| Febuxostat,chemical name 2-[3-cyano-4-isobutoxyphenyl]-4-methyl-5-thiazolar-boxylic acid,is currently the latest drug for the treatment of hyperuricemia gout,which is effective by highly selective inhibition of xanthine oxidoreductase,thereby reducing uric acid concentration in the body.At present,the incidence of gout continues to rise,showing a trend of spreading to young people,but there are a few products on the market in China.Therefore,it is of great significance to study the synthetic process of febuxostat.In this study,based on a large number of literatures,using p-hydroxythiobenzamide as the starting material,through thiazole cyclization,2-?3-formyl-4-isobutoxyl-phenyl?-4-methylthiazole-5-formate was synthesized by formylation reaction.The intermediate was further dehydrated and hydrolyzed by aldoxime.The target compound,febuxostat,was prepared by refining and crystallization process,and the process was optimized.On this basis,a kilogram-scale reaction was conducted.The purity of febuxostat was more than 99.9%,the amount of single impurity was less than 0.05%,the number of impurities was not more than 2,and the total impurity was not more than 0.1%,which meets the medical standard.For the cyanidation of aldehyde intermediates,according to the literature reported at present,the reaction conditions are harsh,or using highly toxic metal cyanide,which is not conducive to industrial production.Based on this,the cyanidation of aldehyde group catalyzed by NaI/FeCl2 was studied.Using ammonia water as nitrogen source,Na2S2O8 as oxidant,cyano intermediates were obtained by oxidation of imines through a catalytic oxidation cycle of iodine.The reaction was easy to operate,and the separation yield was as high as 98%.This method can not only be used in the synthesis of febuxostat,but also suitable for a variety of aryl,alkyl and aldehydes.The cyanation reaction has good tolerance to alkyl,alkoxy,halogen,nitro,cyano,trifluoromethyl and so on,and most of the products were obtained in good yields. |
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