SYNTHESIS OF OMEPRAZOLE, LANSOPRAZOLE AND PANTOPRAZOLE IMPURITIES M. Paz Matía, J. Luis. Novella, Juan J. Vaquero, Julio Alvarez-Builla* Planta Piloto de Química Fina. Universidad de Alcalá. Ctra. Madrid-Barcelona Km. 33,600. 28871 Alcalá de Henares. Madrid. España. INTRODUCTION The final step in the pathway for acid secretion from the parietal cell into the gastric lumen is the so-called ‘proton pump’. The proton pump is an active transport system powered by the enzyme H+/K+-ATPase, which catalyzes the exchange of intra-cellular hydrogen ions for extracellular potassium ions. The inhibition of proton 1 pump prevents acid secretion from the parietal cell . Omeprazole, pantoprazole and lansoprazole (figure 1) are three irreversible proton pump inhibitors (PPIs). The benzimidazole PPIs are essentially prodrugs, that in the acidic biophase of the parietal cell form an active metabolite that irreversibly interact with an essential thiol (SH) function on ATPase of the proton pump. CHF2 H N O CH 3 O CH 3 H N S H 3C CH 3 O H N O CF 3 O S N O O CH 3 O O CH 3 S N Figure 1 N N N Omeprazole Lansoprazole CH3 N Pantoprazole OBJETIVE AND RESULTS In the present work we have prepared2 and analyzed by HPLC-MS3,4 some of the different impurities of omeprazole, lansoprazole and pantoprazole. Compounds 1a, 1b, 1c were commercially available and the corresponding sulfones, the more common impurities, were obtained by oxidation with peracetic acid (Scheme 1). H N R2 R3 S N R Scheme 1 H N CH3CO3H R2 R3 N R N 2a omeprazole sulfone 90% R 4 2b lansoprazole sulfone 92% 2c pantoprazole sulfone 85% N R4 1a omeprazole sulfide 1b lansoprazole sulfide 1c pantoprazole sulfide O O S Additionally, the omeprazole impurities B and E were prepared following the synthesis indicated in the schemes 2 and 3. H3C CH 3 H 3C CH 3 Ac2O H3CCO3H (35%) CH 3 N CH 3 + O_ 94% O CH 3 OH -/H 2O DCM N H3C H3C OH Cl 2SO 90% N H H 3C 80% H 3C O N Impurity B N O H3C CH3 DCM 35 ºC, 1.5h Cl N + O_ H N Scheme 3 CH 3 H3C CH3 CH3 Scheme 2 H3C 87% H N O CH3 O CH3 O Impurity E CH3 N O_ + K2CO3 CH 3 2 3 4 O CH3 S H 3C O N DCM/MeOH 80% N H REFERENCES: 1 N O H N H 3CCO3H (15%) N SH NaOH 1M S N O Cl N H N O H N H3CCO3H (35%) CH3 CH 3 SH S DCM K2CO3 O CH3 N S H N Cl H3CCO3H (35%) H 3C Cl H N NaOH/BNTC H3C CH3 CH3 65% 60% CH3 O N H 47% HCl H3C CH3 Karljikovic-Rajic, K., Novovic, D., Marinkovic, V., Agbaba, D., J. Pharm. Biomed. Anal. 2003, 32, 1019. Madhusudhan Reddy, G., Mukkanti, K.., Laxmi Kumar, T., Moses Babu, J., Pratap Reddy, P., Synthetic Commun. 2008, 38,477. Cirilli, R., Ferretti, R., Gallinella, B., Turchetto, L., Zanitti, L., La Torre, F., J. Pharm. Biomed. Anal. 2009, 50, 9. Espinosa, M., Ruiz, A. J., Sánchez, F., Bosch, C., J. Pharm. Biomed. Anal. 2007, 44, 831. CH3 N + O_