CN102627681B - A kind of preparation method of Abiraterone acetate - Google Patents
A kind of preparation method of Abiraterone acetate Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method of Abiraterone acetate, the method take dehydroepiandrosterone as raw material, priority and hydrazine hydrate, Iod R, obtain 17-iodo-androstane-5,16-diene-3 β-ol, then under the catalysis of four triphen phosphino-palladiums, with 3-pyridine zinc halide, Negishi linked reaction occurs and obtain Abiraterone, finally with Acetyl Chloride 98Min. or diacetyl oxide esterification, obtain target product Abiraterone acetate.
Description
Technical field
The present invention relates to a kind of preparation method of Abiraterone acetate.
Background technology
The chemical name of Abiraterone acetate is 17-(3-pyridyl) androstane-5,16-diene-3 β-acetic ester, and its chemical structural formula is as follows:
Abiraterone acetate is a kind of oral androgenic inhibitor, suppresses androgenic synthesis by suppressing CYP450c17 enzyme.Abiraterone acetate can also by reducing tumor promotion mark---the level of " prostate specific antigen (PSA) ", and for those have adopted pharmacological agent or underwent operative excision and patients with prostate cancer that tumour still increases provides new effective therapy approach.
Abiraterone acetate is synthesized by BritishTechnologyGroupLtd. at first, the said firm makes public for the first time structure and the preparation method of this compound at WO93/20097 subsequently, dehydroepiandrosterone acetic ester and trifluoromethanesulfonic acid anhydride reactant are formed steroid enol trifluoromethyl sulfonic acid by preparation method wherein, then under the catalysis of triphenylphosphine palladium, with diethyl (3-pyridyl) borine, Suzuki linked reaction occurs and obtain Abiraterone acetate, reaction formula is as follows:
Experiment shows that trifluoromethanesulfanhydride anhydride and dehydroepiandrosterone react and can not carry out completely, and the steroid enol trifluoromethyl sulfonic acid crude product color of generation is very dark, and product needed pillar layer separation, yield is lower, is not suitable for scale operation.Under the catalysis of triphen phosphino-palladium chloride, take sodium carbonate as nucleophilic activator, there is Suzuki linked reaction and obtain Abiraterone acetate in steroid enol trifluoromethyl sulfonic acid and diethyl (3-pyridyl) borine, reaction need be carried out in the basic conditions, product needs pillar layer separation equally, is not suitable for scale operation.Organic bases 2, the 6-bis--tertiary butyl-4-picoline (DTBMP) used in preparation process, Trifluoromethanesulfonic anhydride and diethyl (3-pyridyl) borine are all very expensive.
CN101044155A discloses the side reaction that the easy generation of DTBMP participation reaction is not expected, and causes the ethanoyl in dehydroepiandrosterone to be eliminated, and generate the by product being difficult to remove, structure is as figure below:
WO95/09178 adopts dehydroepiandrosterone and hydrazine hydrate to react and forms dehydroepiandrosterone-17-hydrazone, then under the catalysis of tetramethyl guanidine, the iodo-androstane-5 of 17-is generated with iodine effect, 16-diene-3 β-ol, and then under the catalysis of triphen phosphino-palladium chloride, with diethyl (3-pyridyl) borine, Suzuki linked reaction occurs obtain Abiraterone, finally obtain target product by ethyl esterified for Abiraterone:
But, form dehydroepiandrosterone-17-hydrazone reaction in this technique and need additional catalyst hydrazonium sulfate, the iodo-androstane-5 of 17-, 16-diene-3 β-ol and diethyl (3-pyridyl) borine occur Suzuki linked reaction need under basic catalyst sodium carbonate exists back flow reaction, reaction event is longer, big energy-consuming, higher to the requirement of reaction vessel, white elephant is brought to three-protection design, raw material diethyl (3-pyridyl) borine is very expensive simultaneously, the ethyl esterified Abiraterone acetate obtained needs pillar layer separation, is not suitable for scale operation.
Summary of the invention
The object of the invention is the synthetic method providing a kind of Abiraterone acetate, on the basis of existing technique, abandon expensive raw material Trifluoromethanesulfonic anhydride and diethyl (3-pyridyl) borine, select 3-bromopyridine cheap and easy to get and metal reagent (as butyllithium) to react in the ether of-80 ~-60 DEG C, be then obtained by reacting 3-pyridine zinc halide with zinc halide:
Wherein X is Cl, Br or I.
At ambient temperature, adopt a small amount of sulfuric acid as catalyzer, dehydroepiandrosterone and hydrazine hydrate react generation dehydroepiandrosterone-17-hydrazone in ethanol; This hydrazone is under the existence of organic alkali, and can be obtained corresponding 17-iodo-androstane-5,16-diene-3 β-ol by iodate, temperature of reaction is-5 ~ 10 DEG C, the tetramethyl guanidine that organic alkali used is first-selected cheap and easy to get.
Under the catalysis of four triphen phosphino-palladiums, obtain Abiraterone by 17-iodo-androstane-5,16-diene-3 β-ol and 3-pyridine zinc halide Negishi linked reaction, then the esterification Abiraterone in ether equal solvent with Acetyl Chloride 98Min. or diacetyl oxide, obtain Abiraterone acetate:
Wherein four triphen phosphino-palladiums are by triphenylphosphine and PdCl
2reaction, hydrazine hydrate reduction obtains; Negishi linked reaction is at N, carry out in dinethylformamide, reacting middle catalyst four triphen phosphino-palladium and the iodo-androstane-5 of 17-, the ratio of 16-diene-3 β-ol is 0.5: 100 ~ 1.5: 100, the speed that the change of catalyst levels will affect Negishi linked reaction and carries out, zeroth order palladium is unstable, considers reaction times, yield and cost factor, the ratio of first-selected four triphen phosphino-palladiums and 17-iodo-androstane-5,16-diene-3 β-ol is 1.0: 100; The iodo-androstane-5 of 17-, the amount ratio of 16-diene-3 β-ol and 3-pyridine zinc halide is 1: 1 ~ 1: 1.2, first-selected ratio is 1: 1.1, the situation that wherein 3-pyridine zinc halide is greatly excessive we have also been made research, find that greatly excessive 3-pyridine zinc halide can not increase substantially reaction yield very much, and introduce a large amount of metallic compounds and bring huge trouble to post-reaction treatment; The esterification of Abiraterone can be carried out in one or more mixtures in ether, methylene dichloride, trichloromethane, ethyl acetate and acetonitrile, and find in experiment, in ether, the yield of esterification is the highest, so preferred ether is as solvent.
In the Negishi linked reaction that 17-iodo-androstane-5,16-diene-3 β-ol participates in, select the 3-pyridine zinc halide that three kinds are different respectively, at identical conditions, Negishi linked reaction completes time of needs and product yield as following table:
| 3-pyridine chlorination zinc | 3-pyridine zinc bromide | 3-pyridine zinc iodide |
| Reaction times | 7 | 5 | 4 |
| Reaction yield | 35.7％ | 74.5％ | 52.5％ |
The result of contrast reaction can find, the reaction times that the Negishi linked reaction that 3-pyridine chlorination zinc participates in needs is the longest, reaction yield is minimum, may be lower relevant with the reactive behavior of 3-pyridine chlorination zinc, and the reaction times that the Negishi linked reaction that 3-pyridine zinc iodide participates in needs is the shortest, reaction yield is higher, may be the highest because of the activity of 3-pyridine zinc iodide, but the reason of less stable.For better adapting to the requirement of suitability for industrialized production, consider the stability of reaction intermediate, the price of production material and reaction yield, first-selected 3-pyridine zinc bromide simultaneously.
Technique effect of the present invention is, adopts a small amount of dilute sulphuric acid to replace hydrazonium sulfate catalysis in dehydroepiandrosterone and hydrazine hydrate reaction, simple; With the iodo-androstane-5 of 17-, 16-diene-3 β-ol and 3-pyridine zinc halide adopt Negishi linked reaction to obtain Abiraterone, 3-bromopyridine cheap and easy to get has been selected in reaction, avoid the use of expensive diethyl (3-pyridyl) borine, the Negishi linked reaction time shortens greatly simultaneously, reaction, without the need to alkali activator sodium carbonate, requires lower to reaction vessel, and the three wastes are easy to process; The Abiraterone generated is separated out in ethyl acetate, then obtains Abiraterone sterling by re-crystallizing in ethyl acetate, avoids column chromatography separating purification, enormously simplify treating process; Abiraterone is ethyl esterified through Acetyl Chloride 98Min., then uses n-hexane dissolution, decolorizing with activated carbon, and filter, crystallization, recrystallizing methanol obtains Abiraterone acetate, and purity can reach more than 99%, avoids column chromatography separating purification, is more suitable for suitability for industrialized production.
Embodiment
Now further describe beneficial effect of the present invention by following examples, be interpreted as these embodiments only for the object of illustration, do not limit the scope of the invention, the simultaneously apparent change made according to the present invention of those of ordinary skill in the art and modification are also contained within the scope of the invention.
The preparation of embodiment 1 dehydroepiandrosterone-17-hydrazone
Get 1L there-necked flask, install mechanical stirring additional, add dehydroepiandrosterone 28.8g (0.1mol) and 500mL ethanol, room temperature fully stirs, then 20mL80% hydrazine hydrate is measured and 2mL0.25mol/L dilute sulphuric acid adds, stirring at room temperature reacts 40 hours, TLC analyzes, and reacts completely, adds 450mL water and fully stir 30 minutes, then reaction mixture impouring is filled in the beaker of 1L water, static crystallization 2 hours, filters, solid 2 × 50mL water washing, vacuum-drying obtains white crystal 29.8g (yield: 98.7%, mp:204-205 DEG C).
The preparation of embodiment 217-iodo-androstane-5,16-diene-3 β-ol
Get 5L there-necked flask, install mechanical stirring additional, add iodine 110g (0.43mol) respectively, tetrahydrofuran (THF) 2L and ether 1.5L, nitrogen bubble, abundant stirring, cool to 0 DEG C, then tetramethyl guanidine 133mL (1.06mol) is added, dehydroepiandrosterone-17-hydrazone 63.4g (0.21mol) is dissolved in 1.6L tetrahydrofuran (THF), then be slowly added drop-wise in reaction mixture, maintain 0 DEG C of reaction 3 hours, TLC analyzes, react completely, suction filtration reaction mixture, filtrate is concentrated into dry brown oil, oily matter is heated up 100 DEG C, stirring reaction 2.5 hours under nitrogen atmosphere, naturally cool to room temperature, add ethyl acetate 500mL stirring and refluxing 30 minutes, cooling, suction filtration, filtrate regulates pH to 4 with dilute hydrochloric acid, solution is by brown yellowing, solution uses 300mL water and the water washing of 300mL saturated common salt respectively, anhydrous magnesium sulfate drying, filter, filtrate concentrates crystallization, obtain faint yellow solid, with ethyl alcohol recrystallization, vacuum-drying, obtain white crystal 76.0g (yield: 91.0%, fusing point 174-176 DEG C)
Prepared by embodiment 317-(3-pyridyl) androstane-5,16-diene-3 β-ol
(1) 1L there-necked flask is got, install mechanical stirring additional, add 3-bromopyridine 13.7mL (0.142mol) and ether 290mL respectively, logical nitrogen, be cooled to-78 DEG C, hexane solution (2M) 74.5mL of slow instillation n-Butyl Lithium, dropwise and continue stirring 30 minutes, add the diethyl ether solution 522mL of zinc bromide 33.5g (0.149mol), insulated and stirred reacts 1 hour, slowly rise to room temperature, concentrating under reduced pressure, logical nitrogen, add 600mLN, dinethylformamide, abundant stirring and dissolving, then the iodo-androstane-5 of 17-is added respectively, 16-diene-3 β-ol 39.8g (0.1mol) and four triphen phosphino-palladiums 116g (1mmol), stirring at room temperature 5 hours, regulate reaction mixture pH to 1 with the hydrochloric acid of 1mol/L, then reaction mixture is poured into containing in 500mL ethyl acetate and 500mL water beaker, stir 1h, separatory, aqueous phase saturated sodium bicarbonate solution regulates pH to 8, then the 500mL extraction into ethyl acetate of heat is used, separatory, organic layer uses 200mL water and the water washing of 200mL saturated common salt respectively, then with anhydrous magnesium sulfate and activated carbon drying decolouring, filter, filtrate concentrates, crystallization, suction filtration, solid with ethyl acetate recrystallization, vacuum-drying obtains white solid 26.1g (yield 74.5%, fusing point 228-229 DEG C).
(2) 1L there-necked flask is got, install mechanical stirring additional, add 3-bromopyridine 13.7mL (0.142mol) and ether 290mL respectively, logical nitrogen, be cooled to-78 DEG C, hexane solution (2M) 74.5mL of slow instillation n-Butyl Lithium, dropwise and continue stirring 30 minutes, add the diethyl ether solution 522mL of zinc chloride 20.3g (0.149mol), insulated and stirred reacts 1 hour, slowly rise to room temperature, concentrating under reduced pressure, logical nitrogen, add 600mLN, dinethylformamide, abundant stirring and dissolving, then the iodo-androstane-5 of 17-is added respectively, 16-diene-3 β-ol 39.8g (0.1mol) and four triphen phosphino-palladiums 116g (1mmol), stirring at room temperature 7 hours, regulate reaction mixture pH to 1 with the hydrochloric acid of 1mol/L, then reaction mixture is poured into containing in 500mL ethyl acetate and 500mL water beaker, stir 1h, separatory, aqueous phase saturated sodium bicarbonate solution regulates pH to 8, then the 500mL extraction into ethyl acetate of heat is used, separatory, organic layer uses 200mL water and the water washing of 200mL saturated common salt respectively, then with anhydrous magnesium sulfate and activated carbon drying decolouring, filter, filtrate concentrates, crystallization, suction filtration, solid with ethyl acetate recrystallization, vacuum-drying obtains white solid 12.5g (yield 35.7%, fusing point 228-229 DEG C).
(3) 1L there-necked flask is got, install mechanical stirring additional, add 3-bromopyridine 13.7mL (0.142mol) and ether 290mL respectively, logical nitrogen, be cooled to-78 DEG C, hexane solution (2M) 74.5mL of slow instillation n-Butyl Lithium, dropwise and continue stirring 30 minutes, add the diethyl ether solution 522mL of zinc iodide 47.5g (0.149mol), insulated and stirred reacts 1 hour, slowly rise to room temperature, concentrating under reduced pressure, logical nitrogen, add 600mLN, dinethylformamide, abundant stirring and dissolving, then the iodo-androstane-5 of 17-is added respectively, 16-diene-3 β-ol 39.8g (0.1mol) and four triphen phosphino-palladiums 116g (1mmol), stirring at room temperature 4 hours, regulate reaction mixture pH to 1 with the hydrochloric acid of 1mol/L, then reaction mixture is poured into containing in 500mL ethyl acetate and 500mL water beaker, stir 1h, separatory, aqueous phase saturated sodium bicarbonate solution regulates pH to 8, then the 500mL extraction into ethyl acetate of heat is used, separatory, organic layer uses 200mL water and the water washing of 200mL saturated common salt respectively, then with anhydrous magnesium sulfate and activated carbon drying decolouring, filter, filtrate concentrates, crystallization, suction filtration, solid with ethyl acetate recrystallization, vacuum-drying obtains white solid 18.4g (yield 52.5%, fusing point 228-229 DEG C).
The preparation of embodiment 4 Abiraterone acetate
Get 3L there-necked flask, install mechanical stirring additional, add 17-(3-pyridyl) androstane-5 respectively, 16-diene-3 β-ol 35g (0.1mol), ether 1.5L and diisopropylethylamine 27.9mL (0.16mol), abundant stirring, slow instillation Acetyl Chloride 98Min. 10mL (0.14mol), stirring at room temperature 4 hours, filter, filtrate reduced in volume is to dry, remaining solid n-hexane dissolution, decolorizing with activated carbon, filter, filtrate concentrates crystallization, suction filtration obtains white crystal, through recrystallizing methanol, vacuum-drying obtains white crystal 33.3g (yield 85.1%, fusing point 144-146 DEG C), δ 1.05 (3H, s ,-CH
3), 1.06-1.11 (1H, m), 1.08 (3H, s ,-CH
3), 1.14-1.19 (1H, m), 1.47-1.52 (1H, m), 1.57-1.65 (3H, m), 1.66-1.71 (2H, m), 1.74-1.80 (1H, m), 1.85-1.88 (2H, m), 2.04 (3H, s, CH
3cO
2), 2.05-2.09 (3H, m), 2.25-2.29 (1H, m), 2.31-2.38 (2H, m), 4.60-4.64 (1H, m, 3 α-H), 5.42 (1H, m, 6-H), 5.99 (1H, m, 16-H), 7.21-7.23 (1H, m, Py5-H), 7.64-7.65 (1H, m, Py4-H), 8.46-8.47 (1H, m, Py6-H), 8.62 (1H, m, Py2-H).
The preparation of embodiment 5 four triphen phosphino-palladium
Get 250mL there-necked flask, install mechanical stirring additional, add Palladous chloride 1.77g (0.01mol) respectively, triphenylphosphine 13.1g (0.05mol) and dimethyl sulfoxide (DMSO) 120mL, logical nitrogen fully stirs, and oil bath heats up 140 DEG C, treats that solid all dissolves, remove oil bath, add hydrazine hydrate 2mL fast, then water-bath cooling, has yellow solid to separate out very soon, after 30 minutes, filter rapidly, solid uses ethanol and washed with diethylether respectively, uses nitrogen purge dried overnight slowly, obtain yellow crystals 10.8g (yield 94%, fusing point 115-116 DEG C).
Claims (10)
1. prepare a method for Abiraterone acetate, comprise the following steps:
(1) under dilute sulphuric acid catalysis, dehydroepiandrosterone and hydrazine hydrate reaction, obtain dehydroepiandrosterone-17-hydrazone (II)
(2) dehydroepiandrosterone-17-hydrazone (II) under the catalysis of tetramethyl guanidine with Iod R, obtain 17-iodo-androstane-5,16-diene-3 β-ol (III)
(3) 17-iodo-androstane-5,16-diene-3 β-ol (III) obtains Abiraterone (VI) with the coupling of 3-pyridine zinc halide under the catalysis of tetra-triphenylphosphine palladium
X is Cl, Br or I;
(4) under diisopropylethylamine (DIEA) exists, Abiraterone acetate (I) is obtained with Acetyl Chloride 98Min. or diacetyl oxide by ethyl esterified for Abiraterone (VI)
2. method according to claim 1, it is characterized in that solvent used in step (1) is ethanol, catalyzer is dilute sulphuric acid, and temperature of reaction is room temperature.
3. method according to claim 1, it is characterized in that in step (2), solvent for use is tetrahydrofuran (THF), catalyzer is tetramethyl guanidine, and temperature of reaction is-5 ~ 10 DEG C.
4. method according to claim 1, is characterized in that in step (3), 3-pyridine zinc halide first and after butyllithium reaction reacts obtained again with zinc halide by 3-bromopyridine.
5. method according to claim 1, it is characterized in that in step (3), preparation 3-pyridine zinc halide solvent for use is ether, temperature of reaction is-80 ~-60 DEG C.
6. method according to claim 1, is characterized in that in step (3), in ZnX, X is bromine.
7. method according to claim 1, to is characterized in that in step (3) that used catalyst tetra-triphenylphosphine palladium to be reacted with triphenylphosphine and hydrazine hydrate by Palladous chloride to obtain.
8. method according to claim 1, is characterized in that the reaction solvent of 17-iodo-androstane-5,16-diene-3 β-ol and 3-pyridine zinc halide in step (3) is DMF.
9. method according to claim 1, is characterized in that in step (4), solvent for use is one or more mixtures in ether, methylene dichloride, trichloromethane, ethyl acetate, acetonitrile.
10. method according to claim 1, is characterized in that in step (4), solvent for use is ether.
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| CN102816199B (en) * | 2012-08-15 | 2015-04-08 | 武汉长联来福制药股份有限公司 | Preparation and detection method of abiraterone Acetate dimer compound |
| CN102816200B (en) * | 2012-09-05 | 2015-04-15 | 中山大学 | Method for preparing abiraterone acetate |
| CN102816201A (en) * | 2012-09-25 | 2012-12-12 | 成都伊诺达博医药科技有限公司 | Purification method of abiraterone |
| CN102898495B (en) * | 2012-11-12 | 2014-11-26 | 浙江神洲药业有限公司 | Method for preparing abiraterone acetate |
| WO2014083512A1 (en) * | 2012-11-28 | 2014-06-05 | Dr. Reddy's Laboratories Limited | Process for preparation of abiraterone acetate |
| CN103864878A (en) * | 2012-12-12 | 2014-06-18 | 天津大学 | Preparation method for abiraterone acetate |
| CN104370991B (en) * | 2014-11-18 | 2016-04-27 | 仙居县力天化工有限公司 | A kind of synthetic method of Abiraterone acetic ester |
| CN104710500A (en) * | 2015-03-18 | 2015-06-17 | 安润医药科技（苏州）有限公司 | Synthesis method of abiraterone acetate |
| CN106565541A (en) * | 2016-11-05 | 2017-04-19 | 林文练 | Synthesis method for benzamidine derivatives |
| CN106565542A (en) * | 2016-11-05 | 2017-04-19 | 李景丕 | Synthesis method of benjia amidine derivative |
| CN108395463A (en) * | 2018-05-17 | 2018-08-14 | 苏州莱克施德药业有限公司 | A kind of production technology of Abiraterone acetate |
| CN110790809B (en) * | 2018-08-03 | 2021-04-02 | 奥锐特药业股份有限公司 | Preparation method of abiraterone acetate |
| CN109134571B (en) * | 2018-09-13 | 2020-10-02 | 浙江工业大学 | Preparation method of 17-iodo-androstane-5, 16-diene-3 beta-alcohol |
| CN111349138B (en) * | 2018-12-24 | 2023-06-16 | 江苏恒瑞医药股份有限公司 | Method for preparing abiraterone acetate |
| CN113831383A (en) * | 2021-11-03 | 2021-12-24 | 湖北共同药业股份有限公司 | Preparation method of abiraterone |
| CN114478678B (en) * | 2022-02-15 | 2023-05-12 | 赤峰赛林泰药业有限公司 | Method for preparing abiraterone acetate intermediate through microchannel reaction |
| CN115536717B (en) * | 2022-10-10 | 2023-11-24 | 浙江仙居君业药业有限公司 | Synthesis method of androstane-4, 16-diene-3-ketone |
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