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Casar Z.,Sandoz Pharmaceuticals | Steinbucher M.,University of Ljubljana | Kosmrlj J.,University of Ljubljana
Journal of Organic Chemistry

The first entry to statins via lactonized side chain is reported, exemplified by the synthesis of rosuvastatin. The key step is Wittig coupling of (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxotetrahydro-2H-pyran-2-carbaldehyde and phosphonium salt of an appropriately functionalized pyrimidine heterocy'le. One-pot deprotection and hydrolysis of the resulting 4-O-TBS rosuvastatin lactone provided rosuvastatin in high yield. © 2010 American Chemical Society. Source

Casar Z.,Sandoz Pharmaceuticals
Current Organic Chemistry

Satins are the most frequently prescribed and efficient drugs for treatment of lipid disorders. These drugs represent one of the most valuable therapeutic classes of compounds in the pharmaceutical sector. Since their discovery as fungal metabolites, many structural modifications have been performed during the past 30 years to obtain structurally refined and even more potent derivatives. These modifications led to the group of fully synthetic statins which are frequently addressed as super-statins. Structurally these compounds consist of a heterocyclic core attached to the chiral 3,5-dihydroxy-6-heptenoic or heptanoic acid side chain. Given their economical importance and well-established therapeutic applications with new indications continuously rising, much effort has been devoted to the improvement of primary synthetic strategies towards super-statins. Indeed, high consumption and multi-ton world wide production of super-statins pose continuous challenge for their economical and eco-friendly synthesis which makes super-statins attractive synthetic target for the organic chemist. Therefore, over the past two decades synthetic chemists have developed an assortment of routes to super-statins. In pur- suit to develop easy and practical approaches to superstatins array of new and innovative strategies have been developed. Many of these are outstanding synthetic achievements, especially in the area of chiral side chain synthesis. This review highlights the main methods for the synthesis of super-statin chiral side chain and heterocyclic core building blocks and provides a comprehensive survey of the evolution of synthetic approaches to marketed super-statins: fluvastatin, atorvastatin, rosuvastatin and pitavastatin. © 2010 Bentham Science Publishers Ltd. Source

Prebil R.,Jozef Stefan Institute | Stavber G.,Sandoz Pharmaceuticals | Stavber S.,Jozef Stefan Institute
European Journal of Organic Chemistry

A metal-free reaction system of air, NH4NO3(cat), 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)(cat), and H + (cat) is introduced as a simple, safe, inexpensive, efficient and chemoselective mediator for aerobic oxidation of various primary and secondary benzyl and alkyl alcohols, including those bearing oxidizable heteroatoms (N, S, O) to the corresponding aldehydes or ketones. Air oxygen under slight overpressure plays the role of the terminal oxidant, which is catalytically activated by redox cycles of nitrogen oxides released from a catalytic amount of NH4NO3 and cocatalyzed by TEMPO (nitroxyl radical compound), under acidic conditions, which are essential for an overall activation of the reaction system. The synthetic value of this reaction system and its green chemical profile was illustrated by a 10 g scale-up experiment, performed in an open-air system by using a renewable and reusable polymer-supported form of TEMPO (OXYNITROX®S100). The reaction solvent was recovered by distillation under atmospheric pressure, and the pure final product was isolated under reduced pressure; the acid activators (HCl or H 2SO4) were recovered as ammonium salts. A metal-free reaction system of air/NH4NO3(cat)/TEMPO (cat)/H+ (cat) is introduced as a simple, safe, inexpensive, efficient and chemoselective mediator for aerobic oxidation of various primary and secondary benzyl, alkyl and allyl alcohols, including those bearing oxidizable heteroatoms (N, S, O) to the corresponding aldehydes or ketones. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Naversnik K.,Sandoz Pharmaceuticals | Rojnik K.,Roche Holding AG
Value in Health

Objectives: Probabilistic uncertainty analysis is a common means of evaluating pharmacoeconomic models and exploring decision uncertainty. Uncertain parameters are assigned probability distributions and analyses performed by Monte Carlo simulation. Correlations between input parameters are rarely accounted for despite recommendations from several guidelines. By outlining theoretical reasons for including correlations and showing numerous examples of existing correlations, we appeal to the analyst to consider input dependencies. Our objective is to review the available methods to do so, give technical details on implementation and show, by using examples of published studies, the effect input correlations have on model outputs. Methods: A hierarchy of methods for dealing with correlations in Monte Carlo simulation is presented and used. The choice of method depends on the amount of information available on dependency and consists of functional modeling, joint distributions/copulas, and coupling of marginal distributions. Results: We induced input correlation with various methods and showed that in most cases the choice of optimal decision remained the same as in the independent scenario. There was, however, a significant change in the value of further information because of inducing input correlations. The results were similar for various dependency structures and were mainly a function of the strength of correlation, as measured by the linear correlation coefficient. Conclusion: Probabilistic uncertainty analysis reflects joint uncertainty across input parameters only when dependence among input parameters is accounted for. © 2012, International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Source

Jukic M.,University of Ljubljana | Sterk D.,Sandoz Pharmaceuticals | Casar Z.,Sandoz Pharmaceuticals
Current Organic Synthesis

In 1881, Rainer Ludwig Claisen discovered a carbon-carbon bond-forming reaction between two esters or an ester and a carbonyl compound in the presence of a base. The reaction leads to β-keto esters or β-diketones respectively, and it was later named Claisen condensation, or classic Claisen condensation in the former case, and mixed ('crossed') Claisen condensation in the latter. The reaction now sits firmly in the repertoire of organic synthesis as one of the earliest name reactions. In continuing research, it became evident that the products of this aldol type reaction can be cleaved to produce starting materials. Namely, β-diketone moieties were reported to undergo the retro-Claisen reaction, which is β-dicarbonyl carbon-carbon bond cleavage. Although it was first described as a side, or even parasitic reaction, it was later incorporated into the body of carbon-carbon base-promoted cleavage reactions. Moreover, numerous recent reports have demonstrated the wide selection of methodologies that can be used in these transformations. The scope ranges from various base-mediated or acid-mediated reactions and biocatalyzed transformations, and it extends to recently discovered homogeneous catalyzed reactions. Interestingly, further synthetic applications of retro-Claisen reaction are now being realized, and this is reflected in syntheses of natural products and other fine chemicals. This reaction is nowadays a useful synthetic tool and this review surveys and consolidates the recent literature on the retro-Claisen reaction. © 2012 Bentham Science Publishers. Source

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