CN105713062A - Method used for preparing abiraterone acetate - Google Patents
Method used for preparing abiraterone acetate Download PDFInfo
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- CN105713062A CN105713062A CN201410718492.8A CN201410718492A CN105713062A CN 105713062 A CN105713062 A CN 105713062A CN 201410718492 A CN201410718492 A CN 201410718492A CN 105713062 A CN105713062 A CN 105713062A
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- IATHUHWISHJFER-SOFGYWHQSA-N CCB(CC)/C=C/CCN=C Chemical compound CCB(CC)/C=C/CCN=C IATHUHWISHJFER-SOFGYWHQSA-N 0.000 description 1
- WTKFUDDFHUANII-HDCHVNNUSA-N C[C@](CC1)(C(CC2)C3C1[C@@](C)(CCC(C1)O)C1=CC3)/C2=N\N Chemical compound C[C@](CC1)(C(CC2)C3C1[C@@](C)(CCC(C1)O)C1=CC3)/C2=N\N WTKFUDDFHUANII-HDCHVNNUSA-N 0.000 description 1
- FMGSKLZLMKYGDP-WYTRLKPUSA-N C[C@](CC1)(C(CC2)C3C1[C@@](C)(CCC(C1)O)C1=CC3)C2=O Chemical compound C[C@](CC1)(C(CC2)C3C1[C@@](C)(CCC(C1)O)C1=CC3)C2=O FMGSKLZLMKYGDP-WYTRLKPUSA-N 0.000 description 1
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Abstract
The invention discloses a method used for preparing abiraterone acetate. The reaction route is disclosed in the invention. Operation of the method is simple; raw materials are cheap and easily available; reaction conditions are mild; equipment requirement is low; total yield is high; solvent synchronous recycling can be realized; production cost is low; large-scale production can be easily realized; and industrial application value is high.
Description
Technical field
The present invention relates to nitrogenous steroid, be specifically related to a kind of method preparing abiraterone acetas.
Background technology
Abiraterone acetas (Abirateroneacetate, chemistry 17-(3-pyridine radicals)-androstane-4 by name, 16-diene-3 β-ol acetate) it is by the orally active androgen biosynthesis inhibitor of one of centocoroftho company of U.S. exploitation；Within 2011, through FDA (Food and Drug Adminstration) (FDA) and Europe drug assessment office (EMEA) approval listing, commodity are called Zytiga.There is classical hormonal is treated the transitivity advanced prostate cancer of drug resistance with prednisone (Prednisone) coupling treatment clinically in this medicine, not only can reduce its prostate specific antigen level, also contribute to reduce tumor, the life of late stage prostate cancer patient can be extended.Recently, FDA (Food and Drug Adminstration) and Europe drug assessment office also ratify to increase the indication of abiraterone acetas, namely can be used for castration-resistant advanced metastatic prostate cancer patients and use before carrying out chemotherapy.
Preparation method about abiraterone acetas has following several at present:
In world patent WO9509178, prepare abiraterone acetas by the one-tenth hydrazone of dehydroepiandros-sterone and iodo and diethyl (3-pyridine radicals) borine generation coupling reaction and acetylization reaction.But owing to the coupling reaction time in this route is longer, energy consumption is higher, response time product long afterwards becomes assorted, and diethyl (3-pyridine radicals) borine is expensive, hinders large-scale production.
In patent US5604213, utilizing Dehydroepiandrosterone Acetate and trifluoromethanesulfonic acid anhydride reactant to prepare activity sulphonic acid ester, activity sulphonic acid ester prepares abiraterone acetas with diethyl-3-pyridine borane generation coupling reaction again.In this route in the process of preparation activity sulphonic acid ester, raw material reacts incomplete all the time, and needs to use H-NMR monitoring, and diethyl-3-pyridine borane is expensive, is unfavorable for industrialized production.
In Chinese patent CN201210078438.2, utilize Dehydroepiandrosterone Acetate to become hydrazone, after iodo, prepare abiraterone acetas with pyridine zincon, in this route, prepare pyridine zincon complicated operation and severe reaction conditions, need ultralow temperature (-78 DEG C), anhydrous and oxygen-free.It is unfavorable for industrialized production.
In sum; the synthetic route of abiraterone acetas involved in disclosed bibliographical information at present; although at feeding sequence; coupling mode; protective group and deprotection etc. are optimized and improve, but the aspects such as its preparation cost, yield and three wastes eliminating still suffer from many deficiencies, specifically how reduce reactions steps; improving chemo-selective and purification, the economic technology development for abiraterone acetas crude drug has important practical significance.
Summary of the invention
The preparation method being in that to provide a kind of new abiraterone acetas of the present invention, this preparation method raw material is easy to get, and concise in technology is economic and environment-friendly, quality controllable, is suitable for industrialized production.
For achieving the above object, present invention employs following technical scheme:
A kind of preparation method of abiraterone acetas, it is characterised in that: described preparation method comprises the steps:
A) there is additive reaction with compound A in the basic conditions with 3-bromopyridine Grignard reagent, obtain crude compound B through Dehydration；
B) compound B is hydrolyzed in the basic conditions, prepares compound C；
C) compound C obtains high-purity compound C through recrystallization；
D) compound C and acetylation reagent react and prepare compound B, i.e. abiraterone acetas.
Its reaction scheme is as follows:
3-halogen pyridine Grignard reagent of the present invention can be prepared 2-halopropane Grignard reagent by 2-halopropane with magnesium powder, then obtains with 3-halogen pyridine grignard exchange system.
The raw material Dehydroepiandrosterone Acetate of described additive reaction and the molar ratio of 3-halogen Grignard reagent are 1: 1-2, it is preferable that 1: 1.0-1.1.
The temperature of described additive reaction is-10 DEG C～20 DEG C, it is preferable that 0 DEG C.
The solvent of described additive reaction one or more combination in toluene, ether, diisopropyl ether, methyl tert-butyl ether, oxolane, it is preferable that oxolane.
The alkali of described hydrolysis is preferred with inorganic base, inorganic base one or more combination in sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydroxide, Lithium hydrate, it is preferable that sodium hydroxide, potassium hydroxide, the one in Lithium hydrate.
The solvent of described hydrolysis is selected from oxolane, methanol, the one or more combination in ethanol, it is preferable that THF.
One in the preferred isopropanol of solvent of described reclosing crystalline substance or ethanol.
In described acylation reaction, acetylation reagent used is selected from acetic anhydride, the one in chloroacetic chloride.
Technique effect:
The present invention adopts dehydroepiandros-sterone and 3-halogen pyridine grignard to be raw material, prepares abiraterone acetas crude product through condensation reaction one step, again through hydrolyzed under basic conditions; recrystallization; acetylizad process, prepares highly purified abiraterone acetas, and reaction raw materials is cheap and easy to get; operating process is simple; reaction condition is gentle, and equipment requirements is low, and uses solvent can realize synchronizing to reclaim; production cost is low, it is easy to large-scale production；The abiraterone acetas high purity more than 99.8% that yield of the present invention is high, prepare, in end-product, compound C content is lower than one thousandth.
In a word, adopt the inventive method can meet the requirement of industrialized mass production abiraterone acetas better, there is significance industrial application value.
Detailed description of the invention
Following example are served only for technical scheme is described in further detail; it is not intended that limiting the scope of the invention; those skilled in the art is without departing from the spirit and scope of the present invention, it should various modifications may be made and change.Therefore protection scope of the present invention should be considered as appending claims limited range.The present invention is raw materials used is commercially available prod.
Embodiment 1:
Compound B synthesizes
30g (0.091mol) compound A is dissolved in 300mlTHF, it is cooled to 0 DEG C, drips 90.5g (0.100mol) 3-bromopyridine Grignard reagent, drip and finish, rise to room temperature reaction 18h, with saturated aqueous ammonium chloride cancellation reaction at 0 DEG C, oxolane is removed in decompression distillation, steamed, with dichloromethane extraction three times, merge organic layer, wash with saturated brine, dry with anhydrous magnesium sulfate.Decompression is distilled off dichloromethane, steamed, adds 300ml methanol in residue, add 23.3g (0.091mol) burgess reagent, heating reflux reaction 1h under stirring, add 23.3g (0.091mol) burgess reagent, TLC monitoring reaction is complete, and cooling is reacted with frozen water cancellation, separatory, aqueous layer with ethyl acetate extracts, and merges organic facies, washing organic layer with saturated brine, anhydrous sodium sulfate dries, and filters, decompression distillation filtrate, obtains 30.1g compound B, yield 84.7%.
The synthesis of compound C
20g (0.051mol) compound B is dissolved in 100mlTHF, 4.08g (0.102mol) sodium hydroxide 10ml aqueous solution is added in system, room temperature reaction 2h, TLC monitoring reaction is complete, filtering, filter cake is washed with water to neutrality, and 50 DEG C dry, obtain 17.1g compound C, yield 95.8%.
Compound C refines
By 15g (0.042mol) compound C, add 45ml isopropanol, be heated to reflux, molten be cooled to 0 DEG C clearly, crystallize 1h, filter, filter cake washed with isopropyl alcohol, 50 DEG C dry, obtain 12.3g compound C, yield 82%.
The synthesis of compound B
10g (0.028mol) compound C fine work is joined in reaction bulb, it is simultaneously introduced 100ml dichloromethane, 4.2g (0.042mol) triethylamine, 3.5g (0.036mol) acetic anhydride, temperature rising reflux reacts, TLC monitors, react complete, the cancellation that adds water is reacted, separatory, use dichloromethane extraction water layer, merge organic layer, dry with anhydrous sodium sulfate, filter, concentrating under reduced pressure, pull an oar with normal heptane, filter, 40 DEG C dry, obtain 9.7g abiraterone acetas, yield 86.6%, purity is 99.8%, in end-product, the content of compound C is less than 0.1%.δ 1.05 (3H, s ,-CH3), 1.06-1.11 (1H, m), 1.08 (3H, s,-CH3), 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), 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).
Embodiment 2:
The synthesis of compound B
30g (0.091mol) compound A is dissolved in 600ml toluene, it is cooled to 20 DEG C, dropping 164.8g (0.182mol) 3-bromopyridine Grignard reagent, drips and finishes, rise to room temperature reaction 16h, with saturated aqueous ammonium chloride cancellation reaction at 0 DEG C, separatory, is extracted with ethyl acetate three times, merges organic layer, wash with saturated brine, dry with anhydrous magnesium sulfate.Decompression is distilled off organic solvent, steamed, adds 300ml methanol in residue, add 23.3g (0.091mol) burgess reagent, heating reflux reaction 1h under stirring, add 23.3g (0.091mol) burgess reagent, TLC monitoring reaction is complete, and cooling is reacted with frozen water cancellation, separatory, aqueous layer with ethyl acetate extracts, and merges organic facies, washing organic layer with saturated brine, anhydrous sodium sulfate dries, and filters, decompression distillation filtrate, obtains 29.3g compound B, yield 82.5%.
The synthesis of compound C
20g (0.051mol) compound B is dissolved in 100ml methanol, 5.72g (0.102mol) potassium hydroxide 10ml aqueous solution is added in system, room temperature reaction 2h, TLC monitoring reaction is complete, filtering, filter cake is washed with water to neutrality, and 50 DEG C dry, obtain 16.7g compound C, yield 93.6%.
Compound C refines
By 15g (0.042mol) compound C, add 45ml ethanol, be heated to reflux, molten be cooled to 0 DEG C clearly, crystallize 1h, filter, filter cake washing with alcohol, 50 DEG C dry, obtain 12.1g compound C, yield 80.6%.
The synthesis of compound B
10g (0.028mol) compound C fine work is joined in reaction bulb, is simultaneously introduced 100ml dichloromethane, 4.2g (0.042mol) triethylamine, 3.5g (0.036mol) acetic anhydride, temperature rising reflux reacts, and TLC monitors, and reacts complete, the cancellation that adds water is reacted, separatory, uses dichloromethane extraction water layer, merges organic layer, dry with anhydrous sodium sulfate, filter, concentrating under reduced pressure, pull an oar with normal heptane, filter, 40 DEG C dry, obtain 9.3g abiraterone acetas, yield 83.0%, purity is 99.8%, and in end-product, compound C content is less than 0.1%.
Embodiment 3:
The synthesis of compound B
30g (0.091mol) compound A is dissolved in 600ml diisopropyl ether, it is cooled to-10 DEG C, dropping 98.8g (0.109mol) 3-bromopyridine Grignard reagent, drips and finishes, rise to room temperature reaction 16h, with saturated aqueous ammonium chloride cancellation reaction at 0 DEG C, separatory, is extracted with ethyl acetate three times, merges organic layer, wash with saturated brine, dry with anhydrous magnesium sulfate.Decompression is distilled off organic solvent, steamed, adds 300ml methanol in residue, add 23.3g (0.091mol) burgess reagent, heating reflux reaction 1h under stirring, add 23.3g (0.091mol) burgess reagent, TLC monitoring reaction is complete, and cooling is reacted with frozen water cancellation, separatory, aqueous layer with ethyl acetate extracts, and merges organic facies, washing organic layer with saturated brine, anhydrous sodium sulfate dries, and filters, decompression distillation filtrate, obtains 29.6g compound B, yield 83.4%.
The synthesis of compound C
20g (0.051mol) compound B is dissolved in 100ml methanol, 4.27g (0.102mol) Lithium hydrate 10ml aqueous solution is added in system, room temperature reaction 2h, TLC monitoring reaction is complete, filtering, filter cake is washed with water to neutrality, and 50 DEG C dry, obtain 16.6g compound C, yield 93.1%.
Compound C refines
By 15g (0.042mol) compound C, add 45ml ethanol, be heated to reflux, molten be cooled to 0 DEG C clearly, crystallize 1h, filter, filter cake washing with alcohol, 50 DEG C dry, obtain 12.6g compound C, yield 84.0%.
The synthesis of compound B
10g (0.028mol) compound C fine work is joined in reaction bulb, is simultaneously introduced 100ml dichloromethane, 4.2g (0.042mol) triethylamine, 2.8g (0.036mol) chloroacetic chloride, temperature rising reflux reacts, and TLC monitors, and reacts complete, the cancellation that adds water is reacted, separatory, uses dichloromethane extraction water layer, merges organic layer, dry with anhydrous sodium sulfate, filter, concentrating under reduced pressure, pull an oar with normal heptane, filter, 40 DEG C dry, obtain 8.9g abiraterone acetas, yield 79.5%, purity is 99.8%, and in end-product, compound C content is less than 0.1%.
Claims (10)
1. the method preparing abiraterone acetas, it is characterised in that comprise the steps:
A) with compound A and 3-bromopyridine Grignard reagent generation additive reaction, crude compound B is obtained through Dehydration；
B) compound B is hydrolyzed in the basic conditions, prepares compound C；
C) compound C obtains high-purity compound C through recrystallization；
D) compound C and acetylation reagent react and prepare compound B, i.e. abiraterone acetas；
Its reaction scheme is as follows:
。
2. the method for claim 1, it is characterised in that: in described step a), compound A and 3-bromopyridine Grignard reagent molar ratio are 1:1-2.
3. the method for claim 1, it is characterised in that: solvent for use one in toluene, ether, diisopropyl ether, methyl tert-butyl ether, oxolane in described step a).
4. method as claimed in claim 2, it is characterised in that: in described step a), solvent for use is oxolane.
5. the method for claim 1, it is characterised in that: in described step a), additive reaction temperature is-10 DEG C ~ 20 DEG C.
6. the method as described in any one of claim 2-4, it is characterised in that: in described step a), additive reaction temperature is 0 DEG C.
7. the method as described in any one of claim 1-5, it is characterised in that: in described step b), hydrolysis alkali used is inorganic base；Described inorganic base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or Lithium hydrate.
8. the method as described in any one of claim 1-5, it is characterised in that: described step b) is hydrolyzed solvent for use selected from oxolane, methanol, the one or more combination in ethanol.
9. the method as described in any one of claim 1-5, it is characterised in that: the solvent that in step c), reclosing is brilliant is isopropanol or ethanol.
10. the method as described in any one of claim 1-5, it is characterised in that: described acetylation reagent is acetic anhydride or chloroacetic chloride.
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| CN201410718492.8A CN105713062A (en) | 2014-12-02 | 2014-12-02 | Method used for preparing abiraterone acetate |
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Citations (2)
| 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 |
| CN103421073A (en) * | 2013-08-21 | 2013-12-04 | 苏州明锐医药科技有限公司 | Preparation method of Abiraterone |
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Patent Citations (2)
| 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 |
| CN103421073A (en) * | 2013-08-21 | 2013-12-04 | 苏州明锐医药科技有限公司 | Preparation method of Abiraterone |
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Application publication date: 20160629 |