Esomeprazole synthesis

Cotton etal. [14] described an asymmetric synthesis of esomeprazole. Esomeprazole, the (S)-enantiomer of omeprazole, was synthesized via asymmetric oxidation of prochiral sulfide 5-methoxy-2-[[(4-methoxy-3,5-dimethyl pyridin-2-yl)methyl]thio]-lH-benzimidazole 1. The asymmetric oxidation was achieved by titanium-mediated oxidation with cumene hydroperoxide in the presence of (S,S)-diethyl tartarate (DET). The enan-tioselectivity was provided by preparing the titanium complex in the presence of sulfide 1 at an elevated temperature and/or during a prolonged preparation time and by performing the oxidation of sulfide 1 in the presence of amine. An enantioselectivity of 94% ee was obtained using this method. 

A number of pharmaceuticals now contain stereogenic heteroatoms where one enantiomer has the desired biological activity. An example is a sulfoxide, and perhaps the best-known example is esomeprazole (see Chapter 31).207 Access to these compounds by asymmetric synthesis has not been trivial. Although biological methodology continues to advance in terms of ee and substrate promiscuity, there is still considerable progress to be made before a general method is available. 

Enzymes often prove to be the catalyst of choice for numerous transformations, and their prowess is particularly noteworthy for the synthesis of chiral molecules. The ability of biocatalysts to impart chirality through conversion of prochiral molecules or by transformation of only one stereoisomer of a racemic mixture stems from the inherent chirality of enzymes. As noted in the introduction to this book (Chapter 1), the chiral drug market is increasing, partly as a result of the need to produce single enantiomers as advocated by the U.S. Food and Drag Administration.1 The ability to extend the patent life of a drug through a racemic switch also plays a role in this increase. An example of a racemic switch is Astra Zeneca s Esomeprazole, a proton pump inhibitor (see Chapter 31).2... 

The privileged pyridine scaffold is present in a large number of marketed drugs including esomeprazole (Nexium), loratadine (Claritin), and the recently approved cancer therapeutic crizotinib (Xalkori). Sabitha and coworkers have developed the first general method for the synthesis of... 

Esomeprazole (AstraZeneca). Esomeprazole is the (iS)-enantiomer of Omeprazole, the best selling antiulcer compound, and will be produced on a multitons per year scale. The key step of the new synthesis is the Ti-catalyzed oxidation of the sulfide intermediate (27b,47b,48,49). 

An application of the Kagan-Modena procedure for the synthesis of the enantio-merically pure S enantiomer of omeprazol was reported by Cotton et ol. [69] This enantiomer is called esomeprazol and is the active component of Nexium . It is a highly potent gastric acid secretion inhibitor. 

Enantioselective sulfoxidation of prochiral sulfides is also of industrial interest, e.g. in the synthesis of the antiulcer drug, esomeprazole, an enantiomerically pure sulfoxide. ... 

The most practical method that is used in the industrial synthesis of esomeprazole involves titanium-catalyzed oxidation with an alkyl hydroperoxide, and a dialkyltartrate as chiral ligand, in an organic solvent such as dichloromethane. A variety of oxidoreductases are known to catalyze the enantioselective oxidation of prochiral sulfides, usually as whole-cell biotransformations in aqueous media, but no simple metal complexes have been shown to be effective in water and the development of practical systems employing aqueous hydrogen peroxide as the primary oxidant is still an important challenge. In this context it is worth mentioning the enantioselective sulfoxidation of prochiral sulfoxides catalyzed by the semisynthetic peroxidase, vanadium-phytase, in an aqueous medium. 

There are many synthetic techniques for stereoselective synthesis and because of the importance much research is currently devoted to expanding these techniques. Omeprazole, marketed as Prilosec , was the first proton pump inhibitor and is used as a treatment for gastric ulcers. It is a racemic mixture. The S enantiomer has better pharmacokinetics and pharmacodynamics than the racemic mixture and therefore higher efficacy in controlling acid secretion [38]. The S enantiomer is called esomeprazole and is marketed as Nexium . Nexium has annual sales of 8.4 billion [39]. The chiral center is at the sulfur and the enantiomers can be separated by derivatizing with a R-(-) mandelic acid chiral auxiliary to form two diastereomers. Unlike enantiomers, diastereomers have different physical properties. The diastereomers can be separated by HPLC and then the chiral auxiliary removed to afford each of the omeprazole enantiomers. Alternatively, the sulfide precursor can be asymmetrically oxidized to form esomeprazole in 99.99% enantiomeric excess (ee) [40]. Enantiomeric excess means the excess amount of one enantiomer over the racemic mixture. If something is 80% ee that means that 20% is a racemic mixture and the other 80% is excess of that enantiomer. In this example, for 100 g, there are 90 g of the predominant enantiomer and 10 g of the lesser enantiomer in other words, 20 g is a racemic mix (lOg of each enantiomer) and 80g is excess enantiomer. 

Synthesis of Esomeprazole Omeprazole, the racemic form of the proton inhibitor drug sold under the... 

Synthesis of Lansoprazole Lansoprazole 30 was the top-selling drug in 2003, and it is currently employed as a racemate to treat stomach disorders derived by gastric acid thanks to its activity as a potent PPi belonging to the same class of drugs of esomeprazole 8. Thakur and... 

Cotton H, Elebring T, Larsson M, Li L, Sorenson H, von Unge S. Asymmetric synthesis of esomeprazole. Tetrahedron Asymm. 2000 11 3819-3821. 

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