Study On A New Synthesis Of Gliclazide

Gliclazide,1-(hexahgdrocycloxpenta[c]pyrrol-2(1H)-yl)-3-[(4-methylphengl) sulphonyl]urea,which is the second generation of suflonylureas,is an oral antidiabetic agent.It improves the function of blood coagulation and has hypoglycemic effect,thus has been widely used in clinical treatment.It was reported in literatures that Gliclazide can be synthesized from 1,2-cyclopentanedicarboxylic anhydride.1,2-Cycloaentanedicarboxinide was obtained from the imidization of the material,and then by reduction gave 3-azabicyclo[3.3.0]octane,whose nitrosation and reduction successively followed by condensation with p-toluenesulfonyl urea afforded the final product Gliclazide.A novel synthesis route was developed in this thesis.Gliclazide was synthesized from 1,2-cyclopentanedicarboxylic anhydride.N-amino-1,2-cyclohexane dicarboximide was obtained from the condensation reaction between the material and 80%hydrazine hydrate.The reduction of N-amino-1,2-cyclohexane dicarboximide and followed by the condensation with p-toluenesulfonyl urea generated Gliclazide.The effects of the ratios of raw materials,solvents,the concentration of hydrazine hydrate and feeding way were studied in the hydrazinolysis reaction.The optimized reaction conditions are as follows:80%Hydrazine hydrate and 1,2-cyclopentanedicarboxylic anhydride reacted in refluxing methanol for 6 hours with a molar ratio of 1.1:1.N-amino-1,2-cyclohexanedicarboximide was obtained from the desolventization of this reaction mixture.This process was efficient,with an easier treatment,the purity of 97.3%and the yield of 87.7%.The effects of different reductants,materials ratio,solvents,water content were studied in the reduction reaction.The optimized reaction conditions are as follows: using KBH₄ and AlCl₃ as reducing agent,the ratio among the raw material,KBH₄ and AlCl₃ was 1:2.5:1.After refluxing in THF for 7 hours,the product was obtained.The reaction mixture was extracted with toluene,then acidified and the salt of the product was formed.This process was easy to operated with the yield of 78.5%.The effects of different solvents,reagents and material ratio were studied in the condensation reaction.P-toluenesulfonyl urea which was relatively cheap was chosen to react with hexahydro-2-cyclopenta[c]pyrrolamine with a molar ratio of 1.05:1 in the refluxing solvent of toluene and DMF for 2 hours.After that,most of the solvent was removed.Crystallization from water and recrystallization from ethyl acetate give Gliclazide.The purity analyzed by HPLC was 99.5%and the yield was 87.2%.The structures of products in each step were confirmed by instrumental analyse. In conclusion,we succeeded in developing a new synthetic route for Gliclazide characterized by higher efficiency and better reaction conditions.Here,we used 3 steps instead of 5,thus effectively reduced steps.The total yield of this new route has reached to 60.0%,which was of high value for saving energy and reducing environmental pollution.