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Prebil R.,Jozef Stefan Institute | Stavber G.,Sandoz Pharmaceuticals | Stavber S.,Jozef Stefan Institute
European Journal of Organic Chemistry | Year: 2014

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.


Casar Z.,Sandoz Pharmaceuticals | Steinbucher M.,University of Ljubljana | Kosmrlj J.,University of Ljubljana
Journal of Organic Chemistry | Year: 2010

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.


Gaziasmilovia I.,Sandoz Pharmaceuticals | Casas-Arce E.,Johnson Matthey | Roseblade S.J.,Johnson Matthey | Nettekoven U.,Solvias A.G. | And 3 more authors.
Angewandte Chemie - International Edition | Year: 2012

Persistent chlorine: Hydrogenation of borolane-substituted vinylic chlorides catalyzed by Ir-P N complexes greatly preserved the chlorine substituent on the hydrogenated product, with only 3-19 % of dechlorinated byproducts present after hydrogenation. The α-chloro boronic ester products are ideal precursors for proteasome-inhibitor-type anti-cancer drugs, a fact which demonstrates the utility of this hydrogenation method. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Stavber G.,Sandoz Pharmaceuticals | Casar Z.,Sandoz GmbH | Casar Z.,Sandoz Pharmaceuticals | Casar Z.,University of Ljubljana
ChemCatChem | Year: 2014

Purity in water: An interesting course of development took place recently in the area of boron additions to unsaturated precursors. The first Cu II and Cu0 catalyzed B2pin2 additions to alkenes and alkynes in/on pure aqueous media evolved from discovery on racemic versions to asymmetric variants and pharmaceutical applications. All presented methods provide significantly simplified catalytic systems and perform with high efficiency and stereoselectivity in/on pure water. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Naversnik K.,Sandoz Pharmaceuticals | Rojnik K.,Roche Holding AG
Value in Health | Year: 2012

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).


Jevsevar S.,Sandoz Pharmaceuticals | Kunstelj M.,Sandoz Pharmaceuticals | Porekar V.G.,Slovenian National Institute of Chemistry
Biotechnology Journal | Year: 2010

Since the first PEGylated product was approved by the Food and Drug Administration in 1990, PEGylation has been widely used as a post-production modification methodology for improving biomedical efficacy and physicochemical properties of therapeutic proteins. Applicability and safety of this technology have been proven by use of various PEGylated pharmaceuticals for many years. It is expected that PEGylation, as the most established technology for extension of drug residence in the body, will play an important role in the next generation therapeutics, such as peptides, protein nanobodies and scaffolds, which due to their diminished molecular size need halflife extension. This review focuses on several factors important in the production of PEGylated biopharmaceuticals enabling efficient preparation of highly purified PEG-protein conjugates that have to meet stringent regulatory criteria for their use in human therapy. Areas addressed are PEG properties, the specificity of PEGylation reactions, separation and large-scale purification, the availability and analysis of PEG reagents, analysis of PEG-protein conjugates, the consistency of products and processes and approaches used for rapid screening of pharmacokinetic properties of PEG-protein conjugates. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.


Naversnik K.,Sandoz Pharmaceuticals
European Journal of Health Economics | Year: 2014

A comprehensive cost-effectiveness decision model will often go beyond a one-to-one comparison and will include a number of competing alternatives. Only a simultaneous assessment of all relevant treatment alternatives avoids comparing average cost-effectiveness ratios and allows a truly incremental analysis. Two issues arise if the analysis is probabilistic, namely, the occurrence of output correlations and difficulty in presenting the results. I have examined the role of output correlations using a screening model with eight alternatives and have shown that specifically cost-cost and quality-adjusted life years (QALY)-QALY correlations between alternatives have a major impact on decision uncertainty, as measured by the probability of the cost-effectiveness and expected value of perfect information. In particular, the latter strongly depends on between-alternative output correlations. This analysis shows that both the expected value of perfect information plots and acceptability curves/frontiers are sensitive to output correlations and thus appropriate for presentation of multiple alternatives. To avoid confusing statistical significance and economic importance I propose that acceptability curves be augmented by incremental net-benefit density plots at a given willingness to pay threshold. © 2014 Springer-Verlag Berlin Heidelberg.


Troiani V.,Sandoz Pharmaceuticals | Cluzeau J.,Sandoz Pharmaceuticals | Casar Z.,Sandoz Pharmaceuticals
Organic Process Research and Development | Year: 2011

A chemoselective biocatalytic procedure for the synthesis of (4R,6S)-4-(tert-butyldimethylsilyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-2- one, a key lactonized statin side chain intermediate, from its acetate precursor is described. The presented method is based on the pancreatin powder-catalyzed cleavage of the acetyl group in ((2S,4R)-4-(tert-butyldimethylsilyloxy)-6- oxotetrahydro-2H-pyran-2-yl)methyl acetate. The reaction was conducted in aqueous medium. The overall process is performed in a convenient way and economical manner suitable for industrial use. © 2011 American Chemical Society.


Casar Z.,Sandoz Pharmaceuticals
Current Organic Chemistry | Year: 2010

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.


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