The Improvement Of Synthesis Of Esomeprazole Sodium

ABSTRACT:Esomeprazole Sodium was developed by AstraZeneca Swedish, is sodium salt of the S-isomer of omeprazole, which was the first marketed proton pump inhibitor used in clinic. It was used in gastric ulcer, duodenal ulcer, peptic esophagitis and gastritis treatment for the drug. Because of the good effect in Peptic ulcer, high efficiency, low toxin, and high cure rate, esomeprazole sodium had the largest medical sales in the world for several years with annual sales of up to8.2billion dollars.Because of the traditional synthetic route contains complex procedures, low yields, highly difficult purification technical and high cost, this paper focused on the optimization of synthesis process which was the main target, especially studied the reaction conditions of chlorination, condensation and asymmetric catalytic oxidation reaction and obtained optimal process conditions to improve the product yield. The structure of esomeprazole sodium and intermediates were confirmed by1H NMR,13C NMR, IR, MS, etc.In the paper,2-hydroxymethyl-3,5-bimethyl-4-methoxy pyridine as raw material, which was transferred into2-Chloromethyl-3,5-Dimethyl-4-methoxy Pyridine Hydrochloride by SOC12with a yield of90～95%and over purity of99%(chlorination reaction), the product condensed with2-mercapto-5-methoxy benzimidazole to provide Ufiprazole with a yield of90～95%(reported yield was about80%) and over purity of99.5%(condensation reaction); followlly, the Ufiprazole was asymmetric catalytic oxidized by Cumene hydroperoxide, D-tartrate was used as chiral ligands and Titanium(IV) isopropoxide was used as catalyst. After oxidation, the product reacted with sodium methoxide to provide crude esomeprazole sodium, the yieldwas70～80%(reported yield was about45～50%) with over purity of98.5%and96.5%e.e value; the crude was purified by recrystallization with methanol and actone,the yield was80～85%. Total yield was48%-65%(reported yield was about25～35%) with over99.5%purity and99.5%e.e value.