A method for preparing abiraterone acetate intermediate with high purity and high yield

Abstract

The present invention provides a method for preparing a high-purity and high-yield abiraterone acetate intermediate. The preparation method of the present invention comprises the steps of: (1) detecting the water content of raw material iodine: reacting zinc powder with iodine in solvent A, filtering and removing solids, and using Karl Fischer method to determine the water content N1 in the filtrate; performing a blank control experiment without iodine addition at the same time, using Karl Fischer method to determine the water content N2 in the filtrate in the blank control experiment, and calculating the water content of raw material iodine; (2) adding solvent B, iodine, and acetic anhydride to a container, stirring the reaction, adding tetramethylguanidine, adding dehydroepiandrosterone-17-hydrazone I, performing iodination reaction, and obtaining abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-alcohol II; the abiraterone acetate intermediate obtained by the method of the present invention has high yield and high purity.

Description

Technical Field

[0001] The invention relates to a method for preparing a high-purity and high-yield abiraterone acetate intermediate, belonging to the technical field of pharmaceutical chemical synthesis and analysis. Background Art

[0002] 17-iodo-androsta-5,16-diene-3β-ol (Formula II) is a key intermediate commonly used in the production process of abiraterone acetate. Its main preparation method is to obtain it by iodination reaction of dehydroepiandrosterone-17-hydrazone (Formula I) in the presence of tetramethylguanidine. The reaction route is shown in the following formula. The presence of water has a great influence on the conversion process. Excessive water content in the system will increase the amount of iodine used, reduce the yield of 17-iodo-androsta-5,16-diene-3β-ol, and reduce the purity.

[0003]

[0004] At present, in the preparation of 17-iodo-androsta-5,16-diene-3β-ol, a key intermediate of abiraterone acetate, the raw iodine used is of industrial grade, which contains a certain amount of water. Since there is no suitable method for detecting the water content of iodine, the water content of the system cannot be determined, and it is difficult to accurately control the water content in the system, resulting in large impurities in 17-iodo-androsta-5,16-diene-3β-ol and unstable production. Although the use of high-purity iodine can reduce the impact of water, iodine accounts for a very high proportion of the cost of abiraterone acetate products. The use of high-purity iodine will significantly increase the cost of the product. Therefore, the raw iodine currently used is still of industrial grade.

[0005] At present, there is no special detection method for iodine moisture detection in the literature. Due to the easy sublimation of iodine, the drying method, distillation method, microwave method, infrared method, etc. are not applicable; Karl-Fischer method is a common and simple moisture detection method, but because its reagent itself contains iodine, and the judgment of the end point depends on iodine, the presence of iodine directly affects the test results, so it is not suitable for iodine moisture determination. Some iodine manufacturers provide iodine moisture detection, and the method is to subtract the iodine content, sulfate and other known substances from the total sample, and the remaining mass is considered to be moisture. Obviously, due to the deviation of the determination of iodine content, sulfate, etc., and the remaining mass is not necessarily all moisture, this method is not accurate.

[0006] Therefore, it is of great significance to develop a simple and feasible method for detecting the moisture content of iodine, so as to control and optimize the production method of abiraterone acetate intermediates. Summary of the invention

[0007] In view of the deficiencies of the prior art, the present invention provides a method for preparing a high-purity and high-yield abiraterone acetate intermediate. The preparation method of the present invention first uses the iodine moisture detection method of the present invention to detect the moisture content in the raw material iodine, and according to the above water content, a specific dehydrating agent acetic anhydride is added during the preparation of the abiraterone acetate intermediate, and the acetic anhydride is used to reduce the moisture in the system, thereby obtaining a high-yield and high-purity abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-ol.

[0008] The technical solution of the present invention is as follows:

[0009] A method for preparing abiraterone acetate intermediate with high purity and high yield comprises the following steps:

[0010] (1) Detecting the water content of the raw iodine: reacting zinc powder with iodine in solvent A, filtering to remove solids, and determining the water content N1 in the filtrate by Karl Fischer method; at the same time, performing a blank control experiment without adding iodine, and determining the water content N2 in the filtrate in the blank control experiment by Karl Fischer method, and calculating the water content of the raw iodine;

[0011] (2) adding solvent B, iodine, and acetic anhydride to a container, stirring for reaction, adding tetramethylguanidine, and then adding dehydroepiandrosterone-17-hydrazone I to carry out iodination reaction to obtain the abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-ol II;

[0012]

[0013] Preferably according to the present invention, the molar ratio of zinc powder to iodine in step (1) is 1-20:1, more preferably 4-8:1.

[0014] Preferably, according to the present invention, the reaction temperature in step (1) is 40-50° C., the reaction time is 10-30 min, and the reaction is carried out under ultrasonic conditions.

[0015] According to the present invention, the reaction formula of zinc powder and iodine in step (1) is as shown in the following formula (1):

[0016] I2 + Zn=ZnI2 (1)

[0017] According to the preferred embodiment of the present invention, the solvent A in step (1) is one or a combination of two or more of dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, and dioxane, and is further preferably methanol; the mass ratio of the solvent A to iodine is 20-40:1; the present invention adopts a larger amount of solvent to ensure the accuracy of detection.

[0018] According to the present invention, the method of measuring the water content using the Karl Fischer method is an existing method.

[0019] Preferably, according to the present invention, in step (1), the water content of the raw material iodine is calculated according to the following formula (2):

[0020] Water content of iodine = (M1*N1-M2*N2) / M 碘 *100% (2)

[0021] In formula (2), M1 is the mass of the filtrate obtained after the reaction of iodine and zinc, g; N1 is the water content in the filtrate obtained after the reaction of iodine and zinc, %; M2 is the mass of the filtrate obtained in the blank control experiment without adding iodine, g; N2 is the water content in the filtrate obtained in the blank control experiment without adding iodine, %.

[0022] According to the present invention, the mass of the filtrate includes the mass of the filtrate I obtained by filtration and the mass of the residual filtrate II in the filter residue; the mass of the residual filtrate II in the filter residue is obtained according to the following method: the filter paper with the filter residue is weighed, and then dried to constant weight and weighed, and the mass of the residual filtrate II in the solid is obtained by the reduction method.

[0023] According to the preferred embodiment of the present invention, the solvent B in step (2) is one or a combination of two or more of dichloromethane, chloroform, tetrahydrofuran, and dioxane, and is further preferably dichloromethane and / or tetrahydrofuran, and the solvent B is an anhydrous solvent; the ratio of the volume of the solvent B to the mass of dehydroepiandrosterone-17-hydrazone I is 5-20 mL: 1 g.

[0024] Preferably according to the present invention, the molar ratio of iodine to dehydroepiandrosterone-17-hydrazone I in step (2) is 1.8-3:1, more preferably 2-2.2:1; the molar number of iodine is calculated based on the mass of iodine input, and the mass of iodine input includes the mass of water.

[0025] According to a preferred embodiment of the present invention, the molar ratio of tetramethylguanidine to dehydroepiandrosterone-17-hydrazone I in step (2) is 1-10:1, and more preferably 2-4:1.

[0026] According to the preferred embodiment of the present invention, the molar ratio of acetic anhydride to water in iodine in step (2) is 0.5-1.5:1, and more preferably 0.8-1.2:1.

[0027] According to the present invention, the reaction formula of acetic anhydride and water in iodine in step (2) is as follows:

[0028] (CH3CO)2O+H2O=2CH3COOH

[0029] Preferably, according to the present invention, the stirring reaction time in step (2) is 20-40 minutes.

[0030] Preferably, according to the present invention, the temperature of the iodination reaction in step (2) is 30-35° C.; and the time of the iodination reaction is 20-40 min.

[0031] Preferably, in step (2), after the reaction is completed, a post-treatment step is further included, which is specifically as follows: sodium bisulfite is added to the obtained reaction solution to quench the reaction, and then water is added to crystallize, filter, and dry to obtain the abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-ol II; the molar ratio of the sodium bisulfite to dehydroepiandrosterone-17-hydrazone I is 0.2-10:1; the added volume of the water and the molar number of the dehydroepiandrosterone-17-hydrazone I are 2-10mL:1mmol; the crystallization temperature is 0-30°C; the crystallization time is 0.5-1.5h; and the drying is vacuum drying at 50-70°C to constant weight.

[0032] The technical features and beneficial effects of the present invention are as follows:

[0033] 1. The present invention first creatively proposes a simple and feasible method for detecting water in iodine. The method of the present invention can accurately detect the water in iodine, thereby optimizing the production process of abiraterone acetate according to the amount of water in iodine, thereby significantly improving the product quality and yield.

[0034] 2. The method of the present invention adds a specific dehydrating agent, acetic anhydride, according to the detected water content in iodine, reduces the water content in the system, avoids the influence of water on the iodination reaction, and can obtain the abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-ol with high yield and high quality at a lower iodine dosage. The obtained product has high purity, few impurities, and a stable production process. The obtained intermediate product no longer needs to be refined and can be directly used in the next reaction. DETAILED DESCRIPTION

[0035] The following will describe the implementation methods of the present invention in detail with reference to the embodiments, so that the implementation process of how the present invention applies technical means to solve technical problems and achieve technical effects can be fully understood and implemented accordingly.

[0036] The iodine used in the examples is industrial grade, manufactured by SQM SA.

[0037] Example 1

[0038] A method for detecting the water content of raw iodine comprises the following steps:

[0039] Add iodine (0.50 g, M 碘 ), methanol (15.00 g, M 甲醇1 ), ultrasonic for 1 min; zinc powder (0.52 g, M 锌粉1), ultrasonically react at 45°C for 20 min, filter the system, and obtain a filtrate (15.41 g, M1). Samples were taken and the water content was determined by Karl Fischer method (0.066%, N1).

[0040] Control: Add methanol (15.00 g, M 甲醇2 ), ultrasonic for 1 min; zinc powder (0.52 g, M 锌粉2 ), ultrasonically treated at 45°C for 20 min, filtered the system, and obtained a filtrate (14.87 g, M2). Samples were taken and the water content was determined by Karl Fischer method (0.024%, N2).

[0041] Iodine water content = (M1*N1-M2*N2) / M 碘 *100%=1.32%.

[0042] Example 2

[0043] A method for detecting the water content of raw iodine comprises the following steps:

[0044] Add iodine (0.50 g, M 碘 ), methanol (15.00 g, M 甲醇1 ), water (0.0500 g), ultrasonic for 1 min; zinc powder (0.52 g, M 锌粉1 ), ultrasonically react at 45°C for 20 min, filter the system, and obtain a filtrate (15.75 g, M1). Samples were taken and the water content was determined by Karl Fischer method (0.384%, N1).

[0045] Control: Add methanol (15.00 g, M 甲醇2 ), ultrasonic for 1 min; zinc powder (0.52 g, M 锌粉2 ), ultrasonically treated at 45°C for 20 min, filtered the system, and obtained a filtrate (14.87 g, M2). Samples were taken and the water content was determined by Karl Fischer method (0.024%, N2).

[0046] Iodine water content = (M1*N1-M2*N2) / M 碘 *100%=11.38%.

[0047] Embodiment 2 is the control experiment of embodiment 1, and the iodine used in two experiments is the same manufacturer and the same batch. According to embodiment 1, the moisture content of iodine recorded is 1.32%; In embodiment 2, 10% moisture of iodine weight is added, and the moisture quality in the raw material iodine is 0.5*1.32%=0.0066g; The quality of the externally added water detected is 15.75*0.384%-14.87*0.024%-0.0066=0.0503g, and the quality of the water actually added is 0.0500g, and the relative deviation of actual value and theoretical value is (0.0503-0.0500) / 0.05=0.62%. It can be seen that the relative deviation is very small, and this detection method has a higher accuracy.

[0048] Example 3

[0049] A method for preparing abiraterone acetate intermediate with high purity and high yield comprises the following steps:

[0050] Anhydrous tetrahydrofuran (100 mL), iodine (17.2 g, 67.8 mmol, water content 1.32%), acetic anhydride (1.29 g, 12.6 mmol) were added to the reaction bottle, stirred for 30 min, tetramethylguanidine (7.62 g, 66.2 mmol) was added, and then dehydroepiandrosterone-17-hydrazone I (10 g, 33.1 mmol) was added to the system in 5 batches within 30 min, and reacted at 30-35 ° C for 30 min; after the reaction was completed, sodium bisulfite (5 g, 48 mmol) and water (100 mL) were added to the obtained reaction solution, stirred and crystallized at 0-10 ° C for 1 h, filtered, and vacuum dried at 60 ° C to constant weight to obtain high-purity and high-yield abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-ol II (12.6 g, yield 98.67%) with a purity of 97.23%.

[0051] Comparative Example 1

[0052] A method for preparing an abiraterone acetate intermediate comprises the following steps:

[0053] Anhydrous tetrahydrofuran (100 mL) and iodine (20 g, 78.8 mmol, 1.32% water) were added to the reaction bottle, stirred for 30 min, tetramethylguanidine (7.62 g, 66.2 mmol) was added, and then dehydroepiandrosterone-17-hydrazone I (10 g, 33.1 mmol) was added to the system in 5 batches within 30 min, and reacted at 30-35 ° C for 30 min; after the reaction was completed, sodium bisulfite (5 g, 48 mmol) and water (100 mL) were added to the obtained reaction solution, stirred and crystallized at 0-10 ° C for 1 h, filtered, and dried under reduced pressure at 60 ° C to obtain abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-ol II (11.2 g, yield 85%), with a purity of 90.48%.

[0054] In this comparative example, no dehydrating agent was added, and the yield and purity of the obtained product were much lower than those of Example 1 of the present invention.

[0055] Comparative Example 2

[0056] A method for preparing an abiraterone acetate intermediate is as described in Example 1, except that an equimolar amount of calcium oxide is used instead of acetic anhydride to obtain an abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-ol II (10.9 g, yield 82.77%) with a purity of 85.36%.

[0057] In this comparative example, calcium oxide is used instead of acetic anhydride. The calcium hydroxide generated by the reaction of calcium oxide and water consumes a portion of iodine (disproportionation reaction to generate calcium iodide and calcium iodate). At the same time, the oxidizing property of calcium iodate increases, resulting in an increase in the number of impurities.

[0058] Comparative Example 3

[0059] A method for preparing an abiraterone acetate intermediate is as described in Example 1, except that an equimolar amount of calcium chloride is used instead of acetic anhydride to obtain an abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-ol II (11.2 g, yield 85%) with a purity of 88.75%.

[0060] In this comparative example, calcium chloride is used instead of acetic anhydride. Water is adsorbed by calcium chloride and becomes crystal water. The water does not really disappear. From the experimental results, the crystal water still affects the reaction. The yield of the obtained product is similar to that without adding a water removal agent, and the quality is basically similar but slightly worse. The reason may be that calcium chloride has a certain impact on the system.

[0061] Comparative Example 4

[0062] A method for preparing an abiraterone acetate intermediate is as described in Example 1, except that an equimolar amount of anhydrous sodium sulfate is used instead of acetic anhydride to obtain an abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-ol II (11.3 g, yield 85.81%) with a purity of 91.31%.

[0063] In this comparative example, sodium sulfate is used instead of acetic anhydride, and water is adsorbed by sodium sulfate to become crystal water, but the water does not really disappear. From the experimental results, the crystal water still affects the reaction. The yield and quality of the obtained product are slightly better than those without adding a water removal agent, but the degree is very limited.

Claims

1. A method for preparing a high-purity and high-yield abiraterone acetate intermediate, comprising the following steps: (1) Detecting the water content of the raw iodine: reacting zinc powder with iodine in solvent A, filtering to remove solids, and determining the water content N1 in the filtrate by Karl Fischer method; at the same time, performing a blank control experiment without adding iodine, and determining the water content N2 in the filtrate in the blank control experiment by Karl Fischer method, and calculating the water content of the raw iodine; the molar ratio of zinc powder to iodine is 1-20:1; (2) Add solvent B, iodine and acetic anhydride to a container, stir for reaction, add tetramethylguanidine, and then add dehydroepiandrosterone-17-hydrazone I to carry out iodination reaction to obtain abiraterone acetate intermediate 17-iodo-androst-5,16-diene-3β-ol II; the solvent B is one or a combination of two or more of dichloromethane, chloroform, tetrahydrofuran and dioxane, and the solvent B is an anhydrous solvent; the molar ratio of iodine to dehydroepiandrosterone-17-hydrazone I is 2-2.2:1; the molar ratio of tetramethylguanidine to dehydroepiandrosterone-17-hydrazone I is 2-4:1; the molar ratio of acetic anhydride to water in iodine is 0.8-1.2:1; the temperature of the iodination reaction is 30-35°C; the time of the iodination reaction is 20-40 minutes; 。 2. The method for preparing abiraterone acetate intermediate with high purity and high yield according to claim 1, characterized in that: The reaction temperature in step (1) is 40-50° C., the reaction time is 10-30 min, and the reaction is carried out under ultrasonic conditions.

3. The method for preparing abiraterone acetate intermediate with high purity and high yield according to claim 1, characterized in that: The solvent A in step (1) is one or a combination of two or more of dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, and dioxane; and the mass ratio of the solvent A to iodine is 20-40:

1.

4. The method for preparing abiraterone acetate intermediate with high purity and high yield according to claim 1, characterized in that: In step (1), the water content of the raw material iodine is calculated according to the following formula (2): Water content of iodine = (M1*N1-M2*N2) / M 碘 *100% (2) In formula (2), M1 is the mass of the filtrate obtained after the reaction of iodine and zinc, g; N1 is the water content in the filtrate obtained after the reaction of iodine and zinc, %; M2 is the mass of the filtrate obtained in the blank control experiment without iodine addition, g; N2 is the water content in the filtrate obtained in the blank control experiment without iodine addition, %.

5. The method for preparing abiraterone acetate intermediate with high purity and high yield according to claim 1, characterized in that: The ratio of the volume of solvent B to the mass of dehydroepiandrosterone-17-hydrazone I in step (2) is 5-20 mL:1 g.

6. The method for preparing abiraterone acetate intermediate with high purity and high yield according to claim 1, characterized in that: The stirring reaction time in step (2) is 20-40 minutes.

7. The method for preparing abiraterone acetate intermediate with high purity and high yield according to claim 1, characterized in that: In step (2), after the reaction is completed, a post-treatment step is further included, which is specifically as follows: sodium bisulfite is added to the obtained reaction solution to quench the reaction, and then water is added to crystallize, filter, and dry to obtain the abiraterone acetate intermediate 17-iodo-androsta-5,16-diene-3β-ol II; the molar ratio of the sodium bisulfite to dehydroepiandrosterone-17-hydrazone I is 0.2-10:1; the added volume of the water and the molar number of the dehydroepiandrosterone-17-hydrazone I are 2-10mL:1mmol; the crystallization temperature is 0-30°C; the crystallization time is 0.5-1.5h; and the drying is vacuum drying at 50-70°C to constant weight.

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