Asymmetric synthesis of esomeprazole埃索美拉唑的不对称合成.pdfVIP

TETRAHEDRON: ASYMMETRY Pergamon Tetrahedron: Asymmetry 11 (2000) 3819–3825 Asymmetric synthesis of esomeprazole Hanna Cotton,a Thomas Elebring,b Magnus Larsson,a Lanna Li,b Henrik So¨rensenb and Sverker von Ungeb, * aProcess Chemistry, AstraZeneca Process RD So¨derta¨lje, S-151 85 So¨derta¨lje, Sweden bMedicinal Chemistry, AstraZeneca RD Mo¨lndal, S-431 83 Mo¨lndal, Sweden Received 7 August 2000; accepted 1 September 2000 Abstract A highly efficient synthesis of esomeprazole—the (S)-enantiomer of omeprazole—via asymmetric oxidation of prochiral sulphide 1 is described. The asymmetric oxidation was achieved by titanium-medi- ated oxidation with cumene hydroperoxide (CHP) in the presence of (S,S)-diethyl tartrate [(S,S)-DET]. The enantioselectivity was provided by preparing the titanium complex in the presence of 1 at an elevated temperature andor during a prolonged preparation time and by performing the oxidation of 1 in the presence of an amine. An enantioselectivity of 94% ee was obtained using this method. © 2000 Elsevier Science Ltd. All rights reserved. 1. Introduction 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulphinyl]-1H-benzimidazole, which has the generic name omeprazole, is the prototypical compound of a class of highly potent gastric acid secretion inhibitors.1 Omeprazole—a racemic mixture—is successfully used against acid-related diseases. Unlike the histamine H2-receptor antagonist