CN103665084A - Method for preparing abiraterone acetate - Google Patents
Method for preparing abiraterone acetate Download PDFInfo
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- CN103665084A CN103665084A CN201210323193.5A CN201210323193A CN103665084A CN 103665084 A CN103665084 A CN 103665084A CN 201210323193 A CN201210323193 A CN 201210323193A CN 103665084 A CN103665084 A CN 103665084A
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- abiraterone acetate
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- preparing abiraterone
- boric acid
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Abstract
The invention discloses a method for preparing abiraterone acetate. The method comprises the following steps of: (A) carrying out Suzuki coupling reaction on a formula I compound and 3-pyridineboric acid or a 3-pyridineboric acid derivative in a mixed solvent formed by an organic aprotic solvent and water under the action of a metal palladium catalyst and alkali; (B) after the reaction is finished, adding ethyl acetate and the water to a reaction system for liquid separation; collecting organic phases, sequentially washing by using the water and a saturated salt solution, drying and concentrating to obtain an oily crude product; (3) adding a crystallizing solvent to the oily crude product, and stirring for crystallization; (D) collecting solids for recrystallization. The method disclosed by the invention has the advantages of simple process, low cost and easiness for obtaining of raw materials, easiness for purifying treatment, high yield, low cost, high finished product purity, and the like, completely meets the requirement for industrialized batch production and has very high practical value.
Description
Technical field
The present invention relates to a kind of method of preparing Abiraterone acetate, belong to technical field of organic synthesis.
Background technology
Abiraterone acetate, is again Abiraterone-3-acetic ester, is the prodrug of Abiraterone, and its chemical structural formula is:
Abiraterone acetate is a kind of oral Terminal oxidase CYP450c17 inhibitor, key enzyme CYP450c17 in synthetic by inhibition male sex hormone reduces androgen levels, and the male sex hormone to testis and other positions of health has restraining effect, for the treatment of prostate cancer.
First this compound and synthetic method thereof are disclosed in WO9320097A, its synthetic route is to take Dehydroepiandrosterone Acetate as raw material, prepare its fluoroform sulfonyl derivative (formula I), be total to two-step reaction with diethyl (3-pyridyl) borine condensation again and obtain Abiraterone acetate (formula II), described synthetic route is as follows:
The synthetic method of this compound is also shown in WO9509178, J.Med.Chem.1995,38,2463-2471 and Org.Prep.Proced.Int, 1997,29 (1), in the documents and materials of 123-134, the method that above document is recorded is because the reason of impurity is all the methods that adopt column chromatography for the description of purification process.WO2006021777 adopts the route of the acetic acid synthesized Abiraterone identical with WO9320097A, starting raw material Dehydroepiandrosterone Acetate and trifluoromethanesulfonic acid anhydride reactant obtain product fluoroform sulfonyl derivative, because this step reaction can not react completely, unreacted starting raw material is also present in reaction solution, this method is not purified directly carries out next step reaction, under existing, palladium catalyst reacts with diethyl (3-pyridyl) borine, advantage is to save time, efficiency improves, it is more that but impurity produces, the impurity such as diethyl (3-pyridyl) borine except starting raw material, have also been introduced, WO2006021777 is in order to improve the efficiency of aftertreatment purifying, by salify crystallization method, most impurity is removed, by Dichlorodiphenyl Acetate Abiraterone crude product and methylsulfonic acid salify, its mesylate is precipitated in solvent, and other most of impurity comprise that starting raw material Dehydroepiandrosterone Acetate all remains in solvent, filtration obtains Abiraterone acetate mesylate, by this Abiraterone acetate mesylate with in alkali and after obtain Abiraterone acetate.But the purification process existent defect of this technique, that is: during with methylsulfonic acid and Abiraterone acetate salify, form the suspension of stiff, be difficult to filter, the filter cake thickness that filtration obtains, easy residual impurity, filtering the Abiraterone acetate mesylate obtaining needs with alkali, to dissociate and obtain Abiraterone acetate again after recrystallization purifying, increase operating time and difficulty, be unfavorable for industry's enlarging production.
Therefore, this area Kei need be studied a kind of simple to operate, purifies and separates easily and applicable industrial mass is prepared the method for high purity Abiraterone acetate.
Summary of the invention
The problems referred to above and the defect that for prior art, exist, the object of this invention is to provide a kind of method of preparing Abiraterone acetate, prepares the demand of high purity Abiraterone acetate to meet industrial mass.
For achieving the above object, the technical solution used in the present invention is as follows:
A method of preparing Abiraterone acetate, comprises the steps:
A) in the mixed solvent of organic aprotic solvent and water formation, make formula I compound and 3-pyridine boric acid or 3-pyridine boric acid derivatives carry out Suzuki linked reaction under metal palladium catalyst and alkali effect;
B) reaction finishes, and in reaction system, adds ethyl acetate and water to carry out separatory; Collect organic phase, water and saturated aqueous common salt wash successively, dry, concentrated, obtain oily crude product;
C) in oily crude product, add crystallization solvent, stir and make crystallization;
D) collect solid, carry out recrystallization.
As a kind of preferred version, steps A) in organic aprotic solvent be selected from any one in tetrahydrofuran (THF), dioxane, acetonitrile, DMF and toluene.
As a kind of preferred version, steps A) in mixed solvent be to be formed by 1:1～10:1 volume ratio by organic aprotic solvent and water.
As a kind of preferred version, steps A) in, 1 gram of formula I compound mixed solvent described in using 6～10 milliliters.
As a kind of preferred version, described 3-pyridine boric acid derivatives is 3-pyridine boric acid ester, 3-pyridine boron trioxide or 3-pyridine boric acid pinacol ester.
As a kind of preferred version, described metal palladium catalyst is selected from any one or a few in four (triphenyl phosphorus) palladium, two (triphenyl phosphorus) Palladous chlorides and triphenylphosphine palladium acetate.
As a kind of preferred version, described alkali is selected from any one in sodium carbonate, salt of wormwood, dipotassium hydrogen phosphate, sodium-acetate and Sodium phosphate dibasic.
As a kind of preferred version, step C) the crystallization solvent in is the mixed solvent that sherwood oil or normal hexane or itself and ethyl acetate form, wherein better with the mixed solvent of sherwood oil or normal hexane and ethyl acetate formation, with normal hexane and ethyl acetate, press mixed solvent the best that 4:1 volume ratio forms.
As a kind of preferred version, for the solvent of recrystallization, be sherwood oil or normal hexane.
Compared with prior art, the present invention has following beneficial effect:
1) the present invention adopts 3-pyridine boric acid or 3-pyridine boric acid derivatives to carry out Suzuki linked reaction as organoboron reagent, produced and made this step reaction can carry out beat all effect more completely, so that realized through simple crystallization and processed and just can obtain HPLC purity and reach 92% Abiraterone acetate crude product, then realize without process column chromatography or sour salify purification process, and only need process through recrystallization, just can obtain HPLC purity up to 99.85% Abiraterone acetate sterling, not only simplified preparation technology, and significantly improved yield, meet industrialization production requirements,
2) diethyl (3-pyridyl) borine that the 3-pyridine boric acid that the present invention adopts or 3-pyridine boric acid derivatives are used compared with prior art more easily obtains, and its industrial price is far below diethyl (3-pyridyl) borine, there is advantage cheap and easy to get, can significantly reduce raw materials cost, be conducive to suitability for industrialized production;
In a word, the method of preparing Abiraterone acetate provided by the invention, there is many remarkable advantages such as technique is simple, raw material is cheap and easy to get, purification process is easy, yield is high, cost is low, finished product purity height, meet industrialized mass production requirement completely, there is extremely strong practical value.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail and completely.
In embodiment, formula I compound used is that in referenced patent WO2006021777, disclosed method is prepared and obtains, and concrete synthetic route is as follows:
concrete operations are as follows: to being equipped with in three mouthfuls of reaction flasks of constant pressure funnel, thermometer, add 100g Dehydroepiandrosterone Acetate and 1000mL methylene dichloride, be stirred to dissolve; Keeping system temperature to add trifluoromethanesulfanhydride anhydride (96g) under lower than 10 ℃ of conditions in system, in 15 minutes, drip the 300mL dichloromethane solution containing 30mL triethylamine simultaneously; Drip and finish, return to room temperature reaction 3 hours; In reaction solution, add 1000mL water, stir 10min, separatory, methylene dichloride for water (2 * 500mL) extraction; Merge organic phase, first with 500mL washing twice, then wash twice with 500mL saturated common salt; Separatory, Anhydrous potassium carbonate is dry; Remove by filter siccative, the organic solvent in concentrated dry filtrate, obtains 150g brownish black oily matter, treats directly to drop into the next step.
Embodiment 1
Get 15g formula I compound, after dissolving with 100mL dioxane, transfer in a 250mL there-necked flask of being furnished with thermometer, reflux condensing tube and argon gas conduit; Under argon shield, in system, add wet chemical (50mL) and two (triphenyl phosphorus) palladium chloride (35mg) that 3-pyridine boric acid (4.8g), volumetric molar concentration are 2mol/L; Under agitation be heated to reflux, react complete (about back flow reaction 8 hours), in reaction system, add 50mL ethyl acetate and 50mL water, separatory, water extracts by 3 * 50mL ethyl acetate; Collect organic phase, first use 2 * 50mL water washing, then use the water washing of 2 * 50mL saturated common salt; Anhydrous sodium sulfate drying, filters, and the organic solvent in concentrated dry filtrate, obtains 15g brown oily matter; To adding volume ratio in this oily matter, be ethyl acetate-normal hexane mixed solvent of 1:4, under room temperature, stir and make abundant crystallization in 3 hours, obtain 8.0g Dark grey solid, molar yield 67%, HPLC purity reaches 92%; This Dark grey solid is carried out to recrystallization processing with 100mL sherwood oil, obtain 7g white Abiraterone acetate (formula II), HPLC purity reaches 99.85%.
Embodiment 2
Get 15g formula I compound, after dissolving with 50mL toluene, transfer in a 250mL there-necked flask of being furnished with thermometer, reflux condensing tube and argon gas conduit; Under argon shield, in system, add wet chemical (50mL) and two (triphenyl phosphorus) palladium chloride (35mg) that 3-pyridine boron trioxide (5.3g), volumetric molar concentration are 2mol/L; Under agitation be heated to reflux, react complete (about back flow reaction 8 hours), in reaction system, add 50mL ethyl acetate and 50mL water, separatory, water extracts by 3 * 50mL ethyl acetate; Collect organic phase, first use 2 * 50mL water washing, then use the water washing of 2 * 50mL saturated common salt; Anhydrous sodium sulfate drying, filters, and the organic solvent in concentrated dry filtrate, obtains 14g brown oily matter; To adding volume ratio in this oily matter, be ethyl acetate-normal hexane mixed solvent of 1:4, under room temperature, stir and make abundant crystallization in 3 hours, obtain 7.5g Dark grey solid, molar yield 63%, HPLC purity reaches 90%; This Dark grey solid is carried out to recrystallization processing with 100mL normal hexane, obtain 6g white Abiraterone acetate, HPLC purity reaches 99.7%.
Embodiment 3
Get 15g formula I compound, after dissolving with 90mL tetrahydrofuran (THF), transfer in a 250mL there-necked flask of being furnished with thermometer, reflux condensing tube and argon gas conduit; Under argon shield, in system, add aqueous dibasic potassium phosphate solution (50mL) and four (triphenyl phosphorus) palladium (30mg) that 3-pyridine boric acid pinacol ester (8.2g), volumetric molar concentration are 2mol/L; Under agitation be heated to reflux, react complete (about back flow reaction 8 hours), in reaction system, add 50mL ethyl acetate and 50mL water, separatory, water extracts by 3 * 50mL ethyl acetate; Collect organic phase, first use 2 * 50mL water washing, then use the water washing of 2 * 50mL saturated common salt; Anhydrous sodium sulfate drying, filters, and the organic solvent in concentrated dry filtrate, obtains 14.5g brown oily matter; To adding volume ratio in this oily matter, be ethyl acetate-normal hexane mixed solvent of 1:4, under room temperature, stir and make abundant crystallization in 3 hours, obtain 8.1g Dark grey solid, molar yield 68%, HPLC purity reaches 91%; This Dark grey solid is carried out to recrystallization processing with 100mL normal hexane, obtain 6.9g white Abiraterone acetate, HPLC purity reaches 99.8%.
Embodiment 4
Get 15g formula I compound, with 80mLN, after dinethylformamide dissolves, transfer in a 250mL there-necked flask of being furnished with thermometer, reflux condensing tube and argon gas conduit; Under argon shield, in system, add wet chemical (50mL) and two (triphenyl phosphorus) palladium chloride (35mg) that 3-pyridine boric acid pinacol ester (8.2g), volumetric molar concentration are 2mol/L; Under agitation be heated to reflux, react complete (about back flow reaction 8 hours), in reaction system, add 50mL ethyl acetate and 50mL water, separatory, water extracts by 3 * 50mL ethyl acetate; Collect organic phase, first use 2 * 50mL water washing, then use the water washing of 2 * 50mL saturated common salt; Anhydrous sodium sulfate drying, filters, and the organic solvent in concentrated dry filtrate, obtains 16g brown oily matter; To adding volume ratio in this oily matter, be ethyl acetate-normal hexane mixed solvent of 1:4, under room temperature, stir and make abundant crystallization in 3 hours, obtain 7.2g Dark grey solid, molar yield 60%, HPLC purity reaches 90%; This Dark grey solid is carried out to recrystallization processing with 100mL normal hexane, obtain 5.6g white Abiraterone acetate, HPLC purity reaches 99.2%.
Embodiment 5
Get 15g formula I compound, after dissolving with 100mL acetonitrile, transfer in a 250mL there-necked flask of being furnished with thermometer, reflux condensing tube and argon gas conduit; Under argon shield, in system, add wet chemical (50mL) and four (triphenyl phosphorus) palladium (30mg) that 3-pyridine boric acid ester (5.3g), volumetric molar concentration are 2mol/L; Under agitation be heated to reflux, react complete (about back flow reaction 8 hours), in reaction system, add 50mL ethyl acetate and 50mL water, separatory, water extracts by 3 * 50mL ethyl acetate; Collect organic phase, first use 2 * 50mL water washing, then use the water washing of 2 * 50mL saturated common salt; Anhydrous sodium sulfate drying, filters, and the organic solvent in concentrated dry filtrate, obtains 15g brown oily matter; To adding volume ratio in this oily matter, be ethyl acetate-normal hexane mixed solvent of 1:4, under room temperature, stir and make abundant crystallization in 3 hours, obtain 8g Dark grey solid, molar yield 67%, HPLC purity reaches 90%; This Dark grey solid is carried out to recrystallization processing with 100mL normal hexane, obtain 6.5g white Abiraterone acetate, HPLC purity reaches 99.8%.
Embodiment 6
Get 15g formula I compound, after dissolving with 100mL dioxane, transfer in a 1000mL there-necked flask of being furnished with thermometer, reflux condensing tube and argon gas conduit; Under argon shield, in system, add aqueous sodium carbonate (10mL) and four (triphenyl phosphorus) palladium (30mg) that 3-pyridine boric acid (4.8g), volumetric molar concentration are 10mol/L; Under agitation be heated to reflux, react complete (about back flow reaction 8 hours), in reaction system, add 200mL ethyl acetate and 200mL water, separatory, water extracts by 3 * 50mL ethyl acetate; Collect organic phase, first use 2 * 50mL water washing, then use the water washing of 2 * 50mL saturated common salt; Anhydrous sodium sulfate drying, filters, and the organic solvent in concentrated dry filtrate, obtains 14g brown oily matter; To adding volume ratio in this oily matter, be ethyl acetate-normal hexane mixed solvent of 1:4, under room temperature, stir and make abundant crystallization in 3 hours, obtain 7.3g Dark grey solid, molar yield 61%, HPLC purity reaches 91%; This Dark grey solid is carried out to recrystallization processing with 100mL normal hexane, obtain 5.9g white Abiraterone acetate, HPLC purity reaches 99.8%.
Finally be necessary described herein: above embodiment is only for being described in more detail technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (10)
1. a method of preparing Abiraterone acetate, is characterized in that, comprises the steps:
A) in the mixed solvent of organic aprotic solvent and water formation, make formula I compound and 3-pyridine boric acid or 3-pyridine boric acid derivatives carry out Suzuki linked reaction under metal palladium catalyst and alkali effect;
B) reaction finishes, and in reaction system, adds ethyl acetate and water to carry out separatory; Collect organic phase, water and saturated aqueous common salt wash successively, dry, concentrated, obtain oily crude product;
C) in oily crude product, add crystallization solvent, stir and make crystallization;
D) collect solid, carry out recrystallization.
2. the method for preparing Abiraterone acetate according to claim 1, is characterized in that: the organic aprotic solvent steps A) is selected from any one in tetrahydrofuran (THF), dioxane, acetonitrile, DMF and toluene.
3. the method for preparing Abiraterone acetate according to claim 1, is characterized in that: the mixed solvent steps A) is to be formed by 1:1～10:1 volume ratio by organic aprotic solvent and water.
4. the method for preparing Abiraterone acetate according to claim 1, is characterized in that: steps A), and the mixed solvent of 1 gram of formula I compound described in using 6～10 milliliters.
5. the method for preparing Abiraterone acetate according to claim 1, is characterized in that: described 3-pyridine boric acid derivatives is 3-pyridine boric acid ester, 3-pyridine boron trioxide or 3-pyridine boric acid pinacol ester.
6. the method for preparing Abiraterone acetate according to claim 1, is characterized in that: described metal palladium catalyst is selected from any one in four (triphenyl phosphorus) palladium, two (triphenyl phosphorus) Palladous chlorides and triphenylphosphine palladium acetate.
7. the method for preparing Abiraterone acetate according to claim 1, is characterized in that: described alkali is selected from any one in sodium carbonate, salt of wormwood, dipotassium hydrogen phosphate, sodium-acetate and Sodium phosphate dibasic.
8. the method for preparing Abiraterone acetate according to claim 1, is characterized in that: the crystallization solvent step C) is the mixed solvent that sherwood oil or normal hexane or itself and ethyl acetate form.
9. the method for preparing Abiraterone acetate according to claim 8, is characterized in that: the crystallization solvent step C) is the mixed solvent that normal hexane and ethyl acetate form by 4:1 volume ratio.
10. the method for preparing Abiraterone acetate according to claim 1, is characterized in that: the solvent for recrystallization is sherwood oil or normal hexane.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965282A (en) * | 2014-04-21 | 2014-08-06 | 武汉百科药物开发有限公司 | Preparation method for abiraterone acetate |
| CN105713063A (en) * | 2014-12-02 | 2016-06-29 | 重庆安格龙翔医药科技有限公司 | Abiraterone acetate preparation method |
| CN106083977A (en) * | 2016-06-15 | 2016-11-09 | 河北科技大学 | The process for purification of acetyl dehydroepiandros-sterone enol triflate |
| CN108101953A (en) * | 2018-02-08 | 2018-06-01 | 山东科兴生物制品有限公司 | Improved abiraterone acetate preparation method |
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| CN101768199A (en) * | 2009-12-24 | 2010-07-07 | 深圳万乐药业有限公司 | Polymorphs of abiraterone acetate and preparation method thereof |
| CN102030798A (en) * | 2010-12-17 | 2011-04-27 | 深圳万乐药业有限公司 | Purification method of abiraterone acetate |
| WO2012083112A2 (en) * | 2010-12-16 | 2012-06-21 | Biomarin Pharmaceutical Inc. | Cyp11b, cyp17, and/or cyp21 inhibitors |
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2012
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Patent Citations (4)
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| CN101044155A (en) * | 2004-08-24 | 2007-09-26 | 英国技术集团国际有限公司 | Methanesulfonate salts of abiraterone-3-esters and recovery of salts of abirater one-3-esters from solution in methyl tert-butyl ether |
| CN101768199A (en) * | 2009-12-24 | 2010-07-07 | 深圳万乐药业有限公司 | Polymorphs of abiraterone acetate and preparation method thereof |
| WO2012083112A2 (en) * | 2010-12-16 | 2012-06-21 | Biomarin Pharmaceutical Inc. | Cyp11b, cyp17, and/or cyp21 inhibitors |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103965282A (en) * | 2014-04-21 | 2014-08-06 | 武汉百科药物开发有限公司 | Preparation method for abiraterone acetate |
| CN103965282B (en) * | 2014-04-21 | 2016-01-20 | 武汉百科药物开发有限公司 | A kind of preparation method of Abiraterone acetate |
| CN105713063A (en) * | 2014-12-02 | 2016-06-29 | 重庆安格龙翔医药科技有限公司 | Abiraterone acetate preparation method |
| CN106083977A (en) * | 2016-06-15 | 2016-11-09 | 河北科技大学 | The process for purification of acetyl dehydroepiandros-sterone enol triflate |
| CN106083977B (en) * | 2016-06-15 | 2017-11-28 | 河北科技大学 | The process for purification of acetyl dehydroepiandros-sterone enol triflate |
| CN108101953A (en) * | 2018-02-08 | 2018-06-01 | 山东科兴生物制品有限公司 | Improved abiraterone acetate preparation method |
| CN108101953B (en) * | 2018-02-08 | 2020-07-03 | 科兴生物制药股份有限公司 | Improved preparation method of abiraterone acetate |
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Application publication date: 20140326 |