- Preparation method of (R)-bicalutamide intermediate
-
The invention relates to a method for preparing an (R)-bicalutamide intermediate. The method comprises the following steps: taking methacrylic acid as a raw material, and obtaining the (R)-bicalutamide intermediate through several steps of esterification, hydroxylation and sulfonation, namely, (R)-3-(4-fluorophenylsulfydryl)-2-hydroxy-2-methylpropionic acid. (R)-bicalutamide with enantioselectivity of more than 99% can be obtained by two simple follow-up reactions of the intermediate. The preparation method has the advantages of easily available starting materials, high reaction yield, easy operation in reaction, high enantioselectivity and wide industrial application prospects.
- -
-
Paragraph 0068-0070
(2021/04/21)
-
- Meta -Non-flat substituents: A novel molecular design to improve aqueous solubility in small molecule drug discovery
-
Aqueous solubility is a key requirement for small-molecule drug candidates. Here, we investigated the regioisomer-physicochemical property relationships of disubstituted benzenes. We found that meta-isomers bearing non-flat substituents tend to possess the lowest melting point and the highest thermodynamic aqueous solubility among the regioisomers. The examination of pharmaceutical compounds containing a disubstituted benzene moiety supported the idea that the introduction of a non-flat substituent at the meta position of a benzene substructure would be a promising approach for medicinal chemists aiming to improve the thermodynamic aqueous solubility of drug candidates, even though it might not be universally effective. This journal is
- Ichikawa, Yuki,Hiramatsu, Michiaki,Mita, Yusuke,Makishima, Makoto,Matsumoto, Yotaro,Masumoto, Yui,Muranaka, Atsuya,Uchiyama, Masanobu,Hashimoto, Yuichi,Ishikawa, Minoru
-
supporting information
p. 446 - 456
(2021/01/29)
-
- Palladium-catalyzed substitution of allylic alcohols with sulfinate salts: A synthesis of bicalutamide
-
A method is presented for the direct substitution of allylic alcohols with sodium arylsulfinates. The process involves a cooperative action of palladium catalysts, phenylboronic acid and titanium tetraisopropoxide. By taking advantage of this protocol, we achieved a concise synthesis of bicalutamide, an anti-androgen compound for treating prostate cancer.
- Jhang, Yin-Jia,Chang, Chieh-Yu,Lin, Yu-Huan,Lee, Chein-Chung,Wu, Yen-Ku
-
supporting information
(2021/05/04)
-
- Synthesis of Sulfones and Sulfonyl Derivatives using Sodium (tert-butyldimethylsilyl)oxymethanesulfinate
-
The present invention relates to a method for manufacturing a sulfone and sulfonyl derivative compound using sodium (tert-butyldimethylsilyl)oxymethanesulfinate, which is a novel organic sulfin salt, wherein the novel organic sulfin salt has good stability, environmental friendliness and economy, and is easy to handle, and thus significantly reduces the amount of transition metal catalysts and the amount of organic sulfin salts used when introducing aryl or alkenyl. Also, alkylation, arylation, amination, and fluorination are all possible during secondary functionalization. Therefore, the present invention can be usefully used in preparation and mass production of various kinds of sulfones and derivatives thereof including asymmetric sulfone derivatives.
- -
-
Paragraph 0505-0506; 0508-0514
(2021/04/29)
-
- Preparation of a novel bridged bis(β-cyclodextrin) chiral stationary phase by thiol-ene click chemistry for enhanced enantioseparation in HPLC
-
A bridged bis(β-cyclodextrin) ligand was firstly synthesized via a thiol-ene click chemistry reaction between allyl-ureido-β-cyclodextrin and 4-4′-thiobisthiophenol, which was then bonded onto a 5 μm spherical silica gel to obtain a novel bridged bis(β-cyclodextrin) chiral stationary phase (HTCDP). The structures of HTCDP and the bridged bis(β-cyclodextrin) ligand were characterized by the 1H nuclear magnetic resonance (1H NMR), solid state 13C nuclear magnetic resonance (13C NMR) spectra spectrum, scanning electron microscope, elemental analysis, mass spectrometry, infrared spectrometry and thermogravimetric analysis. The performance of HTCDP in enantioseparation was systematically examined by separating 21 chiral compounds, including 8 flavanones, 8 triazole pesticides and 5 other common chiral drugs (benzoin, praziquantel, 1-1′-bi-2-naphthol, Tr?ger's base and bicalutamide) in the reversed-phase chromatographic mode. By optimizing the chromatographic conditions such as formic acid content, mobile phase composition, pH values and column temperature, 19 analytes were completely separated with high resolution (1.50-4.48), in which the enantiomeric resolution of silymarin, 4-hydroxyflavanone, 2-hydroxyflavanone and flavanone were up to 4.34, 4.48, 3.89 and 3.06 within 35 min, respectively. Compared to the native β-CD chiral stationary phase (CDCSP), HTCDP had superior enantiomer separation and chiral recognition abilities. For example, HTCDP completely separated 5 other common chiral drugs, 2 flavanones and 3 triazole pesticides that CDCSP failed to separate. Unlike CDCSP, which has a small cavity (0.65 nm), the two cavities in HTCDP joined by the aryl connector could synergistically accommodate relatively bulky chiral analytes. Thus, HTCDP may have a broader prospect in enantiomeric separation, analysis and detection. This journal is
- Gong, Bolin,Guo, Siyu,Zhang, Ning
-
p. 35754 - 35764
(2021/12/02)
-
- Silyloxymethanesulfinate as a sulfoxylate equivalent for the modular synthesis of sulfones and sulfonyl derivatives
-
An efficient protocol for the modular synthesis of sulfones and sulfonyl derivatives has been developed utilizing sodium tert-butyldimethylsilyloxymethanesulfinate (TBSOMS-Na) as a sulfoxylate (SO22-) equivalent. TBSOMS-Na, easily prepared from the commercial reagents Rongalite and TBSCl, serves as a potent nucleophile in S-alkylation and Cu-catalyzed S-arylation reactions with alkyl and aryl electrophiles. The sulfone products thus obtained can undergo the second bond formation at the sulfur center with various electrophiles without a separate unmasking step to afford sulfones and sulfonyl derivatives such as sulfonamides and sulfonyl fluorides.
- Kim, Dae-Kwon,Um, Hyun-Suk,Park, Hoyoon,Kim, Seonwoo,Choi, Jin,Lee, Chulbom
-
p. 13071 - 13078
(2021/01/09)
-
- Synthetic method for bicalutamide
-
The invention relates to the synthesis of a chemical drug and in particular to a synthetic method for bicalutamide. The method comprises the following steps: using low-grade aliphatic ketone as a solvent, using hydrogen peroxide as an oxidizing agent, and using potassium persulfate compound salt as a catalyst, oxidizing 4-cyano-3-(trifluoromethyl)phenyl]-3-[4-fluorobenzesulfur]-2-hydroxy-2-methylpropanamide as the bicalutamide. The method is capable of avoiding using high-explosive peroxy acid, short in reaction time, high in efficiency, small in reaction solvent toxicity, moderate in reactiontemperature, simple in operation, and high in yield, can be recycled and reused, and is capable of reducing cost and reducing emission.
- -
-
Paragraph 0026
(2019/02/21)
-
- Nickel(II)-Catalyzed Synthesis of Sulfinates from Aryl and Heteroaryl Boronic Acids and the Sulfur Dioxide Surrogate DABSO
-
We report a redox-neutral Ni(II)-catalyzed sulfination of readily available aryl and heteroaryl boronic acids. Using the combination of commercially available, air-stable NiBr2·(glyme), a commercially available phenanthroline ligand, and DABSO, boronic acids are efficiently converted to the corresponding sulfinate salts, which can be further elaborated to valuable sulfonyl-containing groups, including sulfones, sulfonamides, sulfonyl fluorides, and sulfonate esters. The catalyst loading can be reduced to 2.5 mol ?% on a gram scale. This practically simple protocol tolerates an unprecedented range of pharmaceutically relevant and electron-poor (hetero)aryl boronic acids, allowing the direct synthesis of active pharmaceutical ingredients.
- Lo, Pui Kin Tony,Chen, Yiding,Willis, Michael C.
-
p. 10668 - 10673
(2019/11/11)
-
- Bicalutamide synthesis method
-
The invention provides a new method for synthesizing an antitumor drug bicalutamide. The method comprises: taking N-(4-cyano-3-(trifluoromethyl)phenyl) methacrylamide and fluorothiophenol as raw materials, and reacting in an organic solvent under the air or oxygen atmosphere to generate a bicalutamide sulfoxide intermediate; adding an oxidizing agent to oxidize the bicalutamide sulfoxide intermediate into bicalutamide. The bicalutamide is synthesized with high yield and high purity by means of a one-pot two-step method, the process is simple, and the operation is convenient; the source of a reaction reagent is easily obtained, the price is low, the cost is low, the performance is stable, and the use safety is high; a reaction condition is mild, the after-treatment is simple, the environment pollution is small, and the method is green and environment friendly, and suitable for industrialized production.
- -
-
Paragraph 0005; 0013-0020
(2017/08/30)
-
- One-pot synthesis of β-hydroxysulfones and its application in the preparation of anticancer drug bicalutamide
-
An efficient one-pot multistep strategy has been developed, comprising auto-oxidative difunctionalization of alkenes, oxidation of sulfides, and a further reduction of peroxides for the synthesis of complex β-hydroxysulfone derivatives from phenthiols and alkenes. This method has several advantageous characteristics, including readily available substrates, low-cost and environmental benign reagents, nontoxic and renewable solvents, and mild reaction conditions. The application of this transformation to the multigram-scale preparation of the anticancer drug bicalutamide is accomplished.
- Wang, Yajun,Jiang, Wei,Huo, Congde
-
p. 10628 - 10634
(2018/05/31)
-
- Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer
-
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
-
supporting information
p. 230 - 243
(2016/05/10)
-
- Method for synthesizing bicalutamide
-
The invention discloses a method for synthesizing bicalutamide. According to the method, N-(4-cyan-3-trifluoromethylphenyl)-3-(4-fluorothiophenyl)-2-methyl-2-hydroxypropionamide serving as a raw material is oxidized with hydrogen peroxide by using phosphotungstic acid quaternary ammonium salt having the characteristic of reaction-controlled phase as a catalyst and dichloromethane as a solvent at a reaction temperature of 15-30 DEG C to generate bicalutamide. The method has the advantages of mild reaction condition, high reaction yield and high catalyzing efficiency, and the catalyst and reaction solvent can be recycled.
- -
-
Paragraph 0014
(2016/10/27)
-
- Auto-oxidative hydroxysulfenylation of alkenes
-
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
-
p. 7233 - 7236
(2016/06/09)
-
- ANDROGEN RECEPTOR ANTAGONISTS
-
Disclosed herein are compositions and methods for modulating the androgen receptor.
- -
-
Paragraph 0327
(2016/04/26)
-
- Hydroxysulfenylation of electron-deficient alkenes through an aerobic copper catalysis
-
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
-
supporting information
p. 1180 - 1183
(2015/03/14)
-
- A new avenue toward androgen receptor pan-antagonists: C2 sterically hindered substitution of hydroxy-propanamides
-
The androgen receptor (AR) represents the primary target for prostate cancer (PC) treatment even when the disease progresses toward androgen-independent (AIPC) or castration-resistant (CRPC) forms. Because small chemical changes in the structure of nonsteroidal AR ligands determine the pharmacological responses of AR, we developed a novel stereoselective synthetic strategy that allows sterically hindered C2-substituted bicalutamide analogues to be obtained. Biological and theoretical evaluations demonstrate that C2-substitution with benzyl and phenyl moieties is a new, valuable option toward improving pan-antagonist behavior. Among the synthesized compounds, (R)-16m, when compared to casodex, (R)-bicalutamide, and enzalutamide, displayed very promising in vitro activity toward five different prostate cancer cell lines, all representative of CPRC and AIPC typical mutations. Despite being less active than (R)-bicalutamide, (R)-16m also displayed marked in vivo antitumor activity on VCaP xenografts and thus it may serve as starting point for developing novel AR pan-antagonists.
- Guerrini, Andrea,Tesei, Anna,Ferroni, Claudia,Paganelli, Giulia,Zamagni, Alice,Carloni, Silvia,Di Donato, Marzia,Castoria, Gabriella,Leonetti, Carlo,Porru, Manuela,De Cesare, Michelandrea,Zaffaroni, Nadia,Beretta, Giovanni Luca,Del Rio, Alberto,Varchi, Greta
-
p. 7263 - 7279
(2015/01/30)
-
- PROCESS FOR PREPARING BICALUTAMIDE
-
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.
- -
-
Paragraph 0110-0115
(2013/10/22)
-
- Separation of racemic bicalutamide by an optimized combination of continuous chromatography and selective crystallization
-
A racemic mixture of bicalutamide, a drug substance used in the treatment of prostate cancer, was separated by simulated moving bed chromatography, with the objective of maximizing throughput at reduced outlet purity. The enriched extract stream was purified further by a crystallization process exploiting a shift in the eutectic composition. The optimal purity in between both process steps was identified. The separation scheme developed was validated on a scale of 600 g, and the results were compared to those of state-of-the art and discussed. The investigated scheme revealed a wide range of promising coupling conditions while showing superior productivities and enhanced process robustness.
- Kaemmerer, Henning,Horvath, Zoltan,Lee, Ju Weon,Kaspereit, Malte,Arnell, Robert,Hedberg, Martin,Herschend, Bjoern,Jones, Matthew J.,Larson, Kerstin,Lorenz, Heike,Seidel-Morgensten, Andreas
-
experimental part
p. 331 - 342
(2012/06/18)
-
- NON-STEROIDAL COMPOUNDS FOR ANDROGEN RECEPTOR MODULATION
-
The present invention concerns compounds of general Formula (I) : method of preparation and uses thereof.
- -
-
Page/Page column 44
(2010/11/03)
-
- AN IMPROVED PROCESS FOR PRODUCTION OF BICALUTAMIDE USEFUL IN THE TREATMENT OF PROSTATE CANCER
-
The invention relates to an improved process for production of Bicalutamide useful in the treatment of prostate cancer by oxidizing N[4-Cyano-3-trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methyl propanamide with Hydrogenperoxide in the presence of ethylacetate as solvent, methanesulfonic acid and sodiumtungstate as catalysts, washing the reaction mixture with sodiumthiosulphate solution or sodium metabisulphite solution, charcolising and evaporating the reaction mixture adding hydrocarbon solvent, cooling to room temperature and filtering.
- -
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Page/Page column 7-8
(2009/09/04)
-
- Synthesis of potential impurities of bicalutamide
-
Bicalutamide is an oral nonsteroidal, anti-androgen drug used for prostate cancer. It binds to the androgen receptor. During the bulk synthesis of bicalutamide, various impurities are formed. The present work details the development of simple processes for the preparation of impurities of bicalutamide, viz bical-sulfoxides (6), bical-deshydroxy (10), bical-desfluoro (10a), bical-2-fluoro (10b), and bical-3-fluoro (10c). Copyright Taylor & Francis Group, LLC.
- Bhise, Nandu Baban,Sathe, Dhananjay Govind,Radhakrishanan, Tarur,Deore, Raviraj
-
body text
p. 1516 - 1526
(2009/10/17)
-
- Mechanistic studies on the synthesis of bicalutamide
-
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
-
body text
p. 678 - 686
(2009/06/19)
-
- Multicomponent reactions as a powerful tool for generic drug synthesis
-
Multicomponent reactions (MCRs) are not only a powerful tool for drug discovery, they also represent an excellent methodology for synthesis rationalization. Here we wish to illustrate the potential of MCRs in the production of generic drugs by synthesizing, in racemic form, the antiplatelet agent clopidogrel and the nonsteroidal antiandrogen bicalutamide, using Ugi, Petasis and Passerini reactions. Georg Thieme Verlag Stuttgart.
- Kalinski, Cedric,Lemoine, Hugues,Schmidt, Juergen,Burdack, Christoph,Kolb, Juergen,Umkehrer, Michael,Ross, Guenther
-
experimental part
p. 4007 - 4011
(2009/05/27)
-
- Bacillus subtilis epoxide hydrolase-catalyzed preparation of enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether and its application to expeditious synthesis of (R)-bicalutamide
-
Expeditious synthesis of (R)-bicalutamide (1), a synthetic antiandrogen, from enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether (4) was achieved. An engineered Bacillus subtilis epoxide hydrolase worked enantioselectively on the racemic epoxide (7) to provide the above starting material in highly enantiomerically enriched state.
- Fujino, Aya,Asano, Masayoshi,Yamaguchi, Hitomi,Shirasaka, Naoki,Sakoda, Akiko,Ikunaka, Masaya,Obata, Rika,Nishiyama, Shigeru,Sugai, Takeshi
-
p. 979 - 983
(2008/02/04)
-
- A PROCESS FOR PREPARATION OF ANTIANDROGEN COMPOUND
-
The present invention provides a process for the preparation of an antiandrogen compound, N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide, a compound of formula 1, comprising reacting N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methyloxirane-2-carboxamide, a compound of formula 2 with 4-fluorothiophenol, a compound of formula 3 in presence of a phase transfer catalyst and oxidizing the resultant N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methylpropanamide, a compound of formula 4 with a permanganate reagent.
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Page/Page column 10
(2008/06/13)
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- Synthesis and biological evaluation of [18F]bicalutamide, 4-[76Br]bromobicalutamide, and 4-[76Br]bromo- thiobicalutamide as non-steroidal androgens for prostate cancer imaging
-
Androgen receptors (AR) are overexpressed in most primary and metastatic prostate cancers. To develop a nonsteroidal AR-mediated imaging agent, we synthesized and radiolabeled several analogs of the potent antiandrogen bicalutamide: [18F]bicalutamide, 4-[76Br] bromobicalutamide, and [76Br]bromo-thiobicalutamide. Two of these analogs, 4-[76Br]bromobicalutamide and [76Br]bromo- thiobicalutamide, were found to have a substantially increased affinity for the androgen receptor (AR) compared to that of bicalutamide. The synthesis of [ 18F]bicalutamide utilized a pseudocarrier approach to effect addition of a carbanion generated from tracer-level amounts of a radiolabeled precursor to an unlabeled carbonyl precursor. 4-[76Br]Bromobicalutamide and [76Br]bromo-thiobicalutamide were labeled through electrophilic bromination of a tributylstannane precursor. The former could be prepared in high specific activity, and its tissue distribution was tested in vivo. Androgen target tissue uptake was evident in castrated adult male rats; however, in DES-treated, AR-positive, tumor-bearing male mice, tumor uptake was low.
- Parent, Ephraim E.,Dence, Carmen S.,Jenks, Carl,Sharp, Terry L.,Welch, Michael J.,Katzenellenbogen, John A.
-
p. 1028 - 1040
(2008/02/01)
-
- Process for production of bicalutamide
-
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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- METHOD OF CRYSTALLIZING BICALUTAMIDE
-
The present invention provides a method of crystallization of bicalutamide comprising adding an acetone solution containing bicalutamide to water; crystals of bicalutamide wherein particle size distribution of the crystals is 1 to 10μm of Dp 10 , 10 to 25 μm of Dp 50 and 25 to 100 μm of Dp 90 , and the crystals are obtainable by the method described above; and crystals of bicalutamide, wherein particle size distribution of the crystals is 1 to 3 μm of Dp 10 , 2 to 5 μm of Dp 50 and 5 to 15 μm of Dp 90 .
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Page/Page column 5-6
(2008/06/13)
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- Process for preparation of bicalutamide
-
A process for preparation of Bicalutamide of formula (I), comprising oxidation of compound of formula (II), with potassium permanganate in presence of water or a mixture of water and water miscible solvent and isolating Bicalutamide of formula (I) thereof.
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Page/Page column 4-5
(2008/06/13)
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- AN IMPROVED PROCESS FOR PREPARATION OF BICALUTAMIDE
-
A process for preparation of Bicalutamide of formula (I), comprising oxidation of compound of formula (II), with potassium permanganate in presence of water or a mixture of water and water miscible solvent and isolating Bicalutamide of formula (I) thereof.
- -
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Page/Page column 18
(2008/06/13)
-
- An improved process for preparation of bicalutamide
-
A process for preparation of Bicalutamide of formula (I), comprising oxidation of compound of formula (II), with potassium permanganate in presence of water or a mixture of water and water miscible solvent and isolating Bicalutamide of formula (I) thereof.
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Page/Page column 11
(2008/06/13)
-
- A process for the preparation and purification of bicalutamide
-
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 6
(2008/06/13)
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- Procedure for the synthesis of bicalutamide
-
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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- PROCESS FOR PREPARATION OF BICALUTAMIDE
-
The present invention discloses a process for the synthesis of N-[4-Cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) sulphonyl]-2-hydroxy-2-methyl propanamide (Form I). The invention discloses a reagent for oxidation of N-[4-Cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) thio]-2-hydroxy-2-methyl propanamide to N-[4-Cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) sulphonyl]-2-hydroxy-2-methyl propanamide. More particularly, the invention discloses a method of purification of N-[4-Cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) sulphonyl]-2-hydroxy-2-methyl propanamide in a mixture of methylethyl ketone and hexane giving form (I). This form (I) is useful as an active pharmaceutical and has antiandrogenic activity.
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Page/Page column 9
(2008/06/13)
-
- PROCESS FOR PRODUCING BICALUTAMIDE AND METHOD OF PURIFYING INTERMEDIATE THEREFOR
-
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 12-13
(2008/06/13)
-
- Improved procedure for the synthesis of bicalutamide
-
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.
- -
-
Page/Page column 7
(2008/06/13)
-
- Bicalutamide polymorphs
-
The invention provides crystalline form of bicalutamide and amorphous bicalutamide. The invention also provides methods for their preparation and pharmaceutical compositions containing the new forms of bicalutamide.
- -
-
Page/Page column 2
(2008/06/13)
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- PROCESS FOR PURIFYING AND ISOLATING RAC-BICALUTAMIDE
-
The present invention discloses a new process for the isolation and purification of racemic and optically active bicalutamide.
- -
-
-
- A PROCESS FOR THE PRODUCTION OF HIGHLY PURE N-(4-CYANO-3-TRIFLUOROMETHYLPHENYL)-3-(4-FLUOROPHENYLTHIO)-2-HYDROXY-2-METHYLPROPANAMIDE
-
N-(4-Cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropanamide of high purity is produced by oxidation of N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylthio)-2-hydroxy-2-methylpropanamide, using urea-hydrogen peroxide complex (UHP), in a mixture of a C1_4-carboxylic acid and an organic solvent, as the oxidizing reagent. N-(4-Cyano-3-trifluoromethylphenyl)-3-(4-fluorophenylsulfonyl)-2-hydroxy-2-methylpropanamide is a known antiandrogen.
- -
-
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- Process for making bicalutamide and intermediates thereof
-
Bicalutamide and/or its intermediates are made by the use of p-fluorobenzenesulfinic acid salt as a reagent.
- -
-
-
- PROCESS FOR THE SYNTHESIS OF N-(4-CYANO-3-TRIFLUOROMETHYLPHENYL)-3-(4-FLUOROPHENYLSULPHONYL)-2-HYDROXY-2-METHYLPROPIONAMIDE
-
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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- 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 14
(2008/06/13)
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- 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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p. 10181 - 10182
(2007/10/03)
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- Process for making bicalutamide and intermediates thereof
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Bicalutamide and/or its intermediates are made by the use of p-fluorobenzenesulfinic acid salt as a reagent.
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- Syntheses of enantiomerically pure (R)- and (S)-bicalutamide
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The racemic antiandrogen bicalutamide is the leading antiandrogen used for the treatment of prostate cancer. The (R)-isomer possesses virtually all of the activity, but both isomers are metabolized by the liver. A convenient synthetic route to the active enantiomer would be an attractive option for patients who are hepatically impaired. We now demonstrate a rather short synthesis of (R)-bicalutamide, starting with a naturally occurring, chiral precursor.
- James, Kenneth D,Ekwuribe, Nnochiri N
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p. 5905 - 5908
(2007/10/03)
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- A two-step synthesis of the anti-cancer drug (R,S)-bicalutamide
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A short, efficient synthesis of the non-steroidal antiandrogen (R,S)-bicalutamide is presented. This new route generates bicalutamide in only two steps with an overall yield of 73%. The key step is a 1,2 addition of a methyl sulfone to a keto-amide.
- James, Kenneth D.,Ekwuribe, Nnochiri N.
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p. 850 - 852
(2007/10/03)
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- METHODS OF SYNTHESIZING ACYLANILIDES INCLUDING BICALUTAMIDE AND DERIVATIVES THEREOF
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Methods of synthesizing an acylanilide include contacting a compound having the structure of Formula I: with a compound having the structure of Formula II: under conditions sufficient to provide a compound having the structure of Formula III: and treating the compound of Formula III under conditions sufficient to provide an acylanilide. The compound of Formula III may be addition reacted with a compound having the structure of Formula IV: R5—X1—R6—R7??Formula IV under conditions sufficient to provide an acylanilide having the structure of Formula V:
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