaction, the reaction temperature of the esterification reaction is preferably-10 ℃ to 0 ℃, for example, -10 ℃, 5 ℃ or 0 ℃.

In the esterification reaction, the preferable operation steps of the esterification reaction are as follows: adding trifluoromethanesulfonic anhydride to a mixed solvent formed by the compound I, the base and the solvent at-10-0 ℃ to carry out the esterification reaction. The addition is preferably dropwise.

In the esterification reaction, the progress of the reaction can be detected by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and a reaction end point is generally determined when the compound I disappears. The reaction time is preferably 12 to 48 hours, for example, 24 hours.

In the esterification reaction, the esterification reaction post-treatment method may be a conventional post-treatment of such a reaction, and preferably comprises the steps of: after the reaction is finished, quenching the reaction by water, separating by using an organic solvent, extracting an aqueous phase, combining organic phases, washing by water, drying and concentrating to obtain a compound II.

The synthesis method of the compound II can further comprise the following steps: reacting dehydroepiandrosterone with a catalyst in a solvent in the presence of a catalystCarrying out the substitution reaction shown as the following to obtain the compound I;

in the substitution reaction, the solvent may be a conventional solvent in the art for carrying out such a reaction, preferably an N-heteroaromatic hydrocarbon solvent, more preferably pyridine. The solvent may be used in an amount conventional in the art for carrying out such reactions, preferably in a volume molar ratio to dehydroepiandrosterone of 1.5L/mol to 4.0L/mol, for example 2.88L/mol.

In the substitution reaction, the catalyst may be a catalyst conventionally used in the art for carrying out such a reaction, and is preferably a pyridine compound, more preferably 4-dimethylaminopyridine. The catalyst can be used in an amount which is conventional in the art for carrying out such reactions, and preferably has a molar ratio to dehydroepiandrosterone of 0.1-1.0, for example, 0.2.

In the substitution reaction, theThe amount of (A) may be an amount conventionally used in the art for carrying out such reactions, preferably in a molar ratio to dehydroepiandrosterone of 1.0 to 2.0, e.g. 1.5.

In the substitution reaction, the reaction temperature of the substitution reaction is preferably room temperature.

In the substitution reaction, the progress of the substitution reaction can be detected by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and is generally used as the reaction end point when dehydroepiandrosterone disappears. The reaction time is preferably 8 to 20 hours, for example, 12 hours.

In the substitution reaction, the post-treatment method of the substitution reaction may be a conventional post-treatment of such a reaction, and preferably comprises the steps of: after the reaction is finished, quenching the reaction by water, filtering, and drying to obtain the compound I.

The invention also provides a synthesis method of the compound III, which comprises the following steps:

in a solvent, in the presence of alkali and a palladium catalyst, carrying out a coupling reaction shown in the specification on a compound II and diethyl-3-pyridine borane to obtain a compound III;

wherein R is as defined above.

The synthesis method of the compound III can further comprise the following steps: the compound II can be obtained according to the synthesis method of the compound II.

In the coupling reaction, the solvent may be a conventional solvent in the art for performing such a reaction, and is preferably a mixed solvent of an ether solvent and water. The volume ratio of the ether solvent to water is preferably 1.0 to 10.0, for example, 4.0. The ether solvent is preferably tetrahydrofuran. The solvent may be used in an amount conventional in the art, and preferably in a volume molar ratio to the compound II of 6.0L/mol to 12.0L/mol, for example, 9.83L/mol.

In the coupling reaction, the base may be a base conventional in the art for carrying out such a reaction, preferably an alkali metal carbonate, more preferably one or more of sodium carbonate, potassium carbonate and cesium carbonate. The base may be used in an amount conventional in the art for carrying out such reactions, preferably in a molar ratio of 2.0 to 5.0, e.g., 3.6, to compound II.

In the coupling reaction, the palladiumThe catalyst may be a conventional palladium catalyst for carrying out such reactions in the art, preferably Pd (PPh)₃)₄、PdCl₂(PPh₃)₂And PdCl₂(dppf). The palladium catalyst can be used in an amount conventionally used in the art for carrying out such a reaction, and preferably has a molar ratio of 0.005 to 0.05, for example, 0.01, to the compound II.

In the coupling reaction, the diethyl-3-pyridine borane can be used in an amount which is conventional in the art for carrying out such a reaction, and preferably has a molar ratio of 1.0 to 1.5, for example, 1.1, to the compound II.

In the coupling reaction, the reaction temperature of the coupling reaction is preferably the reflux temperature of the solvent.

In the hydrolysis reaction, the progress of the reaction can be monitored by a monitoring method (e.g., TLC, HPLC or NMR) which is conventional in the art, and the end point of the reaction is generally determined when the compound II disappears. The reaction time is preferably 1 to 5 hours, for example, 2 to 3 hours.

In the coupling reaction, the post-treatment of the coupling reaction may be a conventional post-treatment of such reactions, preferably comprising the steps of: after the reaction is finished, cooling to room temperature, separating liquid by using an organic solvent, extracting an aqueous phase, combining organic phases, washing with water, drying and concentrating to obtain a compound III.

The invention also provides a synthetic method of the abiraterone, which comprises the following steps: in a solvent, carrying out hydrolysis reaction on the compound III and alkali as shown in the specification to obtain a compound IV;

wherein R is as defined above.

The synthesis method of the abiraterone can also comprise the following steps: according to the synthesis method of the compound III, the compound III is obtained.

In the hydrolysis reaction, the solvent may be a conventional solvent in the art for performing such a reaction, and is preferably a mixed solvent of an organic solvent and water. The organic solvent is preferably an alcohol solvent and/or an ether solvent. The alcohol solvent is preferably one or more of methanol, ethanol and isopropanol. The ether solvent is preferably tetrahydrofuran. In the mixed solvent, the volume ratio of the organic solvent to water is preferably 10.0-50.0, for example, 20.0 or 40.0.

In the hydrolysis reaction, the solvent may be used in an amount conventional in the art, and preferably in a volume molar ratio to the compound III of 2.0L/mol to 15L/mol, more preferably 4.0L/mol to 9.0L/mol, for example, 9.09L/mol or 4.55L/mol.

In the hydrolysis reaction, the base may be a conventional base used in the art for such reactions, preferably an alkali metal hydroxide, more preferably sodium hydroxide and/or potassium hydroxide. The amount of the base used may be conventional in the art, and is preferably 1.5 to 3.0, for example, 2.0, in terms of a molar ratio to the compound III.

In the hydrolysis reaction, the base and the water in the solvent may be reacted together in the form of an aqueous solution of the base. The mass fraction of the aqueous alkali solution is preferably 20% to 50%, for example, 30%.

In the hydrolysis reaction, the reaction temperature may be conventional in the art, and is preferably room temperature.

In the hydrolysis reaction, the progress of the reaction can be monitored by a monitoring method (e.g., TLC, HPLC or NMR) which is conventional in the art, and the end point of the reaction is generally determined when the compound III disappears. The reaction time is preferably 1 to 20 hours, for example, 2 hours or 18 hours.

In the hydrolysis reaction, the post-treatment of the hydrolysis reaction may be a post-treatment conventional in the art for such reactions, and preferably comprises the steps of: and after the reaction is finished, adjusting the pH value to 7-8, filtering, washing a filter cake with water, and drying the filter cake to obtain a crude compound IV. The drying operations and conditions may be conventional in the art and are typically vacuum dried. The drying temperature is preferably 40 to 60 ℃, for example, 60 ℃. The drying time is preferably 4 to 12 hours. And mixing the crude product of the compound IV with an ester solvent for recrystallization. The volume mass ratio of the ester solvent to the crude product is 3.0mL/g to 5.0mL/g, for example, 4.0 mL/g.

Alternatively, said post-treatment of the hydrolysis reaction preferably comprises the steps of: after the reaction is finished, removing the solvent, extracting the organic matter by using an organic solvent, washing the organic phase by water, and concentrating to obtain a compound IV.

The invention also provides a synthetic method of abiraterone acetate, which comprises the following steps:

(1) obtaining the abiraterone according to the synthesis method of the abiraterone;

(2) in a solvent, under the action of a catalyst, carrying out the reaction shown in the following on the abiraterone synthesized in the step (1) and acetic anhydride to obtain abiraterone acetate;

in step (2), the solvent may be a conventional solvent in the art for carrying out such a reaction, preferably a nitrile solvent, more preferably acetonitrile. The solvent may be used in an amount conventional in the art for carrying out such reactions, preferably in a volume molar ratio to abiraterone of from 1.5L/mol to 4.0L/mol, for example 2.1L/mol.

In step (2), the catalyst may be a catalyst conventionally used in the art for carrying out such reactions, and is preferably a pyridine compound, more preferably 4-dimethylaminopyridine. The catalyst may be used in an amount conventionally used in the art for carrying out such reactions, preferably in a molar ratio to abiraterone of from 0.05 to 1.0, for example 0.1.

In step (2), the amount of acetic anhydride used may be the amount conventionally used in the art for carrying out such reactions, and preferably the molar ratio of acetic anhydride to abiraterone is 1.2-3.0, for example, 2.0.

In the step (2), the reaction temperature of the reaction is preferably room temperature.

In step (2), the progress of the reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and is generally determined as the end point of the reaction when abiraterone disappears.

In step (2), the reaction may further comprise a post-treatment, and the post-treatment may be a conventional post-treatment for such a reaction, and the present invention preferably comprises the steps of: and after the reaction is finished, filtering while the reaction is hot, adding water into the filtrate, adjusting the pH of the filtrate to 7-8, filtering, and drying the filter cake to obtain the abiraterone acetate. The drying is preferably vacuum drying. The drying temperature is preferably 40 ℃ to 60 ℃, for example, 45 ℃.

The invention also provides a compound II or III,

wherein R is as defined above.

Said compound II is preferably

Said compound III is preferably

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

In the invention, the room temperature is 10-35 ℃.

The positive progress effects of the invention are as follows:

potential genotoxicity risks of trifluoroacetyl intermediates and formate intermediates are avoided;

after benzoyl protection, the reaction conversion rate is higher, and the purity of an intermediate and a final product is obviously improved;

the benzoyl intermediate is easy to purify, and is beneficial to subsequent reaction and quality control of final products;

the purity of the final product is higher, and triene impurities mentioned in patent CN 104066744A are not generated;

the method has the advantages of cheap and easily-obtained raw materials, simple operation, suitability for industrial expanded production and higher total yield.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The "purities" in the following examples are all "HPLC purities"

Synthesis of benzoyl dehydroepiandrosterone

Example 1

Dehydroepiandrosterone (16g, 55.52mmol) was dissolved in 160mL pyridine, 4-dimethylaminopyridine (1.36g, 11.10mmol) was added, and benzoyl chloride (11.71g, 83.28mmol) was slowly added dropwise. After 12 hours of reaction at room temperature, 800mL of water was added to the reaction mixture to precipitate a white solid. Suction filtration and drying are carried out to obtain the benzoyl dehydroepiandrosterone (21.61g, 99.17%). The purity is 99.23%.

Example 2

Dehydroepiandrosterone (16g, 55.52mmol) was dissolved in 160mL pyridine, 4-dimethylaminopyridine (1.36g, 11.10mmol) was added, and benzoyl chloride (11.71g, 83.28mmol) was slowly added dropwise. The reaction was carried out at room temperature for 12 hours, 160mL of water and 160mL of methylene chloride were added, extraction was carried out, and the organic layer was washed twice with water and 1M Na₂CO₃Washed once, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered by suction, and the organic layer was spin-dried to give a white solid (21.43g, 98.43%). The purity is 99.08%.

Comparative example 1

Dehydroepiandrosterone (16g, 55.52mmol) was dissolved in 160mL pyridine, 4-dimethylaminopyridine (1.36g, 11.10mmol) was added, and o-chlorobenzoyl chloride (14.58g, 83.28mmol) was slowly added dropwise. After 12 hours of reaction at room temperature, 800mL of water was added to the reaction mixture to precipitate a white solid. The mixture is filtered by suction and dried to obtain benzoyl dehydroepiandrosterone (23.06g, 97.25%). The purity was 93.39%.

Comparative example 2

Dehydroepiandrosterone (16g, 55.52mmol) was dissolved in 160mL pyridine, 4-dimethylaminopyridine (1.36g, 11.10mmol) was added, and p-chlorobenzoyl chloride (14.58g, 83.28mmol) was slowly added dropwise. After 12 hours of reaction at room temperature, 800mL of water was added to the reaction mixture to precipitate a white solid. Suction filtration and drying are carried out to obtain the benzoyl dehydroepiandrosterone (25.19g, 106.24%). The purity was 83.30%.

Comparative example 3

Dehydroepiandrosterone (16g, 55.52mmol) was dissolved in 160mL pyridine, 4-dimethylaminopyridine (1.36g, 11.10mmol) was added, and o-fluorobenzoyl chloride (13.21g, 83.28mmol) was slowly added dropwise. After 12 hours of reaction at room temperature, 800mL of water was added to the reaction mixture to precipitate a white solid. Suction filtration and drying are carried out to obtain the benzoyl dehydroepiandrosterone (22.43g, 98.42%). The purity is 99.85%.

Comparative example 4

Dehydroepiandrosterone (16g, 55.52mmol) was dissolved in 160mL pyridine, 4-dimethylaminopyridine (1.36g, 11.10mmol) was added, and p-fluorobenzoyl chloride (13.21g, 83.28mmol) was slowly added dropwise. After 12 hours of reaction at room temperature, 800mL of water was added to the reaction mixture to precipitate a white solid. Filtering, drying to obtain benzoyl dehydroepiandrosterone (22.07g, 96.84%). The purity is 99.53%.

Synthesis of di-and benzoyl triflate

Example 3

Benzoyl dehydroepiandrosterone (8g, 20.38mmol) was dissolved in 160mL of dichloromethane, Na was added₂CO₃(5.40g, 50.95mmol), under nitrogen, cooling to-5 deg.C, slowly adding trifluoromethanesulfonic anhydride (8.63g, 30.57mmol) dropwise over one hour. The reaction is finished after 24 hours at the temperature of minus 5 ℃. Adding water (60mL) to quench, stirring at room temperature for 10min, separating the liquid, and extracting the aqueous layer with dichloromethane (40mL) onceThe organic layers were combined, washed with an aqueous sodium carbonate solution, water, saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure to give a pale purple solid (10.18g, 95.68%). HPLC retention time 40.25min, purity 93.37%. MS: 547.06[ M + Na ═ M/e]⁺；¹H NMR(400MHz,CDCl₃)δ：1.01(s，3H，19-CH₃)，1.11(s，3H，18-CH₃)，4.84-4.89(m，1H，3α-H)，5.43-5.44(d，1H，J＝2Hz，6-H)，5.59(s，1H，16-H)，7.42-8.05(m，5H，Ph-H)。¹³C NMR(400MHz，CDCl₃)δ：15.11，19.26，20.15，27.80，28.62，29.96，30.59，32.68，36.87，36.90，38.20，44.68，50.39，54.24，74.31，114.50，121.93，128.30，129.55，130.75，132.79，140.17，159.20，166.00。

Example 4

Benzoyl dehydroepiandrosterone (8g, 20.38mmol) was dissolved in 160mL of dichloromethane, Na was added₂CO₃(5.40g, 50.95mmol), under nitrogen, cooling to-10 deg.C, slowly adding trifluoromethanesulfonic anhydride (8.63g, 30.57mmol) dropwise over one hour. The reaction is finished after 24 hours at the temperature of minus 10 ℃. Quenching by adding water (60mL), stirring at room temperature for 10min, separating the liquids, extracting the aqueous layer once with dichloromethane (40mL), combining the organic layers, washing with aqueous sodium carbonate, washing with water, washing with saturated brine, drying over anhydrous magnesium sulfate, and filtering. The solvent was evaporated under reduced pressure to give a pale purple solid (9.74g, 91.11%). HPLC retention time 40.26min, purity 93.55%.

Example 5

Benzoyl dehydroepiandrosterone (8g, 20.38mmol) was dissolved in 160mL of dichloromethane, Na was added₂CO₃(5.40g, 50.95mmol), under nitrogen, and cooled to 0 ℃ and trifluoromethanesulfonic anhydride (8.63g, 30.57mmol) was added dropwise slowly over an hour. And (4) reacting at 0 ℃ for 24 hours, and finishing the reaction. Quenching by adding water (60mL), stirring at room temperature for 10min, separating the liquids, extracting the aqueous layer once with dichloromethane (40mL), combining the organic layers, washing with aqueous sodium carbonate, washing with water, washing with saturated brine, drying over anhydrous magnesium sulfate, and filtering. The solvent was evaporated under reduced pressure to give a pale purple solid (10.03g, 93.83%). HPLC retentionThe time is 40.25min, and the purity is 95.59%.

Comparative example 5

O-chlorobenzoyl dehydroepiandrosterone (8g, 18.73mmol) is dissolved in 160mL dichloromethane, Na is added₂CO₃(4.96g, 46.83mmol) under nitrogen, cooling to-5 deg.C, and slowly adding trifluoromethanesulfonic anhydride (7.93g, 28.10mmol) dropwise over one hour. The reaction is finished after 24 hours at the temperature of minus 5 ℃. Quenching by adding water (60mL), stirring at room temperature for 10min, separating the liquids, extracting the aqueous layer once with dichloromethane (40mL), combining the organic layers, washing with aqueous sodium carbonate, washing with water, washing with saturated brine, drying over anhydrous magnesium sulfate, and filtering. The solvent was evaporated under reduced pressure to give a pale purple solid (9.66g, 92.26%). The purity was 89.84%.

Comparative example 6

O-fluorobenzoyl dehydroepiandrosterone (8g, 19.49mmol) was dissolved in 160mL of dichloromethane, Na was added₂CO₃(5.17g, 48.73mmol) under nitrogen, cooling to-5 deg.C, and slowly adding trifluoromethanesulfonic anhydride (8.25g, 29.24mmol) dropwise over one hour. The reaction is finished after 24 hours at the temperature of minus 5 ℃. Quenching by adding water (60mL), stirring at room temperature for 10min, separating the liquids, extracting the aqueous layer once with dichloromethane (40mL), combining the organic layers, washing with aqueous sodium carbonate, washing with water, washing with saturated brine, drying over anhydrous magnesium sulfate, and filtering. The solvent was evaporated under reduced pressure to give a pale purple solid (9.87g, 93.38%). The purity is 96.48%.

Comparative example 7

P-fluorobenzoyl dehydroepiandrosterone (8g, 19.49mmol) is dissolved in 160mL of dichloromethane, Na is added₂CO₃(5.17g, 48.73mmol) under nitrogen, cooling to-5 deg.C, and slowly adding trifluoromethanesulfonic anhydride (8.25g, 29.24mmol) dropwise over one hour. The reaction is finished after 24 hours at the temperature of minus 5 ℃. Quenching by adding water (60mL), stirring at room temperature for 10min, separating the liquids, extracting the aqueous layer once with dichloromethane (40mL), combining the organic layers, washing with aqueous sodium carbonate, washing with water, washing with saturated brine, drying over anhydrous magnesium sulfate, and filtering. The solvent was evaporated under reduced pressure to give a pale purple solid (10.03g, 94.89%). The purity was 96.24%.

Synthesis of benzoyl abiraterone

Example 6

Diethyl-3-pyridine borane (2.47g, 16.77mmol), palladium bis (triphenylphosphine) dichloride (108.99mg, 0.15mmol), 2mol/L aqueous sodium carbonate (5.82g, 54.90mmol) solution (30mL), benzoyl trifluoroethylene ester (8.00g, 15.25mmol) in tetrahydrofuran (120mL) was added to the reaction flask, the reaction was refluxed for 2-3 hours, monitored by TLC and cooled to room temperature. Water (80mL) and methylene chloride (80mL) were added, the mixture was separated, the aqueous layer was extracted once with methylene chloride (40mL), the organic layers were combined, washed twice with water (80mL), washed with saturated brine (80mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 8.16g of a tan solid. The purity was 85.04%.

To the crude product (8.16g) was added 25mL of ethanol, heated under reflux for 30min, cooled, stirred in an ice bath for two hours, filtered and dried to give an off-white solid (5.28g, 76.31%). Purity: 94.98 percent. MS: 454.19[ M + H ] M/e]⁺；¹H NMR(400MHz,CDCl₃)δ：1.08(s，3H，19-CH₃)，1.15(s，3H，18-CH₃)，4.89-4.91(m，1H，3α-H)，5.48-5.49(d，1H，J＝2Hz，6-H)，6.01-6.03(m，1H，16-H)，7.22-7.69(m，5H，Ph-H)，8.06(d，1H，Py-5H)，8.08(s，1H，Py-4H)，8.49(m，1H，Py-6H)，8.65(d，1H，Py-2H)。¹³C NMR(400MHz，CDCl₃)δ：16.14，18.88，20.40，27.41，29.99，31.11，31.36，34.78，36.41，36.52，37.79，46.90，49.83，57.03，74.01，121.98，122.57，127.83，128.79，129.09，130.35，132.30，132.52，133.25，139.59，147.43，147.49，151.23，165.55。

Comparative example 8

Diethyl-3-pyridine borane (2.38g, 16.21mmol), palladium bis (triphenylphosphine) dichloride (84.38mg, 0.12mmol), 2mol/L aqueous sodium carbonate (5.62g, 53.06mmol) solution (27mL), o-fluorobenzoyltrifluoromethanesulfonate (8.00g, 14.74mmol) in tetrahydrofuran (120mL) were added to the flask, the reaction was refluxed for 2-3 hours, monitored by TLC for completion, and cooled to room temperature. Water (80mL) and methylene chloride (80mL) were added, the mixture was separated, the aqueous layer was extracted once with methylene chloride (40mL), the organic layers were combined, washed twice with water (80mL), washed with saturated brine (80mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 6.87g of a tan solid. The purity is 87.80%.

To the crude product (6.87g) was added 21mL of ethanol, heated under reflux for 30min, cooled, stirred in an ice bath for two hours, filtered and dried to give an off-white solid (4.65g, 66.91%). Purity: 93.16 percent.

Comparative example 9

Diethyl-3-pyridine borane (2.38g, 16.21mmol), palladium bis (triphenylphosphine) dichloride (84.38mg, 0.12mmol), 2mol/L aqueous sodium carbonate (5.62g, 53.06mmol) solution (27mL), p-fluorobenzoyltrifluoromethanesulfonate (8.00g, 14.74mmol) in tetrahydrofuran (120mL) were added to the flask, the reaction was refluxed for 2-3 hours, monitored by TLC for completion, and cooled to room temperature. Water (80mL) and methylene chloride (80mL) were added to separate the layers, the aqueous layer was extracted once with methylene chloride (40mL), the organic layers were combined, washed twice with water (80mL), washed with saturated brine (80mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 7.29g of a tan solid. The purity was 93.77%.

To the crude product (7.29g) was added 21mL of ethanol, heated under reflux for 30min, cooled, stirred in an ice bath for two hours, filtered and dried to give an off-white solid (5.15g, 74.09%). Purity: 98.72 percent.

Synthesis of tetra, abiraterone

Example 7

Benzoyl abiraterone (1g, 2.20mmol) was added to a reaction flask, 20mL of methanol was added, 30% sodium hydroxide (176mg, 4.40mmol) aqueous solution (0.5mL) was added, and the reaction was carried out at room temperature for 18 hours. TLC monitoring reaction was completed, cooled to room temperature, added water (10mL), adjusted pH to weak acidity with 1mol/L hydrochloric acid, then adjusted pH to 7-8 with 1mol/L aqueous sodium carbonate solution, stirred for 2 hours in ice bath, filtered, filter cake washed with water (20mL), dried overnight at 60 ℃ under vacuum to give 0.75g of off-white solid with 94.76% purity.

To the crude product (0.75g) was added 3mL ethyl acetate, heated under reflux for 30min, cooled, stirred in an ice bath for two hours, filtered and dried to give a white solid (0.64g, 83.11%). The purity was 96.33%.

Example 8

Benzoyl abiraterone (1g, 2.20mmol) was dissolved in 10mL tetrahydrofuran and 30% aqueous NaOH (176mg, 4.40mmol) solution (0.5mL) was added dropwise. 10mL of methanol was added and the reaction was allowed to proceed at room temperature for 2 hours, and TLC showed completion of the reaction. 20mL of water was added, the organic phase was spun dry, and 10mL of CH2Cl2 was added and extracted to give a black insoluble impurity which was left in the aqueous layer. The organic layer was washed with water 3 times, saturated brine 1 time, and the organic layer was spin-dried to give light cyan solid abiraterone (0.66g, 85.71%), purity: 96.80 percent.

Example 9

Benzoyl abiraterone (1g, 2.20mmol) was dissolved in 10mL tetrahydrofuran and 30% aqueous KOH (246mg, 4.40mmol) solution (0.5mL) was added dropwise. 10mL of methanol was added and the reaction was allowed to proceed at room temperature for 2 hours, and TLC showed completion of the reaction. 20mL of water was added, the organic phase was spun dry, and 10mL of CH2Cl2 was added and extracted to give a black insoluble impurity which was left in the aqueous layer. The organic layer was washed with water 3 times, saturated brine 1 time, and the organic layer was spin-dried to obtain light cyan solid abiraterone (0.74g, 96.10%), purity: 97.18 percent.

Comparative example 10

Benzoyl abiraterone (1g, 2.20mmol) was dissolved in 15mL tetrahydrofuran and LiAlH was added₄(250.80mg, 6.60mmol), and the reaction was carried out in ice bath for 3 hours. TLC showed the reaction was complete. Adding a small amount of ice to quench the reaction, adding 10mL of water and 10mL of dichloromethane, extracting, emulsifying seriously, filtering to remove insoluble aluminum salt and lithium salt, washing an organic layer for three times by using water, washing the organic layer once by using a saturated sodium chloride solution, wherein the organic layer is light cyan, and spin-drying to obtain 0.76g of light cyan powdery solid with purity: 94.40 percent.

To the crude product (0.76g) was added 3mL ethyl acetate, heated under reflux for 30min, cooled, stirred in an ice bath for two hours, filtered and dried to give a white solid (0.43g, 55.43%). The purity is 98.80%.

Comparative example 11

O-fluorobenzoylabiraterone (1g, 2.12mmol) was dissolved in 15mL tetrahydrofuran, added LiAlH4(241.68mg, 6.36mmol), and reacted in ice bath for 3 hours. TLC showed the reaction was complete. Adding a small amount of ice to quench the reaction, adding 10mL of water and 10mL of dichloromethane, extracting, emulsifying seriously, filtering to remove insoluble aluminum salt and lithium salt, washing an organic layer for three times with water, washing the organic layer once with a saturated sodium chloride solution, wherein the organic layer is light cyan, and spin-drying to obtain 0.60g of light cyan powdery solid with purity: 92.96 percent.

To the crude product (0.60g) was added 3mL ethyl acetate, heated under reflux for 30min, cooled, stirred in an ice bath for two hours, filtered and dried to give a white solid (0.39g, 53.37%). The purity is 99.19%.

Comparative example 12

P-fluorobenzoylabiraterone (1g, 2.12mmol) was dissolved in 15mL tetrahydrofuran, LiAlH4(241.68mg, 6.36mmol) was added, and the reaction was performed in ice bath for 3 hours. TLC showed the reaction was complete. Adding a small amount of ice to quench the reaction, adding 10mL of water and 10mL of dichloromethane, extracting, emulsifying seriously, filtering to remove insoluble aluminum salt and lithium salt, washing an organic layer for three times by using water, washing the organic layer once by using a saturated sodium chloride solution, wherein the organic layer is light cyan, and spin-drying to obtain 0.59g of light cyan powdery solid with the purity: 93.73 percent.

To the crude product (0.59g) was added 3mL ethyl acetate, heated under reflux for 30min, cooled, stirred in an ice bath for two hours, filtered and dried to give a white solid (0.37g, 49.99%). The purity is 99.80%.

Synthesis of abiraterone acetate

Example 11

Abiraterone (4g, 11.44mmol) was added to the reaction flask, acetonitrile (24mL), 4-dimethylaminopyridine (139.27mg, 1.14mmol) were added, acetic anhydride (2.34g, 22.88mmol) was added dropwise over 0.5 h, the reaction was heated to reflux and TLC monitored for reaction completion. And after the reaction is finished, filtering while the solution is hot, adding water (24mL) into the filtrate, adjusting the pH to 7-8 by using a 1mol/L sodium carbonate aqueous solution, stirring for 3 hours at room temperature, filtering, and drying overnight at 45 ℃ in vacuum to obtain 4.29g of light yellow solid with the purity of 98.22%.

To the crude product (4.29g) was added 16mL acetonitrile, heated to reflux for 30min, cooled, stirred in an ice bath for two hours, filtered and dried to give a white solid (3.79g, 84.59%). The purity is 99.44%. MS: 392.17[ M + H ] M/e]⁺；¹H NMR(400MHz，CDCl₃)δ：1.04(s，3H，19-CH₃)，1.06(s，3H，18-CH₃)，2.03(s，3H，CH₃CO₂)，4.57-4.65(m，1H，3α-H)，5.41-5.42(dm，1H，J＝4.0Hz，6-H)，5.99(m，1H，16-H)，7.19-7.22(m，1H，Py 5-H)，7.63-7.65(m，1H，Py 4-H)，8.45-8.46(m，1H，Py 6-H)，8.62(m，1H，Py 2-H)；¹³C NMR(400MHz，CDCl₃)δ：16.56，19.24，20.81，21.40，27.73，30.40，31.50，31.78，35.20，36.77，36.91，38.13，47.31，50.25，57.43，73.83，122.26，122.98，129.17，132.91，133.64，140.02，147.87，147.93，151.67，170.46。

The HPLC purity measurements of examples 1 to 5 and comparative examples 1 to 7 all adopt the following conditions:

the instrument comprises the following steps: agent 1260

A chromatographic column: xbridge^TM Shield RP18 150*4.6mm，3.5μm

Column temperature: 45 deg.C

Mobile phase:

mobile phase A: acetonitrile

Mobile phase B: pure water

The mobile phase gradients are shown in table 1:

TABLE 1

Flow rate: 1.00mL/min

Detection wavelength: 210nm

Sample introduction amount: 20 μ L

The HPLC purity measurements of the other examples and comparative examples were carried out using the following conditions of the United states Pharmacopeia method:

the instrument comprises the following steps: agent 1260

A chromatographic column: prontosil C18150 mm 3.0mm, 3 μm

Column temperature: 30 deg.C

Mobile phase:

mobile phase A: acetonitrile

Mobile phase B: ethanol

Mobile phase C: 0.01M ammonium acetate solution

The mobile phase gradients are shown in table 2:

TABLE 2

Flow rate: 0.46mL/min

Detection wavelength: 254nm

Sample introduction amount: 20 μ L

The final product retention time was around 33min and the stereosynthetic alpha configuration retention time was 29min as measured using HPLC (usp method). The alpha isomer was not detected in the product. United states pharmacopoeia does not report [ alpha ]]²⁵ _DData, impurities described in pharmacopoeia also do not contain enantiomeric impurities. The final product has a melting point of 145.1-145.6 ℃.

Synthesis example of α -configuration impurities:

triphenylphosphine (10.5g, 40mmol) and toluene (80ml) were cooled to 0 deg.C, diisopropyl azodicarboxylate (7.9ml, 40mmol) and dehydroepiandrosterone (5.76g, 20mmol) were slowly added dropwise, stirred at room temperature for 20 min, p-nitrobenzoic acid (6.68g, 40mmol) was added, heated to 60 deg.C for reaction for 2.5 h, concentrated under reduced pressure and methanol (30ml) was added, stirred at room temperature for 1 h, filtered to give a white solid (5.6 g).

Sodium hydroxide (1.33g, 33.4mmol), methanol (60ml), and a white solid (5.6g, 12.8mmol) were added to a reaction flask, heated to 70 ℃ and reacted for 2 hours, and the reaction solution was poured into ice water and stirred, filtered, and dried under reduced pressure to obtain a white solid (1.74 g).

The reaction flask was charged with white solid (1.74g, 6.04mmol), acetonitrile (10ml), N, N-lutidine (74mg, 0.60mmol), acetic anhydride (0.99g, 9.67mmol) was slowly added dropwise, the reaction was refluxed for 1 hour after the addition was complete, and column purification was carried out to give white solid (1.5 g).

A white solid (1.5g, 4.54mmol), dichloromethane (16ml), potassium carbonate (1.26g, 9.08mmol) was added to the reaction flask, the reaction solution was cooled to-20 ℃ and trifluoromethanesulfonic anhydride (1.9g, 6.81mmol) was added dropwise and reacted for 20 hours. Water (10.5ml) was added to the reaction mixture, followed by extraction with methylene chloride (6ml), washing with an aqueous solution of sodium carbonate, washing with water, drying, filtration and concentration under reduced pressure to give a brown-red oil (2.1 g).

Diethyl-3-pyridine borane (0.74g, 5.00mmol), bis-triphenylphosphine palladium dichloride (16mg, 0.02mmol), 2mol/L aqueous sodium carbonate solution (8.5ml, 16.34mmol), and a reddish-brown oily substance (2.1g, 4.54mmol) were dissolved in tetrahydrofuran (25ml) and added to a reaction flask, followed by heating and refluxing for 3 hours, followed by addition of water (25ml), ethyl acetate (25ml), extraction, water washing, sulfur drying, filtration, and concentration under reduced pressure to give a dark brown oily substance (2.3 g). Column purification gave an off-white solid (0.25 g). Hexane (2.5ml) was added and the mixture heated to reflux, cooled to room temperature and filtered to give a white solid (0.1g, 1.28%) with a purity of 95.95%.