CN104370991A - Synthetic method of abiraterone acetic ester - Google Patents
Synthetic method of abiraterone acetic ester Download PDFInfo
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- CN104370991A CN104370991A CN201410654955.9A CN201410654955A CN104370991A CN 104370991 A CN104370991 A CN 104370991A CN 201410654955 A CN201410654955 A CN 201410654955A CN 104370991 A CN104370991 A CN 104370991A
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- acetic ester
- synthetic method
- molecular sieve
- abiraterone acetic
- abiraterone
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- 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
Abstract
The invention discloses a synthetic method of abiraterone acetic ester. The synthetic method is characterized by taking dehydro-epiandrosterone acetic ester shown by a formula (I) as a raw material, and performing reduction, dehydration and Heck coupling reaction to prepare abiraterone acetic ester shown by a formula (II). The synthetic method is easy to operate, is high in total yield and is a new synthesis technical route which is safe, and the raw material is easily-available to facilitate industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of Abiraterone acetic ester.
Background technology
Abiraterone acetic ester (Abiraterone acetate), chemistry by name (3
β)-acetoxyl group-17-(3-pyridyl) androstane-5,16-diene is the prodrug of Abiraterone.Researched and developed by Britain's ICR (Institute of Cancer Research, ICR) at first, technology group of Britain (The British Technology Group, BTG) provides and subsidizes and exploitation clinical application.First phase is clinical to be completed by German Boehringer Ingelheim (Boehringer Ingelheim), and Cougar biotech company of the U.S. bears the second stage of and that three phases are clinical work.After having purchased Cougar biotechnology in July, 2009 Johson & Johnson (Johnson & Johnson), Janssen Biotech Inc has been responsible for the clinical evaluation of three phases and listing.Abiraterone acetic ester Nikkei U.S. FDA April 28 in 2011 approval listing, commodity are called Zytiga, ratify it Europe drug administration in July in the same year (EMA) and go on the market in European Union.
At present, the synthesis report about Abiraterone acetic ester on document mainly contains two kinds.Method one: this route take trans-Dehydrorosterone acetate as starting raw material, 2,6-, bis--tertiary butyl-4-picoline makes alkali, first generates 3 with trifluoromethanesulfanhydride anhydride generation enol esterification
β-Acetoxyandrost-5,16-diene-17-triflate, and then at PdCl
2(PPh
3)
2catalysis under there is Suzuki coupling with diethyl (3-pyridyl)-borine and obtain Abiraterone acetic ester, two-step reaction total recovery 48.7%.This route is shorter, but in the first step enol esterification, acetoxyl group can occur to eliminate and generate androstane-3,5,16-triolefin-17-triflate by product, and this elimination by product not easily passs through recrystallization removing.Method two: this route with dehydroepiandros-sterone (DHEA) for starting raw material, first react with hydrazine hydrate under the catalysis of hydrazonium sulfate and generate dehydroepiandros-sterone 17-hydrazone, then tetramethyl guanidine makes alkali, is oxidized to 17-iodo-androstane-5 through iodine, 16-diene-3 β-ol d, then at PdCl
2(PPh
3)
2catalysis under there is Suzuki coupling with diethyl (3-pyridyl)-borine and obtain Abiraterone, finally 3 acetylating hydroxyl groups are obtained Abiraterone acetic ester, four-step reaction total recovery 41.5%.The weak point of this route is that Suzuki linked reaction required time is longer, the product Abiraterone of generation easily and raw material alkene iodine compound generate by product.
Summary of the invention
Technical problem to be solved by this invention is, provides a kind of new reaction route of Abiraterone acetic ester, this reaction scheme is short, mild condition, yield are high, raw material is easy to get.
For solving above technical problem, the synthetic method of Abiraterone acetic ester of the present invention, with trans-Dehydrorosterone acetate as shown in the formula (I) for raw material, through reduction, dehydration, Heck linked reaction obtained as shown in formula II Abiraterone acetic ester,
；
Reaction formula is as follows:
。
Further, the method specifically comprises following reactions steps:
(1), add trans-Dehydrorosterone acetate, aluminum isopropylate in reaction vessel, and add Virahol and toluene solvant, trans-Dehydrorosterone acetate and aluminum isopropylate carry out reduction reaction in a heated condition, and reaction terminates rear cooling;
(2), add siccative and the dehydration of discoloring agent reflux, then cool;
(3), 3-bromopyridine is added, palladium and triethylamine, reflux, and concentrated;
(4), column chromatography hexanaphthene: the mixed solvent of ethyl acetate (volume ratio)=5: 2 obtains product as developping agent separation and purification.
Further, Virahol consumption described in step (1) is 1:1 ~ 10(volume with the ratio of toluene consumption).
Further, the temperature of step (1) described reduction reaction is 50 ~ 150 DEG C, and the time is 1 ~ 15 hour.
Further, step (2) described siccative and discoloring agent are the mixture of molecular sieve or molecular sieve and diatomaceous mixture or molecular sieve and gac or the mixture of molecular sieve and diatomite and gac, and the quality consumption of siccative and discoloring agent with gram metering time for 5 ~ 30% when reaction solvent volumetric usage is measured with milliliter, when with kilogram, rise metering time, consumption expands in proportion, the like.
Further, when described siccative and discoloring agent are a kind of mixture in molecular sieve and diatomite or gac, the weight ratio of molecular sieve and diatomite or gac is 1: 1 ~ 3.
Further, described siccative and discoloring agent be molecular sieve, diatomite and gac three mixture time, its weight ratio is 1: 1 ~ 3: 1 ~ 3.
Compared with prior art, beneficial effect is embodied in technology of the present invention: this technology is easy to operate, and total recovery is high, and be a new synthetic technology route, safety, raw material is easy to get, and is conducive to suitability for industrialized production.
Embodiment
Embodiments of the invention 1:
Trans-Dehydrorosterone acetate 3.3g(10 mmol is added) in 250mL there-necked flask, aluminum isopropylate 2.5g(12 mmol), Virahol 10 mL, toluene 10 mL, reduction reaction is carried out 10 hours at 130 DEG C, suitable cooling adds molecular sieve 6g(simultaneously as siccative and discoloring agent) reflux dehydration, cooling adds 3-bromopyridine 1.6g(11 mmol again), palladium 0.3g(1.1 mmol), triethylamine 1.1g(1.1 mmol), reflux 15 hours, concentrated, column chromatography hexanaphthene: the mixed solvent of ethyl acetate (volume ratio)=5: 2 is as developping agent separation and purification, obtain product 2.34g, yield 60%.
Fusing point 128 ~ 130 DEG C.1H NMR (400 MHz, CDCl3) δ: 1.05 (s, 3H, 19-CH3), 1.08 (s, 3H, 18-CH3), 2.04 (s, 3H, CH3CO2), 3.51 ~ 3.58 (m, 1H, 3α-H), 5.39 (d, J=4.7 Hz, 1H, 6-H), 6.00 (s, 1H, 16-H)，7.22 (dd, J1=4.8 Hz, J2=7.8 Hz, 1H, Py 5-H), 7.66 (d, J=7.9 Hz, 1H, Py 4-H), 8.45 (d, J=4.6 Hz, 1H, Py 6-H), 8.62 (s, 1H, Py 2-H)。
Embodiments of the invention 2:
Trans-Dehydrorosterone acetate 3.3g(10 mmol is added) in 250mL there-necked flask, aluminum isopropylate 2.5g(12 mmol), Virahol 10 mL, toluene 50 mL, reduction reaction is carried out 15 hours at 50 DEG C, suitable cooling adds molecular sieve 1g, gac 2g(is simultaneously as siccative and discoloring agent) reflux dehydration, cooling adds 3-bromopyridine 1.6g(11 mmol again), palladium 0.3g(1.1 mmol), triethylamine 1.1g(1.1 mmol), reflux 15 hours, concentrated, column chromatography hexanaphthene: the mixed solvent of ethyl acetate (volume ratio)=5: 2 is as developping agent separation and purification, obtain product 2.34g, yield 60%.
Embodiments of the invention 3:
Trans-Dehydrorosterone acetate 3.3g(10 mmol is added) in 250mL there-necked flask, aluminum isopropylate 2.5g(12 mmol), Virahol 5mL, toluene 50 mL, reduction reaction is carried out 5 hours at 150 DEG C, suitable cooling adds molecular sieve 3g, diatomite 9g(is simultaneously as siccative and discoloring agent) reflux dehydration, cooling adds 3-bromopyridine 1.6g(11 mmol again), palladium 0.3g(1.1 mmol), triethylamine 1.1g(1.1 mmol), reflux 15 hours, concentrated, column chromatography hexanaphthene: the mixed solvent of ethyl acetate (volume ratio)=5: 2 is as developping agent separation and purification, obtain product 2.4g, yield 61%.
Embodiments of the invention 4:
Trans-Dehydrorosterone acetate 3.3g(10 mmol is added) in 250mL there-necked flask, aluminum isopropylate 2.5g(12 mmol), Virahol 10 mL, toluene 10 mL, reduction reaction is carried out 10 hours at 130 DEG C, suitable cooling adds molecular sieve 1g, both gac 3g(are all simultaneously as siccative and discoloring agent) reflux dehydration, cooling adds 3-bromopyridine 1.6g(11 mmol again), palladium 0.3g(1.1 mmol), triethylamine 1.1g(1.1 mmol), reflux 15 hours, concentrated, column chromatography hexanaphthene: the mixed solvent of ethyl acetate (volume ratio)=5: 2 is as developping agent separation and purification, obtain product 2.3g, yield 59%.
Embodiments of the invention 5:
Trans-Dehydrorosterone acetate 3.3g(10 mmol is added) in 250mL there-necked flask, aluminum isopropylate 2.5g(12 mmol), Virahol 5mL, toluene 50 mL, reduction reaction is carried out 5 hours at 110 DEG C, suitable cooling adds molecular sieve 1.5g, both diatomite 4g(are all simultaneously as siccative and discoloring agent) reflux dehydration, cooling adds 3-bromopyridine 1.6g(11 mmol again), palladium 0.3g(1.1 mmol), triethylamine 1.1g(1.1 mmol), reflux 15 hours, concentrated, column chromatography hexanaphthene: the mixed solvent of ethyl acetate (volume ratio)=5: 2 is as developping agent separation and purification, obtain product 2.4g, yield 61%.
Embodiments of the invention 6:
Trans-Dehydrorosterone acetate 3.3g(10 mmol is added) in 250mL there-necked flask, aluminum isopropylate 2.5g(12 mmol), Virahol 10mL, toluene 50 mL, reduction reaction is carried out 5 hours at 110 DEG C, suitable cooling adds molecular sieve 2g, diatomite 6g, gac 6g(three is all simultaneously as siccative and discoloring agent) reflux dehydration, cooling adds 3-bromopyridine 1.6g(11 mmol again), palladium 0.3g(1.1 mmol), triethylamine 1.1g(1.1 mmol), reflux 15 hours, concentrated, column chromatography hexanaphthene: the mixed solvent of ethyl acetate (volume ratio)=5: 2 is as developping agent separation and purification, obtain product 2.4g, yield 61%.
Above-mentioned embodiment is exemplary, being to better enable those skilled in the art understand the present invention, can not being interpreted as it is limiting the scope of the invention; As long as any equivalent change done by disclosed spirit or modification, all fall into the scope of protection of the invention.
Claims (7)
1. a synthetic method for Abiraterone acetic ester, is characterized in that the method with trans-Dehydrorosterone acetate as shown in the formula (I) for raw material, through reduction, dehydration, Heck linked reaction obtained as shown in formula II Abiraterone acetic ester,
。
2. the synthetic method of Abiraterone acetic ester according to claim 1, is characterized in that the method specifically comprises following reactions steps:
(1), add trans-Dehydrorosterone acetate, aluminum isopropylate in reaction vessel, and add the mixed solvent of Virahol and toluene, reduction reaction is carried out in heating, and reaction terminates rear cooling;
(2), add siccative and the dehydration of discoloring agent reflux, then cool;
(3), 3-bromopyridine is added, palladium and triethylamine, reflux, and concentrated;
(4), column chromatography hexanaphthene: the mixed solvent of ethyl acetate (volume ratio)=5: 2 obtains product as developping agent separation and purification.
3. the synthetic method of Abiraterone acetic ester according to claim 2, is characterized in that Virahol consumption described in step (1) is 1:1 ~ 10(volume with the ratio of toluene consumption).
4. the synthetic method of Abiraterone acetic ester according to claim 2, it is characterized in that the temperature of step (1) described reduction reaction is 50 ~ 150 DEG C, the time is 1 ~ 15 hour.
5. the synthetic method of Abiraterone acetic ester according to claim 2, it is characterized in that step (2) described siccative and discoloring agent are the mixture of molecular sieve or molecular sieve and diatomaceous mixture or molecular sieve and gac or the mixture of molecular sieve and diatomite and gac, and the quality consumption of siccative and discoloring agent with gram metering time for 5 ~ 30% when reaction solvent volumetric usage is measured with milliliter.
6. the synthetic method of Abiraterone acetic ester according to claim 5, when it is characterized in that described siccative and discoloring agent are a kind of mixture in molecular sieve and diatomite or gac, the weight ratio of molecular sieve and diatomite or gac is 1: 1 ~ 3.
7. the synthetic method of Abiraterone acetic ester according to claim 5, it is characterized in that described siccative and discoloring agent be molecular sieve, diatomite and gac three mixture time, its weight ratio is 1: 1 ~ 3: 1 ~ 3.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558274A (en) * | 2010-12-08 | 2012-07-11 | 深圳万乐药业有限公司 | Synthetic method applicable to industrial production of Abiraterone acetate |
| CN102627681A (en) * | 2012-03-23 | 2012-08-08 | 山东新时代药业有限公司 | Preparation method of abiraterone acetate |
| CN102816200A (en) * | 2012-09-05 | 2012-12-12 | 中山大学 | Method for preparing abiraterone acetate |
| WO2013030410A2 (en) * | 2011-12-23 | 2013-03-07 | Crystal Pharma, S.A.U. | Synthesis of abiraterone and related compounds |
| CN103193849A (en) * | 2012-01-04 | 2013-07-10 | 连云港润众制药有限公司 | Preparation method of high-purity abiraterone acetate |
| CN103360458A (en) * | 2012-03-26 | 2013-10-23 | 信泰制药（苏州）有限公司 | Synthesis method of abiraterone |
-
2014
- 2014-11-18 CN CN201410654955.9A patent/CN104370991B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558274A (en) * | 2010-12-08 | 2012-07-11 | 深圳万乐药业有限公司 | Synthetic method applicable to industrial production of Abiraterone acetate |
| WO2013030410A2 (en) * | 2011-12-23 | 2013-03-07 | Crystal Pharma, S.A.U. | Synthesis of abiraterone and related compounds |
| CN103193849A (en) * | 2012-01-04 | 2013-07-10 | 连云港润众制药有限公司 | Preparation method of high-purity abiraterone acetate |
| CN102627681A (en) * | 2012-03-23 | 2012-08-08 | 山东新时代药业有限公司 | Preparation method of abiraterone acetate |
| CN103360458A (en) * | 2012-03-26 | 2013-10-23 | 信泰制药（苏州）有限公司 | Synthesis method of abiraterone |
| CN102816200A (en) * | 2012-09-05 | 2012-12-12 | 中山大学 | Method for preparing abiraterone acetate |
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