Process Optimization And Industrial Design Of An Intermediate Of Febuxostat

Febuxostat,as the first drug approved for the treatment of gout with hyperuricemia,has ended the history of allopurinol for gout.Compared with similar drugs,it has exhibited significant selectivity,better efficacy and higher drug safety.2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester is an important intermediate in the synthesis of febuxostat,the industrial production of it has remarkable economic and social benefits.In this paper,based on the literature,the synthesis route of 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester was screened and optimized:the compound was synthesized from p-hydroxythiobenzylamide by two steps of cyclization and aldehyde-alkylation,each step was analyzed in detail,and the optimum process parameters were screened by orthogonal test.Cyclization was carried out under reflux.The optimum material ratio of p-hydroxythiobenzylamide and 2-chloroacetoacetate was determined,and the kinds and dosage of solvents were selected.Polyphosphoric acid were used as protonic acid in aldehydealkylation.The optimum material ratio,reaction temperature and reaction time were determined by orthogonal test.According to the screened process parameters,the yield of each step was about 5%higher than that of references.On the basis of the completion of the laboratory process research,we used the tool of FMEA to assess the risk of pilot scale production.On the premise that all risks are acceptable,we carried out pilot scale-up.In the process of pilot scale production,the risk of intense temperature rise of cyclization was reduced,and the acid waste liquid from aldehyde reaction was treatedBased on the determined process above,the industrial production of 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester was designed.The annual output of the design is 15 tons,the preliminary material balance is carried out.According to the production process,the equipment of the production device is selected.The safety analysis and design is carried out on the production process and the selected production device.The treatment of three wastes is discussed.Finally,the economic benefit of the whole project is analyzed.The results show that the process is suitable for industrial production.