A kind of preparation method of abiraterone acetasTechnical field
The present invention relates to a kind of method preparing abiraterone acetas, belong to technical field of medicine synthesis.
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；Its structure is as follows:
Research shows, abiraterone acetas and prednisone (Prednisone) coupling may be used for classical hormonal is treated the transitivity advanced prostate cancer of drug resistance, 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.There are some researches show, for repellence, advanced metastatic prostate cancer patients uses effective in cure 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, route is long, cost is high, yield is low, there is very big problem in three wastes aspect, specifically how improves chemo-selective and purification, and 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 main technical schemes:
The preparation method of a kind of abiraterone acetas, comprises the steps:
A) Dehydroepiandrosterone Acetate and 3-chloropyridine Grignard reagent are when ether is solvent, condensation reaction occurs, obtains abiraterone acetas crude product through Dehydration；
B) abiraterone acetas crude product does solvent, hydrolyzed under basic conditions at methanol, prepares 17-(3-pyridine radicals)-androstane-4,16-diene-3 β-ol；
C) 17-(3-pyridine radicals)-androstane-4,16-diene-3 β-ol recrystallization；
D) 17-(3-pyridine radicals)-androstane-4,16-diene-3 β-ol prepares abiraterone acetas with excess acetyl chloride.
Raw material Dehydroepiandrosterone Acetate and the molar ratio of 3-chloropyridine Grignard reagent that described step a) reacts are 1: 1-2, it is preferable that 1: 1.0-1.1.
The temperature that described step a) reacts is-10 DEG C～20 DEG C, it is preferable that 0 DEG C.
The dehydrant that described step a) dehydration uses is preferred with burgess reagent.
The alkalescence of described step b) hydrolyzed under basic conditions is inorganic base, it is preferable that sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydroxide, Lithium hydrate, it is preferable that sodium hydroxide, potassium hydroxide, Lithium hydrate.
The recrystallization solvent of described step c) is isopropanol.
The solvent of described step d) is dichloromethane.
Specifically,
The preparation method of a kind of abiraterone acetas, adopts following steps:
Dehydroepiandrosterone Acetate is dissolved in solvent ether, it is cooled to 0 DEG C, dropping 3-bromopyridine Grignard reagent is dripped complete, rise to room temperature reaction 18h, then with saturated aqueous ammonium chloride cancellation reaction, remove solvent, with dichloromethane extraction three times, merge organic layer, remove dichloromethane, prepare abiraterone acetas crude product；
Being dissolved in methanol by abiraterone acetas crude product, add sodium hydrate aqueous solution, filter after room temperature reaction 2h, filter cake is washed with water to neutrality, dry prepared 17-(3-pyridine radicals)-androstane-4,16-diene-3 β-ol；
17-(3-pyridine radicals)-androstane-4,16-diene-3 β-ol recrystallisation from isopropanol；
By 17-(3-pyridine radicals)-androstane-4 after recrystallization, 16-diene-3 β-ol adds in dichloromethane, adds appropriate triethylamine, adding chloroacetic chloride, temperature rising reflux reacts, and reacts complete, the cancellation that adds water is reacted, and separatory uses dichloromethane extraction water layer, merge organic layer, dry with anhydrous sodium sulfate, filter, concentrating under reduced pressure, pulls an oar with normal heptane, filters, dry, to obtain final product.
Technique effect:
The present invention adopts grignard reagent reaction to prepare abiraterone acetas crude product, then 17-(3-pyridine radicals)-androstane-4 it is hydrolyzed to obtain, 16-diene-3 β-ol, adds excess acetyl chloride afterwards and prepares abiraterone acetas sterling, and reactions steps is short, yield is high, high purity more than 99.5%, 17-(3-pyridine radicals)-androstane-4 in end-product, 16-diene-3 β-ol content is lower than 0.1%, and the present invention does not use the raw material that toxicity is big, and the solvent used can synchronize to reclaim；The present invention is simple to operate, and reaction condition is gentle, and equipment requirements is low, it is easy to large-scale production, has significance industrial application value.
Detailed description of the invention
In conjunction with embodiment, the present invention is described in further detail and completely, but and non-limiting the scope of the present invention.
Embodiment 1: compound B synthesizes
30g (0.091mol) compound A is dissolved in 300ml ether, 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, ether 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%.
Embodiment 2: the synthesis of compound C
20g (0.051mol) compound B is dissolved in 100ml methanol, 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%.
Embodiment 3: 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%.
Embodiment 4: 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 9.7g abiraterone acetas, yield 89.8%, purity 99.6%, in end-product, compound C content is lower 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 5-7 is according to following parameter experiment, and all the other are with reference to embodiment 1-4 corresponding steps.
The end-product that embodiment 5-9 prepares is through structural confirmation, identical with the abiraterone acetas (target compound B) that embodiment 4 prepares.The present invention prepares abiraterone acetas, and yield is high, and purity is more than 99.5%, and in end-product, the content of compound C is lower than 0.1%, and single impurity is less than 0.1%.The present invention does not use the raw material that toxicity is big, and the solvent used can synchronize to reclaim；The present invention is simple to operate, and reaction condition is gentle, and equipment requirements is low, it is easy to large-scale production, has significance industrial application value.