Synthesis Study Of Enzalutamideas Prostate Cancer Treatment

Enzalutamide is a new anti-prostate cancer drug which is developed by b the US pharmaceutical company Medivation and Astellas Pharma Japan.On August 31,2012 by the US Food and Drug Administration(FDA)approved for marketing,specifically for the treatment of castration-resistant prostate cancer(CRPC).Due to excellent anti-tumor effect and huge market potential,the synthesis of Enzalutamide has received extensive attention.The existing methods reported in literatures have different drawbacks and disadvantages,so to explore a much more concise,high-yield,low cost route and process will have great significance and value.In this thesis a new synthetic method for Enzalutamide was invented,firstly we get through new synthetic routes of Enzalutamide 's two key intermediates N-[3-fluoro-4-[(methylamino)carbonyl] phenyl]-2-methyl-alanine methyl ester and 4-isothiocyanato-2-(trifluoromethyl)benzonitrile and each synthetic step was optimized to manage to obtain optimum yield.Finally,the two key intermediates occur ring closure reaction to give the desired product Enzalutamide.In the synthetic research of N-[3-fluoro-4-[(methylamino)carbonyl] phenyl]-2-methyl alanine methyl ester,we choose the 2-fluoro-4-nitrotoluene as the starting starting material,firstly after potassium permanganate oxidation,immediately under the reaction of thionyl chloride,methylamine amidation,followed by Pd/C catalytic hydrogenation to give N-methyl-2-fluoro-4-aminophenyl formamide,and ethylene glycol as the reaction solvent,4-dimethylaminopyridine(of DMAP)as the acid scavenger,of Nmethyl-2-fluoro-4-aminobenzamide and 2-bromo-isobutyric acid methyl nucleophilic substitution reaction of the key intermediate?,through process optimization,the total yield of the synthesis route reached 51.5%.For 4-isothiocyanato-2-trifluoromethyl benzonitrile,first,we synthetic raw material 3-trifluoromethyl-4-cyano-aniline,and then were used two different synthetic carbon disulfide the method of the experiment,and finally determine the best method for the synthesis of key intermediates? were as follows: 3-trifluoromethyl-4-cyano-aniline,first generation dithio formate react with carbon disulfide,followed by cyanuric chloride synthesis desulfurization target product.Through process optimization,the reaction yield of as high as 78.0%.Base on the synthesis of two key intermediates,let them happen ring closure reaction to produce Enzalutamide.The total yield 41.4%(based on 2-fluoro-4-nitrotoluene),the purity as high as 99.58%.Finally,the recrystallization process of Enzalutamide has been studied.The optimization riments was conduct on these such as altering reaction time,temperature,molar ratio,solvent and reagents.Satisfactory yield can beassured and intermediate has been confirmed by TLC,m.p.method,~1H-NMR,MS,HPL.In a word,this synthesis work has lot of advantages such as mild condition,high yield,low cost and environmental compact and good industrial prospects.