An Improved Process For The Production Of Pantoprazole And Esomeprazole

Pantoprazole sodium and esomeprazole sodium(S-omeprazole sodium) belong to proton pump inhibitors(PPI). They have been proved to be the most effective drugs in the treatment of gastric ulcer, duodenal ulcer and peptic esophagitis, etc.. The synthesis process of pantoprazole sodium and esomeprazole sodium were developed in this paper.Pantoprazole sodium was prepared from 2-chloromethyl-3,4-dimethoxy-pyridini-um chloride and 5-difluromethoxy-2-mercapto-1H-benzimidazole via three steps of condensation, oxidation and salification. Firstly, in the step of condensation reaction, a single water phase was used instead of the mixture of organic solvent and water, then obtained intermediate was extracted into CH2Cl2 and directly used to the next step. Secondly, in the step of oxidation reaction, sodium hypochlorite was chosen as oxidant, the effect of the reaction temperature, dosage of oxidant and the dropping speed of oxidant on the purity of pantoprazole was studied, and the optimized parameters for preparing pantoprazole sodium was obtained as follows: the reaction temperature is-10 to-5 ℃, the molar ratio of sodium hypochlorite and pantoprazole sulfide is 0.9:1, the dropping time of oxidant is 45 min. The target compound was produced with a purity 99.7% and yield 78.3%, and its structure was confirmed by using infrared, ultraviolet and mass spectrum.Esomeprazole sodium was prepared from 2-hydroxymethyl-3,5-bimethyl-4-methoxy pyridine via four steps of chlorination, condensation, oxidation and salification. The Key step is asymmetric oxidation of omeprazole sulfide. In this step, toluene was used as solvent, D-tartrate was used as chiral ligand, titanium isopropoxide was used as catalyst, and cumene hydroperoxide was used as oxidant. The effect of the reaction temperature, dosage of oxidant and the dropping speed of oxidant on the purity of esomeprazole was studied, and the optimized parameters for asymmetric oxidation were obtained as follows: the reaction temperature was at-5 ℃, the molar ratio of cumene hydroperoxide and omeprazole sulfide was 1.1:1, the dropping time of oxidant was 45 min, then the reaction was kept for 30-40 min. The target compound was produced with a purity 99.8%, a enantiomeric purity 99.95% and yield 87.4%, and its structure was confirmed by using infrared, ultraviolet and mass spectrum.A method for determination of enantiomeric purity of esomeprazole sodium by High Performance Liquid Chromatography(HPLC) was developed as follows: a chiral column, CHIRALPAK-AGP column(2.5μm, 100 mm × 4mm), packed with α1-acid glycoprotein immobilized on silica gel was chosen as stationary phase, a mixed solution of acetonitrile and phosphate buffer(pH 6.0) in a 15:85 ratio(v/v) was used as the mobile phase, and UV detection at 302 nm was utilized. Under these conditions, there is good linear relation between the peak area and concentration of R-omeprazole sodium from 0.0032μg/mL to 0.08μg/mL, the correlation coefficient(R2) is 0.9996. The detection limit(3S/N) of R-omeprazole sodium is 0.128 ng. The resolution between R-omeprazole sodium and S-omeprazole sodium is more than 3.0.