- Nucleophilic Aromatic Substitution of Methacrylamide Anion and Its Application to the Synthesis of the Anticancer Drug Bicalutamide
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The anticancer drug (R,S)-biscaltamide was prepared in three steps in >90% overall yield. A key step in the new synthesis involved a new nucleophilic aromatic substitution reaction of methacrylamide anion.
- Chen, Bang-Chi,Zhao, Rulin,Gove, Stacey,Wang, Bei,Sundeen, Joseph E.,Salvati, Mark E.,Barrish, Joel C.
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- Chemical degradation of androgen receptor (Ar) using bicalutamide analog–thalidomide protacs
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A series of PROTACs (PROteolysis-TArgeting Chimeras) consisting of bicalutamide analogs and thalidomides were designed, synthesized, and biologically evaluated as novel androgen receptor (AR) degraders. In particular, we found that PROTAC compound 13b could successfully demonstrate a targeted degradation of AR in AR-positive cancer cells and might be a useful chemical probe for the investigation of AR-dependent cancer cells, as well as a potential therapeutic candidate for prostate cancers.
- Kim, Ga Yeong,Song, Chae Won,Yang, Yo-Sep,Lee, Na-Rae,Yoo, Hyung-Seok,Son, Seung Hwan,Lee, Soo Jin,Park, Jong Seon,Lee, Jong Kil,Inn, Kyung-Soo,Kim, Nam-Jung
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- Preparation method of bicalutamide thioether intermediate
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The invention relates to a preparation method of a bicalutamide thioether intermediate, and relates to the synthesis of chemical drugs, in particular to a preparation method of N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[4-fluorophenylthio]-2-hydroxy-2-methylpropionamide. According to the method, a lower fatty acid ester is taken as a solvent, an alkali metal salt of a lower aliphatic alcohol is taken as a catalyst, 4-fluorothiophenol first reacts with the alkali metal salt of the lower aliphatic alcohol to generate 4-fluorfenthiolate, then N-[4-cyano-3-(trifluoromethyl)phenyl]-1,2-epoxy-2-methylpropionamide is added into 4-fluorfenthiolate for a reaction at room temperature, and a finished product is obtained after separation and purification. The preparation method provided by the inventionis mild in reaction conditions, the use of high-risk sodium hydride and expensive tetrahydrofuran is avoided, and a reaction solvent can also be recycled and reused, thereby reducing cost and reducing emissions.
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Paragraph 0018; 0020-0026
(2019/02/26)
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- Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer
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Prostate cancer (PC) is one of the major causes of male death worldwide and the development of new and more potent anti-PC compounds is a constant requirement. Among the current treatments, (R)-bicalutamide and enzalutamide are non-steroidal androgen receptor antagonist drugs approved also in the case of castration-resistant forms. Both these drugs present a moderate antiproliferative activity and their use is limited due to the development of resistant mutants of their biological target. Insertion of fluorinated and perfluorinated groups in biologically active compounds is a current trend in medicinal chemistry, applied to improve their efficacy and stability profiles. As a means to obtain such effects, different modifications with perfluoro groups were rationally designed on the bicalutamide and enzalutamide structures, leading to the synthesis of a series of new antiproliferative compounds. Several new analogues displayed improved in vitro activity towards four different prostate cancer cell lines, while maintaining full AR antagonism and therefore representing promising leads for further development. Furthermore, a series of molecular modelling studies were performed on the AR antagonist conformation, providing useful insights on potential protein-ligand interactions.
- Bassetto, Marcella,Ferla, Salvatore,Pertusati, Fabrizio,Kandil, Sahar,Westwell, Andrew D.,Brancale, Andrea,McGuigan, Christopher
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supporting information
p. 230 - 243
(2016/05/10)
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- Auto-oxidative hydroxysulfenylation of alkenes
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One-pot auto-oxidation mediated hydroxysulfenylation of electron-deficient and electron-rich olefins with phenthiols was explored. The method illustrates a selective and convenient synthesis of complex β-hydroxysulfides using O2 as both the oxidant and the oxygen source under mild transition-metal-free conditions. The application of this new methodology to the gram-scale synthesis of anti-cancer drug bicalutamide has been accomplished in a two-step sequence with 71% overall yield. A plausible radical involved mechanism is proposed.
- Huo, Congde,Wang, Yajun,Yuan, Yong,Chen, Fengjuan,Tang, Jing
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p. 7233 - 7236
(2016/06/09)
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- Hydroxysulfenylation of electron-deficient alkenes through an aerobic copper catalysis
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A copper-catalyzed hydroxysulfenylation of α,β-unsaturated esters/amides is reported. The method presents a selective and efficient synthesis of β-hydroxysulfides bearing electron-withdrawing groups. The synthetic utility of this method is demonstrated by the concise synthesis of the anticancer drug bicalutamide.
- Xi, Hui,Deng, Bicheng,Zong, Zhenzhen,Lu, Shenglin,Li, Zhiping
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supporting information
p. 1180 - 1183
(2015/03/14)
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- PROCESS FOR PREPARING BICALUTAMIDE
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The present invention provide processes for the preparation of N-[4-Cyano-3-(trifluoro methyl)phenyl]-3-[(4-fluorophenyl)sulphonyl]-2-hydroxy-2-methyl propanamide (I). The present application also provides a method of purification of N-[4-Cyano-3-(trifluoro methyl)phenyl]-3-[(4-fluorophenyl)sulphonyl]-2-hydroxy-2-methyl propanamide (I) using ethyl acetate solvent resulting in the product, substantially free from process related impurities A, B, C and D. The crystalline product of the process according to the present invention having an XRDP pattern as per FIG. 1, is useful as an active pharmaceutical and has anti-androgenic activity.
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Paragraph 0107; 0108; 0109
(2013/10/22)
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- Mechanistic studies on the synthesis of bicalutamide
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Bicalutamide, a therapeutically important anti-androgen used in the treatment of hormone-sensitive cancers, may be synthesised from the appropriate halohydrin or epoxide. We report here studies aimed at demonstrating unambiguously that preparation of bica
- Asaad, Nabil,Fillery, Shaun
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body text
p. 678 - 686
(2009/06/19)
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- Process for production of bicalutamide
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A process which includes the reacting of sodium perborate with N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methylpropanamide to form bicalutamide. The process is efficient, inexpensive, environmentally friendly and produces bicalutamide in good yield.
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Page/Page column 2; 4
(2010/11/25)
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- A process for the preparation and purification of bicalutamide
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The invention relates to a process for the preparation of bicalutamide (I) which comprises oxidizing N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methyl-propanamide (II) in a solution of peracetic acid in acetic acid and an aromatic solvent. The preparation of (II) from 4-fluorothiophenol and 4-cyano-N-(2,3-epoxy-2-methylpropionyl)-3-trifluoromethylaniline is also disclosed.
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Page/Page column 5
(2008/06/13)
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- PROCESS FOR PRODUCING BICALUTAMIDE AND METHOD OF PURIFYING INTERMEDIATE THEREFOR
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The present invention provides a process for producing bicartamide of the formula (4); which comprises Step A comprising reacting Compound (1) of the formula (1); with peroxycarboxylic acid to obtain Compound (2) of the formula (2); Step B comprising reacting said Compound (2) with 4-fluorothiophenol to obtain crude crystals of Compound (3) of the formula (3); dissolving the crude crystals in a solvent and crystallizing to obtain purified crystals of Compound (3), andStep C comprising reacting Compound (3) and percarboxylic acid to obtain bicalutamide, and also provides a method for purifying crystals of Compound (3) which comprises dissolving crude crystals of Compound (3) in a solvent and crystallizing.
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Page/Page column 11; 12-13
(2008/06/13)
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- Improved procedure for the synthesis of bicalutamide
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The object of the invention is an improved procedure for the synthesis of bicalutamide, characterised in that the 2-hydroxy-2-methyl-3-(4-fluorophenylthio) propionic acid initially produced undergoes a step to acylate the hydroxyl group in position 2 to give an intermediate 2-acyloxy-2-methyl-3-(4-fluorophenylthio) propionic acid, which allows the formation of a successive N-[4-cyano-3-(trifluoromethyl)-phenyl-]-3-[4-fluorophenylthio]-2-acyloxy-2-methyl-propionamide intermediate.
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Page/Page column 7
(2008/06/13)
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- Procedure for the synthesis of bicalutamide
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The object of the invention is an improved procedure for the synthesis of bicalutamide, characterised in that the 2-hydroxy-2-methyl-3-(4-fluorophenylthio) propionic acid initially produced undergoes a step to acylate the hydroxyl group in position 2 to give an intermediate 2-acyloxy-2-methyl-3-(4-fluorophenylthio) propionic acid, which allows the formation of a successive N-[4-cyano-3-(trifluoromethyl)-phenyl-]-3-[4-fluorophenylthio]-2-acyloxy-2-methyl-propionamide intermediate.
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Page/Page column 4; 6
(2010/10/19)
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- Crystal of bicalutamide and production method thereof
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The present invention relates to a crystal of bicalutamide having a defined form, as well as economical and industrially practical production methods of bicalutamide and a crystal thereof, which are superior in environmental benignity and safety. Accordingly, the present invention provides a production method of bicalutamide represented by the formula (I): which includes at least a step of reacting a compound represented by the formula (3): with an oxidizing agent, a production method of a crystal of bicalutamide, as well as a crystal form of bicalutamide as defined by X-ray diffraction (XRD) or solid 13C NMR measurement.
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Page/Page column 5; 11
(2008/06/13)
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- PROCESS FOR THE SYNTHESIS OF N-(4-CYANO-3-TRIFLUOROMETHYLPHENYL)-3-(4-FLUOROPHENYLSULPHONYL)-2-HYDROXY-2-METHYLPROPIONAMIDE
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A new process is disclosed for the synthesis of racemic or optically pure N-[4-cyano-3-trifluoro-methyl-phenyl]-3[4-fluorophenyl-sulfonyl]-2-hydroxy-2-methylpropionamide. The process includes the formation of several novel intermediates in the synthesis.
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- Methods of asymmetrically synthesizing enantiomers of Casodex, its derivatives and intermediates thereof
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Methods of synthesizing pure enantiomers of acylanalides such as Casodex? (bicalutamide) and its derivatives utilizing a compound having a ring structure that, when opened, provides a substituent having the structure of Formula I: wherein R1is alkyl or haloalkyl having up to 4 carbons; R2is alkyl having up to 6 carbon atoms; and R3is CH2OR4where R4is hydrogen or benzyl, C(O)CH3, or C(O)OR5where R5is hydrogen or alkyl; are disclosed. Methods of synthesizing acylanalides such as Casodex? (bicalutamide) and/or derivatives thereof from a starting material of citramalic acid are also provided.
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- Process for the preparation of N-(substituted phenyl)-3-alkyl-,aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl-and haloalkylpropanamide compounds
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The present invention provides an improved process for the preparation of N-(substituted phenyl)-3-alkyl-, aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds of formula I The formula I compounds exhibit antiandrogenic activity and are useful in the treatment of malignant or benign pro static disease or of androgen dependent disease conditions such as acne, hirsutism or seborrhoea.
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- Method of treatment for prostatic cancer
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Disclosed is a new treatment for men with prostatic cancer involving combination therapy of a 5α-reductase inhibitor, i.e., a 17β-substituted 4-azasteroid, a 17β-substituted non-azasteroid, 17β-acyl-3-carboxyandrost-3,5-diene, benzoylaminophenoxybutanoic acid derivative, fused benz(thio)amide or cinnamoylamide derivative, aromatic 1,2-diethers or thioethers, aromatic ortho acylaminophenoxy alkanoic acids, ortho thioalkylacylamino-phenoxy alkanoic acids, pharmaceutically acceptable salts and esters thereof, and particularly finasteride, in combination with an antiandrogen, i.e. flutamide. Pharmaceutical compositions useful for treatment are also disclosed.
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- Nonsteroidal antiandrogens. Synthesis and structure-activity relationship of 3-substituted derivatives of 2-hydroxypropionanilides
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A series of 3-(substituted thio)-2-hydroxypropionanilides and some corresponding sulfones and sulfoxides of general structure 7, in which R' is methyl or trifluoromethyl, were prepared and tested for antiandrogen activity. Members of the trifluoromethyl series (7,R' = CF3) generally exhibited partial androgen agonist activity whereas the members of the methyl series (7,R' = CH3) were pure antagonists. Lead optimization in the methyl series has led to the discovery of novel, potent antiandrogens, which are peripherally selective. One of these, (RS)-4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'-(trifd luoromethyl)propionanilide, 40 (ICI 176334), is being developed currently for the treatment of androgen-responsive benign and malignant disease.
- Tucker,Crook,Chesterson
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p. 954 - 959
(2007/10/02)
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- AMIDE DERIVATIVES
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Acylanilides of the formula wherein R1 and R2, the same or different, each is cyano, carbamoyl, nitro, halogeno, perfluoroalkyl or other defined substituents; R3 is hydrogen or halogen; R4 is hydrogen or alkyl, or is joined to R5; R5 is hydrogen, hydroxy, alkoxy or acyloxy or is joined to R4; R6 is alkyl or halogenoalkyl, or has the formula ?A-3-R8 or -A4-X2-A5-R9. A1 and A4, the same or different, each is alkylene; A2, A3 and A5, the same or different, each is a direct link or alkylene; X1 and X2, the same or different, each is oxygen, sulphur, sulphinyl, sulphonyl, imino or alkylimino; R7 and R9, the same or different, each is alkyl, alkenyl, hydroxyalkyl, cycloalkyl, phenyl optionally substituted, naphthyl or heterocyclic optionally substituted; and R8 is phenyl, naphthyl or heterocyclic as defined above for R7 or R9; processes for their manufacture and pharmaceutical compositions containing them. The acylanilides possess antiandrogenic activity
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