154229-18-2Relevant articles and documents
Improved procedure for preparation of abiraterone acetate
Madhra, Mukesh Kumar,Sriram, Hari Mohan,Inamdar, Murad,Sharma, Mukesh Kumar,Prasad, Mohan,Joseph, Sony
, p. 555 - 558 (2014)
An improved procedure for the preparation of abiraterone acetate is described. The present process highlights reduced reaction time, isolation with acid-base treatment without involving column chromatography, multiple crystallization and is amenable to la
Synthesis of the anti-prostate cancer drug abiraterone acetate
Ma, Siyue,Li, Jianheng,Tang, Huayang,Xu, Feng
, p. 461 - 469 (2018)
Abiraterone acetate is used for the treatment of castration-resistant prostate cancer. Abiraterone acetate was synthesized from dehydroepiandrosterone via a three-step reaction including the formation of tosylhydrazone, cross-coupling reaction and acetylation, and a two-step purification including column chromatography and recrystallization with an overall yield of 51.9%. Here, an improved procedure for the preparation of abiraterone acetate is described. This synthetic process is of easy operation and low cost, which is suitable for industrialization.
Application of trifluoromethanesulfonate in preparation of abiraterone acetate and synthesis method of trifluoromethanesulfonate
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Paragraph 0036-0045, (2021/06/12)
The invention particularly relates to application of trifluoromethanesulfonate in preparation of abiraterone acetate and a synthesis method. The invention provides a novel method for synthesizing abiraterone acetate. According to the method, a trifluoromethanesulfonate, such as iron trifluoromethanesulfonate and scandium trifluoromethanesulfonate, is adopted as a catalyst, isopropenyl acetate is adopted as an acylation reagent, and acetylation is carried out on the 3-site hydroxyl of abiraterone to synthesize abiraterone acetate. The method is simple to operate and high in product yield, and the use of irritant acetylation reagents such as acetic anhydride and acetyl chloride and chemical amounts of basic groups such as pyridine and triethylamine is avoided.
Synthetic method of abiraterone acetate and intermediate thereof (by machine translation)
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, (2021/01/04)
The invention relates to a synthesis method of abiraterone acetate and a dragon intermediate thereof. In the synthesis method of abiraterone acetate intermediate, a compound of formula (I), a chloro reagent and a base are chlorinated to obtain the abiraterone acetate intermediate of formula (II). The mass ratio of the compound of the formula (I) to the base is 1: (1.5 -3). The structure of the compound of formula (I) and abiraterone acetate is as follows. To the synthesis method, the occurrence probability of side reactions in the chlorination reaction process can be reduced while the high reaction activity is maintained, so that the yield and purity of the abiraterone acetate intermediate can be improved, and the process is simple. (by machine translation)
Slow-, tight-binding inhibition of CYP17A1 by abiraterone redefines its kinetic selectivity and dosing regimen
Cheong, Eleanor Jing Yi,Nair, Pramod C.,Neo, Rebecca Wan Yi,Tu, Ho Thanh,Lin, Fu,Chiong, Edmund,Esuvaranathan, Kesavan,Fan, Hao,Szmulewitz, Russell Z.,Peer, Cody J.,Figg, William D.,Chai, Christina Li Lin,Miners, John O.,Chan, Eric Chun Yong
, p. 438 - 451 (2020/09/04)
Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex. The in vitro inhibition constant of the final high-affinity CYP17A1-abiraterone complex ( ( Ki? = 0.39 nM )yielded a binding free energy of -12.8 kcal/mol that was quantitatively consistent with the in silico prediction of 214.5 kcal/mol. Prolonged suppression of dehydroepiandrosterone (DHEA) concentrations observed in VCaP cells after abiraterone washout corroborated its protracted CYP17A1 engagement. Molecular dynamics simulations illuminated potential structural determinants underlying the rapid reversible binding characterizing the two-step induced-fit model. Given the extended residence time (42 hours) of abiraterone within the CYP17A1 active site, in silico simulations demonstrated sustained target engagement even whenmost abiraterone has been eliminated systemically. Subsequent pharmacokineticpharmacodynamic (PK-PD) modeling linking time-dependent CYP17A1 occupancy to in vitro steroidogenic dynamics predicted comparable suppression of downstream DHEA-sulfate at both 1000- and 500-mg doses of abiraterone acetate. This enabled mechanistic rationalization of a clinically reported PK-PD disconnect, inwhich equipotent reduction of downstreamplasma DHEAsulfate levels was achieved despite a lower systemic exposure of abiraterone. Our novel findings provide the impetus for reevaluating the current dosing paradigmof abiraterone with the aim of preserving PD efficacy while mitigating its dose-dependent adverse effects and financial burden. SIGNIFICANCE STATEMENT With the advent of novel molecularly targeted anticancer modalities, it is becoming increasingly evident that optimal dose selection must necessarily be predicated on mechanistic characterization of the relationships between target exposure, drug-target interactions, and pharmacodynamic endpoints. Nevertheless, efficacy has always been perceived as being exclusively synonymous with affinity-based measurements of drug-target binding. This work demonstrates how elucidating the slow-, tight-binding inhibition of CYP17A1 by abiraterone via in vitro and in silico analyses was pivotal in establishing the role of kinetic selectivity in mediating time-dependent CYP17A1 engagement and eventually downstream efficacy outcomes.
Method for preparing abiraterone acetate
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, (2020/07/14)
The invention provides a method for preparing abiraterone acetate. Specifically, the invention relates to an improved method for synthesizing abiraterone or a derivative thereof through a key 3 beta-benzoyloxy intermediate. According to the process, intermediate DHEA 3-benzoyloxy ester is a solid, the intermediate with higher purity can be obtained through a crystallization method, and the processoperability is high. Meanwhile, benzoyl is strong in electric negative force, easy to react with hydroxyl and high in acylation rate, and a six-membered ring structure is twisted in a space structureof a benzoyl functional group, so that elimination reaction is not easy to perform, and generation of process byproducts is effectively avoided.
Abiraterone acetate preparation method
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Paragraph 0025-0039, (2020/03/06)
The invention provides an abiraterone acetate preparation method, which comprises: dissolving 17-iodoandrosta-5,16-dien-3 beta-hydroxyl and 3-pyridine zinc neopentanoate in an organic solvent, reacting at 50-80 DEG C for 3-12 h under the catalysis of a palladium catalyst, removing the solvent after the reaction is finished, and esterifying with acetic anhydride to obtain an abiraterone acetate product. According to the invention, the method overcomes the defects of expensive raw materials, high cost, harsh reaction conditions and the like in the prior art, is low in cost, mild in preparation conditions, simple and convenient in production method and suitable for industrial production, and has high application value.
Preparation method of abiraterone acetate
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Paragraph 0033-0035, (2019/05/15)
The invention provides a preparation method of abiraterone acetate: dissolving an alkenyl iodide (17-iodoandrostane-5,16-diene-3[beta]-acetate or 17-iodoandrostane-5,16-diene-3[beta]-hydroxyl), a compound (I), an aryl boride (diethyl(3-pyridyl)borane), a compound (II), pyridine-3-boronic acid or pyridine-3-boronic acid pinacol ester, an alkaline substance, and a Pd/C catalyst in an organic solvent, and performing a reaction at 60-120 DEG C for 3-12 h; after the reaction is finished, carrying out post-treatment on the reaction liquid to obtain the abiraterone acetate and recycling the Pd catalyst; wherein the compound (I) and compound (II) are represented as the formulas as follows. The method is high in yield, is less in impurity and has convenience of recycling the noble metal catalyst and obtaining raw materials, is simple in operation, is available to industrial production, and has great application value.
Abiraterone acetate preparation method
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, (2018/07/30)
The invention discloses an abiraterone acetate preparation method, and particularly provides an abiraterone acetate preparation process. In the prior art, the preparation process comprises a palladiumcatalyzed coupling reaction, the palladium catalyzed reaction can cause the pollution on the reaction product, and palladium is difficultly separated from the target product. According to the presentinvention, palladium is removed with the substituted phosphine-containing compound so as to effectively control the palladium residue.
Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2
Fehl, Charlie,Vogt, Caleb D.,Yadav, Rahul,Li, Kelin,Scott, Emily E.,Aubé, Jeffrey
, p. 4946 - 4960 (2018/06/20)
Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects.
