A Study On The Synthesis Of Allopurinol

Allopurinol,as an isomer of hypoxanthine,is a valuable pharmaceutical chemicals.It is currently an efficient drug for the treatment of gout,leukemia as well as kidney disease and also an important intermediate for the synthesis of antineoplastic agents and drugs.Allopurinol has been served as an inhibitor of xanthine oxidase(XO),which prevents the metabolism of hypoxanthine and xanthine to uric acid,thereby reducing the production of uric acid.Until now,allopurinol has been seen as the unique chemical which can inhibit uric acid synthesis in human body.Thus,allopurinol has been clinically widely used to treat recurrent or chronic gout,primary and secondary hyperuricemia,tophi,uric acid kidney stones and/or uric acid nephropathy,hyperuricemia with renal insufficiency,etc.In this thesis,the synthesis process of allopurinol was studied.The influence factors of each step were investigated separately.The impacts of reaction time,temperature,feed ratio and other conditions were evaluated and optimized to be industrialized.Firstly,the optimized reaction parameters for the synthesis of intermediate 1(2-cyano-3-morpholinepropanamide)were measured to be 100 °C,4 h and the corresponding mass ratio of cyanoacetamide,triethyl orthoformate,morpholine and ammonium chloride was 1.0:1.9:1.23:0.07,with the conversion,selectivity and molar yield of 90%,95% and about 80%,respectively.The optimum process parameters for the intermediate 2(3-amino-4-carboxamidopyrazole hemisulfate)were 80 ° C,4 h,and the molar ratio of intermediate 1 to hydrazine hydrate was 1.0:1.2.The conversion and selectivity reached 87% and 92%,respectively,and the final molar yield reached about 75%.The optimum process parameters for final product(allopurinol)were 135 ° C 11 h,and the optimal reaction molar ratio of 3-amino-4-carboxamidopyrazole hemisulfate to formamide was 1:13.The conversion and selectivity reached 98% and 95%,respectively,and the final molar yield reached about 90%.In this thesis,the process flow,mechanism and influence factors of the synthesis of allopurinol were studied and the optimized reaction parameters were obtained,which was of great significance to the industrial application of the allopurinol synthesis.Additionally,a simple process flow chart was designed for industrialization.