An Investigation on Key Parameters That Influence the Resolution of Omeprazole Sodium † Lekkala Amarnath Reddy, ‡ Golla China Malakondaiah, ‡ Karrothu Srihari Babu, ‡ Apurba Bhattacharya, ‡ Rakeshwar Bandichhor, ‡ Vimmidi Himabindu, § Padi Pratap Reddy, ‡ and Ramasamy Vijaya Anand* ,‡ Center of Excellence, Integrated Product DeVelopment, InnoVation Plaza , Dr. Reddy’s Laboratories Ltd., Bachupalli, Qutubullapur, R. R. Dist. 500 072 Andhra Pradesh, India, and Center for EnVironment, Institute of Science and Technology, Jawaharlal Nehru Technological UniVersity, Kukatpally, Hyderabad 500 072, India Abstract: In this document are highlighted systematic studies on factors such as water content, temperature, solvent, and mole ratio of the resolving agents that influence the resolution of omeprazole sodium. Introduction Chiral sulfoxides are useful synthons for the construction of many chemically and pharmaceutically significant mol- ecules. 1 The traditional approach to the preparation of optically active sulfoxides involves either optical resolution of racemates 2 or asymmetric oxidation of the prochiral sulfides. 3 Prazoles are a class of active pharmaceutical ingredients that contain a chiral sulfoxide group as an active component. Prazoles are known as proton pump inhibitors, which inhibit gastric acid secretion and are thus used as antiulcer agents. 4 Nexium, the magnesium salt of S-omeprazole, was one such prazole developed by AstraZeneca and used for the treatment of acid-related diseases. 5 Earlier we have reported a resolution process for the synthesis of the magnesium salt of S-omeprazole through a transition metal complex using a combination of D-(-)-diethyl tartrate, Ti(O i Pr) 4 , and L-(+)-mandelic acid as resolving agents. 6 Herein we wish to report our systematic investigation on the significant role of water, temperature, and the mole ratio of the resolving agents in the resolution of omeprazole sodium. Though the influence of water and temperature in asymmetric sulfoxidation is well precedent in the literature, 7 the effect of these parameters on the resolution of sulfoxides is not yet explored. Results and Discussions In one of our earlier experiments, we observed that no resolution occurred when racemic omeprazole 1 was exposed to a resolving agent such as a mixture of Ti(O i Pr) 4 , D-(-)-diethyl tartrate, L-(+)-mandelic acid, and triethylamine. Later, this resolution process was optimized using the sodium salt of racemic omeprazole 3 (Scheme 1). Although this process gave S-omeprazole S-1 in >99% ee, some inconsistency was observed as some of the batches failed in plant. This prompted us to investigate the influence of various factors that affect the resolution process, such as water content, temperature, and mole ratio of the resolving agents. To investigate the role of water in the resolution process, we examined the water content of the omeprazole sodium 3 in both failed and successful batches. This revealed that the water content of 3 in the failed batch was 0.5 mol (hemihydrate), whereas in the successful batch it was 1–2 mol. These † DRL-IPD Communication number: IPDO-IPM-00073. * To whom correspondence should be addressed. Tel: +91 40 44346430. Fax:+91 40 44346164. E-mail: vijayaanandr@drreddys.com. ‡ Dr. Reddy’s Laboratories Ltd. § Jawaharlal Nehru Technological University. (1) For reviews, see: (a) Pellissier, H. Tetrahedron 2006, 62, 5559–5601. (b) Bentley, R. Chem. Soc. ReV. 2005, 34, 609–624. (c) Fernandez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651–3705. (d) Legros, J.; Dehli, J. R.; Bolm, C. AdV. Synth. Catal. 2005, 347, 19–31. (2) (a) Sun, J.; Zhu, C.; Dai, Z.; Yang, M.; Pan, Y.; Hu, H. J. Org. Chem. 2004, 69, 8500. (b) Bortolini, O.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. Chem. Commun. 2000, 5, 365. (c) Serreqi, A. N.; Kazlauskas, R. J. Can. J. Chem. 1995, 73, 1357. (d) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 7624. (e) Davis, F. A.; Billmers, J. M. J. Org. Chem. 1983, 48, 2672. (3) (a) Kagan, H. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; p 203. (b) Bolm, C.; Muniz, K.; Hildebrand, J. P. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamammoto, H., Eds.; Springer: Berlin, 1999; p 697. (4) For reviews, see: (a) Sachs, G.; Shin, J. M.; Howden, C. W. Aliment. Pharmacol. Ther. 2006, 23, 2–8. (b) Tonini, M.; Giorgio, R, D.; Ponti, F. D Expert Opin. Ther. Pat. 2003, 13, 639–649. (5) Baker, D. Eur. ReV. Gastroenterol. Disord. 2001, 1, 32–41. (b) Cotton, H.; Elebring, T.; Larsson, E. M.; Li, L.; Sörensen, H.; Unge, S, V. Tetrahedron Asymmetry 2000, 11, 3819. (6) Raju, S. V. N.; Purandhar, K.; Reddy, P. P.; Reddy, G. M.; Reddy, L. A.; Reddy, K. S.; Sreenath, K.; Mukkanti, K.; Reddy, G. S. Org. Process Res. DeV. 2006, 10, 33. (7) Pitchen, P.; Dunach, E.; Deshmukh, M. N.; Kagan, H. B. J. Am. Chem. Soc. 1984, 106, 8188. Scheme 1. Resolution of omeprazole sodium 3 Organic Process Research & Development 2008, 12, 66–68 66 • Vol. 12, No. 1, 2008 / Organic Process Research & Development 10.1021/op700151c CCC: $40.75  2008 American Chemical Society Published on Web 11/27/2007