CN115466302A - Synthesis and purification method of abiraterone acetate - Google Patents
Synthesis and purification method of abiraterone acetate Download PDFInfo
- Publication number
- CN115466302A CN115466302A CN202211319342.0A CN202211319342A CN115466302A CN 115466302 A CN115466302 A CN 115466302A CN 202211319342 A CN202211319342 A CN 202211319342A CN 115466302 A CN115466302 A CN 115466302A
- Authority
- CN
- China
- Prior art keywords
- abiraterone
- acid
- abiraterone acetate
- acetate
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of drug synthesis, in particular to a synthesis and purification method of abiraterone acetate. The synthesis and purification method of abiraterone acetate comprises the following steps: (a) Reacting the crude abiraterone product with acid in a good solvent, and cooling to separate out abiraterone salt; (b) Carrying out acetylation reaction on the abiraterone salt and acetic anhydride in an organic base system, and then treating to obtain the abiraterone acetate. According to the method, the crude abiraterone product is salified and purified, and then the abiraterone salt is directly subjected to acetylation reaction under an alkaline condition to synthesize the abiraterone acetate, so that the synthesis and purification process is greatly simplified, the production efficiency is improved, the cost is reduced, the product quality and yield are ensured, and the method is suitable for commercial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a synthesis and purification method of abiraterone acetate.
Background
The chemical name of the abiraterone acetate is 17- (3-pyridyl) androstane-5,16-diene-3 beta-acetate, and the structural formula is as follows:
abiraterone acetate was initially synthesized by British Technology Group Ltd. By reacting dehydroepiandrosterone acetate with trifluoromethanesulfonic anhydride to form steroid enol triflate, followed by Suzuki coupling with diethyl (3-pyridyl) borane under the catalysis of triphenylphosphine palladium dichloride to produce abiraterone acetate. The prior art also reports a preparation method of abiraterone acetate, although the methods are different, the used materials are different, but the impurities generated by the reaction are more, and a column chromatography method is adopted for the purification method of the final product, so the operation is complex, and the method is not suitable for industrial production.
In the prior art, a salifying crystallization method is adopted to improve the purification efficiency, specifically, a crude abiraterone acetate product and methanesulfonic acid are salified, the formed salt is precipitated in a solvent, most other impurities are remained in the solvent, the abiraterone acetate mesylate is obtained by filtering, and then alkali is used for dissociating the abiraterone acetate to obtain the abiraterone acetate.
The purification process of salifying abiraterone acetate and mesylate and then dissociating is adopted, so that the step of column chromatography purification is avoided, but the defects are also existed: the methanesulfonic acid and the abiraterone acetate form a viscous suspension when salifying, the filtration is difficult, a filter cake obtained by the filtration is viscous, impurities are easy to remain, the methanesulfonic acid salt needs to be further purified by recrystallization, and the abiraterone acetate is obtained by dissociating with alkali, so that the operation time and difficulty are increased, and the industrial large-scale production is not facilitated.
In patent application with publication number CN102030798a, the triflic acid reacts with crude abiraterone acetate to obtain the abiraterone acetate triflate which is easy to filter, and then the abiraterone acetate triflate is dissociated to obtain the abiraterone acetate. Compared with the abiraterone acetate mesylate, the abiraterone acetate triflate obtained by the method has high purity and good color, simplifies the purification process, but because the triflic acid is expensive and is easy to generate acid mist, the reaction can only be controlled below low temperature (5 ℃), the operation is not facilitated, and the triflic acid also has strong corrosivity, serious corrosion to equipment and great difficulty in post-treatment and production operation, the abiraterone acetate triflate is not suitable for industrial large-scale production.
In patent application publication No. CN105503992A, crude abiraterone acetate is directly prepared from pure abiraterone by purifying and refining a mixed solvent system of alcohol and water, and then acetylizing the pure abiraterone product, so that the crude abiraterone acetate with similar white color, relatively high purity and less impurities can be directly prepared, and the crude product is further recrystallized to prepare the abiraterone acetate with high purity and meeting the medicinal requirement, thereby avoiding the purification step of chromatography in the traditional method. The method is simple and convenient, but the solubility of the precursor abiraterone is poor, a large amount of alcohol is needed for dissolving, in addition, the crude abiraterone product components are complex, and a system consisting of alcohol and water is used for refining once and can not effectively remove all organic impurities, so that the finished abiraterone acetate product needs to be recrystallized and purified again, main quality risk factors are transferred to the purification process of the final product abiraterone acetate product, and meanwhile, the abiraterone acetate has very good solubility, so that the product loss is high when the abiraterone acetate is recrystallized, and the yield is low.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a synthesis and purification method of abiraterone acetate, which aims to solve the technical problems of incomplete impurity removal, large solvent consumption and the like in abiraterone acetate purification in the prior art.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the synthesis and purification method of abiraterone acetate comprises the following steps:
(a) Reacting the crude abiraterone product with acid in a good solvent, and cooling to separate out abiraterone salt;
(b) Carrying out acetylation reaction on the abiraterone salt and acetic anhydride in an organic base system, and then treating to obtain the abiraterone acetate.
In a specific embodiment of the present invention, the good solvent includes at least one of an ether solvent, an alcohol solvent, and an ester solvent.
In a particular embodiment of the invention, the acid comprises at least one of an organic acid and/or an inorganic acid.
In a specific embodiment of the invention, the ratio of the crude abiraterone to the good solvent is 1 g/10-35 mL.
In a particular embodiment of the invention, the molar ratio of the acid to the crude abiraterone is (1.05-3): 1.
In a particular embodiment of the invention, in step (a), the temperature of the reaction is between 30 and 70 ℃, preferably between 60 and 70 ℃.
In a specific embodiment of the invention, in the step (a), the abiraterone salt is precipitated by cooling, wherein the temperature is 0-40 ℃.
In a particular embodiment of the invention, the organic base comprises any one or more of triethylamine, diisopropylethylamine and pyridine.
In a particular embodiment of the invention, the organic base system further comprises an aprotic solvent. Further, the aprotic solvent includes any one or more of dichloromethane, tetrahydrofuran, N-dimethylformamide, dioxane, acetone, and acetonitrile.
In a particular embodiment of the invention, the molar ratio of abiraterone salt to the acetic anhydride is 1: 1 (1.5 to 8).
In a particular embodiment of the invention, the abiraterone salt and the organic base are present in a ratio of 1 g: 4 to 15mL.
In a specific embodiment of the invention, the temperature of the acetylation reaction is 30-40 ℃; the time of the acetylation reaction is 1.5 to 8 hours.
In a specific embodiment of the present invention, the processing includes: and adding water into the reaction liquid after the acetylation reaction for crystallization to obtain the abiraterone acetate.
In a specific embodiment of the present invention, the temperature of the crystallization is 0 to 35 ℃; the crystallization time is 1-2 h.
Compared with the prior art, the invention has the beneficial effects that:
(1) According to the method, the crude abiraterone product is salified and purified, and then the abiraterone salt is directly subjected to acetylation reaction under an alkaline condition to synthesize the abiraterone acetate, so that the synthesis and purification process is greatly simplified, the production efficiency is improved, the cost is reduced, the product quality and yield are ensured, and the method is suitable for commercial production;
(2) The purity of the abiraterone acetate obtained by the method is more than 99.0% (only one single impurity with the content of more than 0.1%) and the purity of the obtained abiraterone acetate is more than 99.8% (no single impurity with the content of more than 0.1%).
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
Fig. 1 is an HPLC profile of crude abiraterone provided in example 1 of the present invention.
Fig. 2 is an HPLC profile of abiraterone hydrochloride provided in example 1 of the present invention.
Fig. 3 is an HPLC profile of abiraterone acetate provided in example 1 of the present invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and the detailed description, but those skilled in the art will understand that the following described embodiments are some, not all, of the embodiments of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The synthesis and purification method of abiraterone acetate comprises the following steps:
(a) Reacting the crude abiraterone product with acid in a good solvent, and cooling to separate out abiraterone salt;
(b) Carrying out acetylation reaction on the abiraterone salt and acetic anhydride in an organic base system, and processing to obtain the abiraterone acetate.
In the known synthesis method of abiraterone acetate, most of purification methods related to the abiraterone acetate adopt a column chromatography method, and the column chromatography method is time-consuming, high in cost and low in yield, so that the method becomes a bottleneck for restricting the large-scale production of the abiraterone acetate. Moreover, in the process of practical experimental research, it is found that the alkali dissociation process adopted by the prior art has important defects: in the dissociating process, abiraterone acetate can be hydrolyzed in an alkaline environment to generate abiraterone, even if very mild alkali such as sodium bicarbonate and the like is used, 2% -5% of abiraterone is generated, and the quality of the abiraterone acetate is seriously influenced.
Moreover, researches show that the abiraterone has poor solubility, and after the abiraterone is salified, alkali is used for dissociation to obtain an abiraterone pure product, acetylation is carried out on the abiraterone pure product, a large amount of solvent is used for dissolution, extraction, concentration and the like in the dissociation process, and great waste is caused to materials, manpower, equipment, water and electricity and other costs in production.
According to the invention, the crude abiraterone product is subjected to salt purification in a good solvent, the obtained abiraterone salt is insoluble in the good solvent and is precipitated, the impurities are still dissolved in the good solvent, the impurities are very well removed through filtration, the purity of the obtained abiraterone salt is more than 99.0% (only one single impurity with the content of more than 0.1%), and the yield is more than 80%; as no obvious impurity is generated in the process of generating the abiraterone acetate through acetylation reaction, the salification and purification of the abiraterone become key quality control steps, the quality controllability is high, the quality and the yield of the final product abiraterone acetate are ensured, and the purity of the abiraterone acetate is more than 99.8% (no single impurity more than 0.1%).
The obtained abiraterone salt is directly subjected to acetylation reaction with acetic anhydride in organic alkali, the organic alkali can directly neutralize acid in the abiraterone salt and then perform acetylation reaction, so that the step of dissociating the abiraterone salt by using alkali alone is omitted, and the dissociating reaction and the acetylation reaction are combined into one step. Because abiraterone has poor solubility, and a large amount of solvent is consumed for dissolution, extraction and concentration after salt formation and independent dissociation by using alkali, the process is complex, the dissociation step is omitted, the process is greatly simplified, the efficiency is improved, and the cost is saved.
After the acetylation reaction is finished, water is added into the reaction liquid to separate out the abiraterone acetate, the purification is not needed, the process is simple and easy to operate, the abiraterone acetate obtained by the process conditions of the invention has high purity, high yield and less three wastes, and is suitable for commercial production.
In a specific embodiment of the present invention, the good solvent includes at least one of an ether solvent, an alcohol solvent, and an ester solvent.
In a specific embodiment of the present invention, the ether solvent includes any one or more of diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, and dioxane.
In a specific embodiment of the present invention, the alcohol solvent includes any one or more of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, and tert-butanol.
In a specific embodiment of the present invention, the ester solvent includes ethyl acetate and/or isopropyl acetate.
In a preferred embodiment of the present invention, the good solvent includes tetrahydrofuran. Tetrahydrofuran is adopted as a good solvent, so that the abiraterone dissolving agent has good solubility and has an excellent impurity removing effect.
In a particular embodiment of the invention, the acid comprises at least one of an organic acid and/or an inorganic acid. Further, the organic acid includes any one or more of formic acid, acetic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid; the inorganic acid includes any one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and perchloric acid.
In a particular embodiment of the invention, the acid is hydrochloric acid. The hydrochloric acid and the crude abiraterone are adopted for salt forming reaction, so that the price is low, and the salt forming purification effect is good.
In a particular embodiment of the invention, in step (a), the ratio of crude abiraterone to the good solvent is 1 g: 10-35 mL, such as 1 g: 10-20 mL, preferably 1 g: 15mL.
In various embodiments, the crude abiraterone product and the good solvent can be in a ratio of 1g to 10mL, 1g to 15mL, 1g to 20mL, 1g to 25mL, 1g to 30mL, 1g to 35mL, and so forth. Wherein 1 g/XmL is XmL good solvent for 1g crude abiraterone, and the similar expression is as follows.
In a particular embodiment of the invention, in step (a), the molar ratio of the acid to the crude abiraterone is (1.05-3) to 1, such as (1.2-1.8) to 1, such as 1.5 to 1.
In various embodiments, the molar ratio of the acid to the crude abiraterone can be 1.05: 1, 1.2: 1, 1.5: 1, 1.8: 1, 2.2: 1, 2.5: 1, 2.8: 1, 3: 1, etc.
In a particular embodiment of the invention, in step (a), the temperature of the reaction is between 30 and 70 ℃, preferably between 60 and 70 ℃.
As in the different embodiments, the temperature of the reaction in step (a) may be 50 ℃,55 ℃,60 ℃, 65 ℃,70 ℃ and the like. The invention reacts to form salt at relatively high temperature, so that the salt formation is relatively uniform and the wrapping phenomenon cannot occur; and after the salt forming reaction is finished, the temperature is reduced, the temperature for cooling and crystallizing is relatively high, and the purity of the salt is further ensured. If the salt forming reaction is carried out at low temperature and the impurities are separated out at low temperature, the formed salt is separated out too fast and is easy to wrap impurities, and the impurities are also separated out at low temperature, so that the purity of the salt is insufficient, and if the subsequent reaction is directly carried out without purification and other treatment, the purity of the obtained abiraterone acetate product is insufficient.
In a specific embodiment of the invention, in the step (a), the abiraterone salt is separated out by cooling, and the temperature is 0-40 ℃; the preferred temperature is 20 to 35 ℃.
As in the different embodiments, in the step (a), the abiraterone salt is precipitated by reducing the temperature, which can be 0 ℃,5 ℃,10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃ and the like.
In a specific embodiment of the present invention, step (a) comprises: dissolving the crude abiraterone product in a good solvent, adding acid for reaction, and cooling to separate out abiraterone salt.
In a particular embodiment of the invention, the temperature of the dissolution is between 35 and 80 ℃, preferably between 60 and 70 ℃.
As in various embodiments, the temperature of the dissolution can be 35 deg.C, 40 deg.C, 45 deg.C, 50 deg.C, 55 deg.C, 60 deg.C, 65 deg.C, 70 deg.C, 75 deg.C, 80 deg.C, and the like.
In a particular embodiment of the invention, the organic base comprises any one or more of triethylamine, diisopropylethylamine and pyridine.
In a particular embodiment of the invention, the organic base system further comprises an aprotic solvent. Further, the aprotic solvent includes any one or more of dichloromethane, tetrahydrofuran, N-dimethylformamide, dioxane, acetone, and acetonitrile.
In a preferred embodiment of the invention, the organic base system is pyridine. Pyridine is independently used as a solvent, so that the purity and the yield of the abiraterone acetate obtained by the reaction can be further ensured.
In a particular embodiment of the invention, the molar ratio of abiraterone salt to the acetic anhydride is 1: 1 (1.5-8), preferably 1: 5-6.
In various embodiments, the mole ratios of abiraterone salt to acetic anhydride can be 1: 1.5, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, etc.
In a particular embodiment of the invention, the abiraterone salt and the organic base are present in a ratio of 1g to (4 to 15) mL, such as 1g to (4 to 6) mL, preferably 1g to 5mL. By adopting the proportion, the excess organic alkali can directly neutralize the acid in the abiraterone salt and then carry out acetylation reaction, so that the step of independent alkali dissociation is omitted, and the purity and the yield of the product are ensured.
In various embodiments, the abiraterone salt and the organic base can be in a ratio of 1 g: 4mL, 1 g: 5mL, 1 g: 6mL, 1 g: 8mL, 1 g: 10mL, 1 g: 12mL, 1 g: 15mL, and the like.
In a specific embodiment of the invention, the temperature of the acetylation reaction is 30-40 ℃; the time of the acetylation reaction is 1.5 to 8 hours, preferably 2 to 3 hours.
The time of acetylation reaction can be adjusted and selected according to the actual reaction degree.
In a specific embodiment of the present invention, the processing includes: and adding water into the reaction liquid after the acetylation reaction for crystallization to obtain the abiraterone acetate.
In a particular embodiment of the invention, the temperature of the crystallization is between 0 and 35 ℃, preferably between 15 and 25 ℃; the crystallization time is 0.5 to 5 hours, preferably 1 to 2 hours.
In particular embodiments of the invention the volume ratio of water to organic base is from (1 to 3) to 1, such as (1.1 to 2.5) to 1, or the like.
By adopting the crystallization temperature and the crystallization time, the abiraterone acetate can be fully precipitated, the yield is ensured, and the purity is considered at the same time.
In one embodiment of the present invention, the method for synthesizing and purifying abiraterone acetate comprises the following steps:
(a) Adding the crude abiraterone product into tetrahydrofuran, heating to 60-70 ℃ for dissolving, dropwise adding hydrochloric acid for salifying, cooling to 15-25 ℃, separating abiraterone hydrochloride, filtering and drying to obtain abiraterone hydrochloride;
(b) Adding abiraterone hydrochloride into pyridine, dropwise adding acetic anhydride, reacting for 2-3 h at 30-40 ℃, adding water while stirring, cooling to 15-25 ℃, crystallizing for 1-2 h, filtering, washing with water, and vacuum drying at 55-65 ℃ to obtain white abiraterone acetate crystals, wherein the purity is more than or equal to 99.8%, and the yield is 90-98%.
Example 1
The embodiment provides a method for synthesizing and purifying abiraterone acetate, which comprises the following steps:
(1) Adding ethanol (115L), dehydroepiandrosterone (23 kg) and 80% hydrazine hydrate (12.47 kg) into a 1000L reaction kettle, heating to 60 ℃, and stirring for 2-3 h; after the reaction is finished, slowly adding 115L of water into the reaction kettle, cooling to 30-40 ℃ after the addition is finished, performing time crystallization for 1h, centrifuging to obtain an abiraterone acetate intermediate 1 wet product, and performing vacuum drying for 12h at 50-60 ℃ to obtain a white or off-white abiraterone acetate intermediate 1, wherein the yield is 96%, and the purity is 99.12%;
(2) Adding N, N-dimethylformamide (116L) and tetramethylguanidine (64 kg) into a 1000L reaction kettle, cooling to below 10 ℃, slowly adding iodine (45 kg) and abiraterone acetate intermediate 1 (23.15 kg) in batches, and stirring at 70-80 ℃ for reacting for 3-4 h; after the reaction is finished, adding 116L of ice water into the reaction kettle, keeping the internal temperature at 30-40 ℃ for crystallization for 0.5h after the addition is finished, centrifuging to obtain an abiraterone acetate intermediate 2 wet product, and performing vacuum drying at 50-60 ℃ for 12h to obtain an almost white or light yellow abiraterone acetate intermediate 2, wherein the yield is 95%, and the purity is 96.26%;
(3) Adding a potassium hydroxide aqueous solution (12.24 kg of potassium hydroxide, 29L of water), tetrahydrofuran (290L), diethyl- (3-pyridyl) borane (11.76 kg), abiraterone acetate intermediate 2 (28.96 kg) and bis (triphenylphosphine) palladium dichloride (510.50 g) into a 1000L reaction kettle, and heating to 50-60 ℃ for reacting for 4-6 h; after the reaction is finished, cooling to below 40 ℃, slowly adding 290L of water into the reaction kettle, after the addition is finished, keeping the internal temperature at 30-40 ℃ for crystallization for 1h, centrifuging to obtain a wet crude product of the abiraterone, and performing vacuum drying at 50-60 ℃ for 12h to obtain a gray black abiraterone crude product, wherein the yield is 98%, and the purity is 86.22%; its HPLC chromatogram is shown in FIG. 1;
(4) Adding an abiraterone crude product (24.9 kg) and tetrahydrofuran (498L) into a 1000L reaction kettle, heating to 65 ℃, and stirring for 1h; after the crude abiraterone product is dissolved out, dropwise adding concentrated hydrochloric acid (36%, 10.7L), and when a large amount of solid is separated out, cooling; cooling to 30-35 ℃, centrifuging to obtain an abiraterone hydrochloride wet product, and vacuum drying at 50-60 ℃ for 12h to obtain white or off-white abiraterone hydrochloride, wherein the yield is 80.5%, and the purity is 99.90%; its HPLC chromatogram is shown in FIG. 2;
(5) Adding abiraterone hydrochloride (22.14 kg) and pyridine (111L) into a 1000L reaction kettle, and stirring for 0.5h; then slowly adding acetic anhydride (35.14 kg), heating to 25-35 ℃ and reacting for 2-3 h; after the reaction is finished, slowly adding 221L of water into the reaction kettle, keeping the internal temperature less than 35 ℃, stirring at room temperature for crystallization for 1h after the addition is finished, centrifuging to obtain an abiraterone acetate wet product, and drying in vacuum at 55-60 ℃ to obtain 21.18kg of white-like abiraterone acetate, wherein the yield is 94.3%, and the purity is 99.96%; the HPLC chromatogram is shown in FIG. 3.
Wherein, the synthetic route is as follows:
example 2
The embodiment provides a method for synthesizing and purifying abiraterone acetate, which comprises the following steps:
(1) Adding ethanol (275 mL), dehydroepiandrosterone (55 g) and 80% hydrazine hydrate (29.83 g) into a 1L three-neck flask, heating to 60 ℃, and stirring for 2-3 h; after the reaction is finished, slowly adding 275mL of water into a three-neck flask, cooling to 30-40 ℃ after the addition is finished, performing timed crystallization for 1h, performing suction filtration to obtain an abiraterone acetate intermediate 1 wet product, and performing vacuum drying for 12h at 50-60 ℃ to obtain a white or white-like abiraterone acetate intermediate 1, wherein the yield is 95%, and the purity is 99.33%;
(2) Adding N, N-dimethylformamide (550 mL) and tetramethylguanidine (110 mL) into a 2L three-neck flask, cooling to below 10 ℃, slowly adding iodine (100 g) and an abiraterone acetate intermediate 1 (55 g) in batches, and stirring at 60-65 ℃ for reacting for 3-4 h; adding 440mL of ice water into the reaction kettle after the reaction is finished, keeping the internal temperature at 30-40 ℃ for crystallization for 0.5h after the addition is finished, performing suction filtration to obtain an abiraterone acetate intermediate 2 wet product, and performing vacuum drying for 12h at 50-60 ℃ to obtain an almost white or light yellow abiraterone acetate intermediate 2, wherein the yield is 92.5%, and the purity is 95.58%;
(3) Adding a sodium hydroxide aqueous solution (28.31 g of sodium hydroxide, 67L of water), tetrahydrofuran (670 mL), diethyl- (3-pyridyl) borane (24.73 g), abiraterone acetate intermediate 2 (67 g) and bis (triphenylphosphine) palladium dichloride (1.2 g) into a 2L three-neck flask, heating to 70-80 ℃ and reacting for 4-6 h; after the reaction is finished, cooling to below 40 ℃, slowly adding 469mL of water into a 2L three-neck flask, keeping the internal temperature at 30-40 ℃ after the addition is finished, crystallizing for 1h, performing suction filtration to obtain a crude product of the abiraterone, and performing vacuum drying at 50-60 ℃ for 12h to obtain 57g of a gray black abiraterone crude product, wherein the yield is 97%, and the purity is 87.44%;
(4) Adding crude abiraterone (22.00 g) and ethanol (330 mL) into a 1L reaction bottle, heating to reflux and stirring for 1h; after the crude abiraterone product is dissolved and cleared, concentrated sulfuric acid (98 percent, 4.7 mL) is dripped, and when a large amount of solid is separated out after the concentrated sulfuric acid is added, the temperature is reduced; cooling to 15 ℃, centrifuging to obtain an abiraterone sulfate wet product, and vacuum drying at 50-60 ℃ for 2-3 h to obtain white or off-white abiraterone sulfate, wherein the yield is 82.6%, and the purity is 99.06%;
(5) Abiraterone sulfate (23.00 g) and pyridine (150 mL) were added to a 500mL reaction flask and stirred for 0.5h; then slowly adding acetic anhydride (31.36 g), heating to 25-35 ℃ and reacting for 2-3 h; after the reaction is finished, slowly adding 250mL of ice water into the reaction bottle, keeping the internal temperature to be less than 35 ℃, stirring and crystallizing for 1h at 10-15 ℃, filtering, and drying the filter cake in vacuum at 55-60 ℃ to obtain 18.15g of white-like abiraterone acetate, wherein the yield is 90.2%, and the purity is 99.83%.
Wherein, the synthetic route is as follows:
example 3
The embodiment provides a method for synthesizing and purifying abiraterone acetate, which comprises the following steps:
(1) Crude abiraterone (same batch as used in example 2) (22.00 g) and tetrahydrofuran (500 mL) were added to a 1L reaction flask, and the mixture was heated to reflux and stirred for 1h; after the crude abiraterone product is dissolved out, dropwise adding concentrated hydrochloric acid (36%, 9.4 mL), and when a large amount of solid is separated out, cooling; cooling to 25 ℃, filtering to obtain an abiraterone hydrochloride wet product, and vacuum-drying at 50-60 ℃ for 2-3 h to obtain the abiraterone hydrochloride, wherein the yield is 81.6%, and the purity is 99.69%;
(2) Abiraterone hydrochloride (18.00 g), triethylamine (180 mL) and dichloromethane (180 mL) were added to a 1L reaction flask and stirred for 0.5h; then slowly adding acetic anhydride (28.54 g), heating to 25-35 ℃ and reacting for 2-3 h; after the reaction is finished, slowly adding 200mL of ice water into the reaction kettle, keeping the internal temperature less than 35 ℃, and stirring for 1h at room temperature after the addition is finished; standing for layering, separating liquid, and concentrating the organic phase under reduced pressure to obtain white-like abiraterone acetate 16.74g, with yield of 91.7% and purity of 99.88%.
Wherein, the synthetic route is as follows:
example 4
This example refers to example 3 with the difference that: in the step (1), adding an abiraterone crude product (12.00 g) and tetrahydrofuran (360 mL) into a 1L reaction bottle at room temperature, stirring for 1h, transferring the reaction bottle into an ice bath to cool to 0-5 ℃ after the abiraterone crude product is melted down, then dropwise adding concentrated hydrochloric acid (36%, 5.2 mL), controlling the internal temperature to be not more than 10 ℃, after the addition is finished, precipitating a large amount of viscous solid, continuing stirring for 30min in the ice bath, filtering, leaching a filter cake with 30mL of precooled THF to obtain an abiraterone hydrochloride wet product, and performing vacuum drying for 2-3 h at 50-60 ℃ to obtain the abiraterone hydrochloride, wherein the yield is 80.5%, and the purity is 92.63%;
with reference to the step (2) of example 3, abiraterone acetate was prepared with a yield of 82.6% and a purity of 96.21%.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. The synthesis and purification method of abiraterone acetate is characterized by comprising the following steps:
(a) Reacting the crude abiraterone product with acid in a good solvent, and cooling to separate out abiraterone salt;
(b) Carrying out acetylation reaction on the abiraterone salt and acetic anhydride in an organic base system, and treating to obtain the abiraterone acetate.
2. The method for synthesizing and purifying abiraterone acetate of claim 1, wherein the good solvent comprises at least one of an ether solvent, an alcohol solvent and an ester solvent;
preferably, the ether solvent includes any one or more of diethyl ether, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, tetrahydrofuran and dioxane;
preferably, the alcohol solvent includes any one or more of methanol, ethanol, isopropanol, n-butanol, isobutanol, and t-butanol;
preferably, the ester solvent comprises ethyl acetate and/or isopropyl acetate.
3. The method for synthesizing and purifying abiraterone acetate of claim 1, wherein the acid comprises at least one of an organic acid and/or an inorganic acid;
preferably, the organic acid comprises any one or more of formic acid, acetic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid;
preferably, the inorganic acid comprises any one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and perchloric acid.
4. The synthesis and purification process of abiraterone acetate as claimed in claim 1, wherein in step (a), the ratio of crude abiraterone acetate to the good solvent is 1 g/mL (10-35), preferably 1 g/mL (10-20);
and/or in step (a), the molar ratio of the acid to the crude abiraterone product is (1.05-3) to 1, preferably (1.2-1.8) to 1.
5. The method for synthesizing and purifying abiraterone acetate of claim 1, wherein in the step (a), the reaction temperature is 30-70 ℃;
preferably, in the step (a), the temperature is reduced to separate out the abiraterone salt, and the temperature is 0-40 ℃.
6. The synthesis and purification method of abiraterone acetate of claim 1, wherein the organic base comprises any one or more of triethylamine, diisopropylethylamine and pyridine;
optionally, the organic base system further comprises an aprotic solvent;
preferably, the aprotic solvent comprises any one or more of dichloromethane, tetrahydrofuran, N-dimethylformamide, dioxane, acetone and acetonitrile.
7. The synthesis and purification process of abiraterone acetate as claimed in claim 1, wherein the molar ratio of the abiraterone salt to the acetic anhydride is 1: 1.5 to 8, preferably 1: 5 to 6;
and/or the abiraterone salt and the organic base are present in a ratio of 1 g/mL (4-15) mL, preferably 1 g/mL (4-6) mL.
8. The method for synthesizing and purifying abiraterone acetate of any of claims 1-7, wherein the good solvent comprises tetrahydrofuran;
and/or, the acid comprises hydrochloric acid;
and/or, the organic base comprises pyridine.
9. The method for synthesizing and purifying abiraterone acetate of claim 1, wherein the temperature of the acetylation reaction is 30-40 ℃; the time of the acetylation reaction is 1.5 to 8 hours.
10. The method for synthesizing and purifying abiraterone acetate of claim 1, wherein the treatment comprises: adding water into the reaction liquid after the acetylation reaction for crystallization to obtain the abiraterone acetate;
preferably, the crystallization temperature is 0-35 ℃, and preferably 15-25 ℃; the crystallization time is 0.5 to 5 hours, preferably 1 to 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211319342.0A CN115466302A (en) | 2022-10-26 | 2022-10-26 | Synthesis and purification method of abiraterone acetate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211319342.0A CN115466302A (en) | 2022-10-26 | 2022-10-26 | Synthesis and purification method of abiraterone acetate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115466302A true CN115466302A (en) | 2022-12-13 |
Family
ID=84336651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211319342.0A Pending CN115466302A (en) | 2022-10-26 | 2022-10-26 | Synthesis and purification method of abiraterone acetate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115466302A (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898495A (en) * | 2012-11-12 | 2013-01-30 | 浙江神洲药业有限公司 | Method for preparing abiraterone acetate |
| CN103570791A (en) * | 2012-07-30 | 2014-02-12 | 成都伊诺达博医药科技有限公司 | Novel synthesis method of Abiraterone acetate |
| CN103665085A (en) * | 2012-09-24 | 2014-03-26 | 成都伊诺达博医药科技有限公司 | Improved abiraterone acetate synthesis method |
| CN104066744A (en) * | 2011-10-10 | 2014-09-24 | 扎克系统公司 | Process for preparing 17-substituted steroids |
| US20160347786A1 (en) * | 2014-01-28 | 2016-12-01 | Olon S.P.A. | Procedure for the preparation of abiraterone acetate and intermediates thereof |
| CN111349138A (en) * | 2018-12-24 | 2020-06-30 | 江苏恒瑞医药股份有限公司 | Method for preparing abiraterone acetate |
-
2022
- 2022-10-26 CN CN202211319342.0A patent/CN115466302A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104066744A (en) * | 2011-10-10 | 2014-09-24 | 扎克系统公司 | Process for preparing 17-substituted steroids |
| CN103570791A (en) * | 2012-07-30 | 2014-02-12 | 成都伊诺达博医药科技有限公司 | Novel synthesis method of Abiraterone acetate |
| CN103665085A (en) * | 2012-09-24 | 2014-03-26 | 成都伊诺达博医药科技有限公司 | Improved abiraterone acetate synthesis method |
| CN102898495A (en) * | 2012-11-12 | 2013-01-30 | 浙江神洲药业有限公司 | Method for preparing abiraterone acetate |
| US20160347786A1 (en) * | 2014-01-28 | 2016-12-01 | Olon S.P.A. | Procedure for the preparation of abiraterone acetate and intermediates thereof |
| CN111349138A (en) * | 2018-12-24 | 2020-06-30 | 江苏恒瑞医药股份有限公司 | Method for preparing abiraterone acetate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111423452B (en) | Intermediate of Rayleigh Lu Geli and preparation method and application thereof | |
| EP3778568B1 (en) | Method of preparing high chiral purity lactam intermediate and brivaracetam | |
| CN106866553A (en) | A kind of synthetic method of Favipiravir | |
| CN111470983B (en) | Preparation method of bromhexine hydrochloride | |
| CN113956312A (en) | Preparation method of mopilavir | |
| CN105884628B (en) | The preparation method of 2,4- di-t-butyl -5- amino phenols | |
| WO2011079672A1 (en) | Preparation method for 3-β-arachidylamido-7α,12α,5β-cholan-24-carboxylic acid | |
| CN107602651A (en) | A kind of preparation method of dehydroepiandros-sterone intermediate and dehydroepiandros-sterone | |
| CN111646998B (en) | Synthesis method of ibrutinib | |
| CN113880846B (en) | Preparation method of 7-iodopyrrolo [2,1-F ] [1,2,4] triazin-4-amine | |
| CN107698538B (en) | Preparation method of intermediate 3- (1-piperidinylmethyl) phenol of roxatidine acetate hydrochloride | |
| WO2021098847A1 (en) | Clindamycin phosphate purification method | |
| CN115466302A (en) | Synthesis and purification method of abiraterone acetate | |
| WO2023142797A1 (en) | Preparation process for sulfonic acid-containing compound | |
| CN114195844B (en) | Preparation method of dehydroepiandrosterone | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN111518156B (en) | One-step preparation method of astragaloside | |
| CN114105800A (en) | Preparation method of 2, 3-diaminobenzoic acid methyl ester | |
| CN111848486B (en) | Method for preparing ethanesulfonic acid nintedanib | |
| CN110240551B (en) | Preparation method of Fmoc-beta-Ala-Gly-OH | |
| CN110759962B (en) | Preparation method of high-purity fluocinolone acetonide | |
| CN102333775A (en) | Preparation method for nortropine benzilate and its salts and intermediates used in said method | |
| CN113979886A (en) | Protected amino acid with amide side chain and preparation method thereof | |
| CN116589519A (en) | Abiraterone acetate and synthesis method of intermediate product thereof | |
| CN107709313A (en) | A kind of method for preparing trityl candesartan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |