The Synthetic New Process Study Of Gliclazide

Gliclazide belongs to the second generation sulfonylurea oral hypoglycemic medications,it has effect both on regulating blood sugar level and improving blood coagulation function. Itcan not only improve the diabetics’metabolism but also improve or delay the onset of diabeticvascular complications. It has been widely used for clinical purposes at home and abroad, and ithas become one of the most commonly used medicine for type2diabetes at present. Thedomestic demand is great and the volume of business has been increasing last for years. It canbe seen that gliclazide will have a good market prospect. In this work, we committed to find asuitable route for industrial production based on the literature.In this paper, cyclohexanone and urea were chose as raw materials, after they were dealedwith Spiro reaction, hydrolysis, bromation and amination, we could get1,2-cyclopentanedicarboximide from which could get amino heterocycle hydrochloride afterreduction, nitrosation and nitroso reduction, then gliclazide could be gotten afteraminoheterocycle hydrochloride was condensed with4-toluenesulfonylurea. At the same time,influential factors of the yield and quality were studied in this work.In the process of preparation of2-formamide cyclohexanone, p-toluenesulfonic acid wasused as catalysis for Spiro reaction, this improve the product′s yields, effects of reactiontemperature and the addition of ammonium carbonate which used as polymerization inhibitorswas investigated as emphasis. Potential of hydrogen of reaction liquid was studied forhydrolysis. Through these the reactions conditions were optimized, and the yield of productwas reached to65%.In the process of bromation reaction, acetic anhydride was used as bromation catalysis,which improved the reaction yield. Effects of molar ratio of bromine and2-formamidecyclohexanone, reaction temperature and addition of catalysis were stressed and optimized, as aresult,90%yield of the product was achieved.In the synthesis of1,2-cyclopentanedicarboximide, the reaction mechanism ofrearrangement reaction was discussed, and autoclave was used for reaction, which save the useof ammonia. Except these, the amination temperature was investigated and improved. In this case, yield of product was60%.In the reduction process of imide, NaBH₄was used as reducing agent, and Zncl₂instead ofCoCl₂was used as catalysis, from which the yield was increased, and the reaction time wasreduced. In this process, we focused on the feeding rate of NaBH4and Zncl₂, reaction conditionof each step was improved and the yield of product got to91%.In the nitrosation process, we studied effects of adding time, reaction temperature and theamount of NaNO₂for the yield, in the same time, we also investigated the effect of pH aboutnitrosation reaction. Based on the result, we improved the conditions, and the reaction wasalmost developed quantitatively.In the preparation of amino heterocyclic hydrochloride, metallic reducing agent andrecrystallization reagent were studied, at last, Zn power was selected as reducing agent andmethanol was used as recrystallization reagent. The yield of product reached to93%.In the final process of condensation reaction, p-toluene sulfonylurea was used to react withamino heterocyclic hydrochloride, DMSO/ethyl acetate was used as solvent instead of DMF/ethyl acetate, and the conversion was improved effectively. Effects of the amount of water,reaction time, reaction temperature and temperature of the crystal precipitation for the yieldwere examined. Based on these, reaction conditions were improved, and as a result of this,93%of the yield and99.5%of purity were achieved.In terms of cyclohexanone as the starting material, yield of the product was45%, whichwas relatively high and the raw material was cheap, so it was suitable for industrial production.