Ring-Opening/Recyclization Reactions of (Dimethylamino)propenoyl-Substituted Cyclopropanes: Facile Synthesis of Halogenated Pyridin-2(1H)-ones

A facile and efficient synthesis Of Substituted pyridin-2(1H)-ones has been developed by the reaction of readily available 1-carbamoyl-]-[3-(dimethylamino)propenoyl]cyclopropanes with phosphoryl chloride or phosphorus tribromide in dichloromethane at room temperature.

Efficient one-pot synthesis of highly substituted pyridin-2(1H)-ones via the Vilsmeier-Haack reaction of 1-acetyl,1-carbamoyl cyclopropanes

A facile and efficient one-pot synthesis of highly substituted pyridin-2(1H)-ones is developed via the Vilsmeier-Haack reaction of readily available 1-acetyl,1-carbamoyl cyclopropanes, and a mechanism involving sequential ring-opening, haloformylation, and intramolecular nucleophilic cyclization reactions is proposed.

Cost-Effectiveness of Non-Vitamin K Antagonist Oral Anticoagulants for Atrial Fibrillation in Portugal

INTRODUCTION AND OBJECTIVES:Recently, three novel non-vitamin K antagonist oral anticoagulants received approval for reimbursement in Portugal for patients with non-valvular atrial fibrillation (AF). It is therefore important to evaluate the relative cost-effectiveness of these new oral anticoagulants in Portuguese AF patients. METHODS: A Markov model was used to analyze disease progression over a lifetime horizon. Relative efficacy data for stroke (ischemic and hemorrhagic), bleeding (intracranial, other major bleeding and clinically relevant non-major bleeding), myocardial infarction and treatment discontinuation were obtained by pairwise indirect comparisons between apixaban, dabigatran and rivaroxaban using warfarin as a common comparator. Data on resource use were obtained from the database of diagnosis-related groups and an expert panel. Model outputs included life years gained, quality-adjusted life years (QALYs), direct healthcare costs and incremental cost-effectiveness ratios (ICERs). RESULTS:Apixaban provided the most life years gained and QALYs. The ICERs of apixaban compared to warfarin and dabigatran were €5529/QALY and €9163/QALY, respectively. Apixaban was dominant over rivaroxaban (greater health gains and lower costs). The results were robust over a wide range of inputs in sensitivity analyses. Apixaban had a 70% probability of being cost-effective (at a threshold of €20 000/QALY) compared to all the other therapeutic options. CONCLUSIONS:Apixaban is a cost-effective alternative to warfarin and dabigatran and is dominant over rivaroxaban in AF patients from the perspective of the Portuguese national healthcare system. These conclusions are based on indirect comparisons, but despite this limitation, the information is useful for healthcare decision-makers.

Stereoselektive Synthesen von Stickstoffheterocyclen aus 4-substituierten N-Galactosyl-dehydropiperidinonen

Ziel dieser Arbeit war es, an in 4-Position substituierten N-Galactosyl-dehydropiperidinonen die übrigen Positionen des Heterocycluses selektiv zu funktionalisieren und die erarbeiteten Methoden im Rahmen von Total- und Partialsynthesen biologisch aktiver Verbindungen anzuwenden. Ausgehend von N-Galactosyl-2-pyridon, welches sich in drei Stufen aus D-Galactose im Gramm-Maßstab erhalten lässt, konnten die in Position 4-substituierten Dehydropiperidinone in regio- und diastereoselektiv verlaufenden Additionen von Grignard-Reagenzien und Organocupraten synthetisiert werden. Es gelang die Einführung sowohl unverzweigter als auch sekundärer, tertiärer und cyclischer Alkylreste. Ebenfalls gute Ausbeuten und exzellente Diastereoselektivitäten wurden bei der konjugierten Addition verschieden substituierter Aryl- und Benzyl-Grignard-Reagenzien erhalten. Das Kohlenhydratauxiliar kontrolliert dabei nicht nur die faciale Selektivität, sondern es bestimmt gleichzeitig die Regioselektivität. Die absolute Konfiguration der 4-substituierten 2-Pyridone konnte durch Röntgenstrukturanalysen zweier Produkte zweifelsfrei geklärt werden. Dass die so dargestellten Heterocyclen wertvolle Synthone zur asymmetrischen Synthese mehrfach substituierter Piperidinverbindungen sind, konnte gezeigt werden durch die Ausarbeitung verschiedener Methoden zur weitergehenden Funktionalisierung an den Positionen C-2, C-3, C-5 und C-6 sowie durch die Entwicklung eines Verfahrens zur Freisetzung der stereoselektiv synthetisierten Heterocyclen. Diese systematisch untersuchten Synthesewege konnten in Partial- und Totalsynthesen von pharmakologisch relevanten Verbindungen erfolgreich beschritten werden. So gelang die Synthese des biologisch aktiven (3S)-Piperidinols, sowie die des 3-Hydroxy-4-(4-fluorphenyl)-piperidin-Derivates. Weiterhin gelang die formale Totalsynthese von (+)-Paroxetin, welches einen pharmakologisch interessanten Wirkstoff mit der Struktur eines 3,4-trans-disubstituierten Piperidins darstellt. Ein weiterer Themenschwerpunkt dieser Arbeit war die regio- und stereoselektive Synthese von Benzomorphan-Derivaten. Diese gelang durch intramolekulare Amino-Alkylierung der 4-Benzyl-substituierten Dehydropiperidinone. Durch Anwendung dieser Methodik konnte eine Reihe verschieden substituierter 7,8-Benzomorphan-Derivate synthetisiert werden, die interessante Zwischenstufen in der asymmetrischen Benzomorphansynthese darstellen. In einer exemplarischen Synthese wurde so das 7,8-Benzomorphan hergestellt.

Studies in asymmetric and heterocyclic synthesis: I. chiral ketones II. Quinolones III. Trifluoromethylated pyrones

This thesis is split into three sections based on three different areas of research. In the first section, investigations into the α-alkylation of ketones using a novel chiral auxiliary is reported. This chiral auxiliary was synthesised containing a pyrrolidine ring in the chiral arm and was applied in the preparation of α-alkylated ketones which were obtained in up to 92% ee and up to 63% yield over two steps. Both 3-pentanone and propiophenone based ketones were used in the investigation with a variety of both alkyl and benzyl based electrophiles. The novel chiral auxiliary was also successful when applied to Michael and aldol reactions. A diamine precursor en route to the chiral auxiliary was also applied as an organocatalyst in a Michael reaction, with the product obtained in excellent enantioselectivity. In the second section, investigations into potential anti-quorum sensing molecules are reported. The bacteria Pseudomonas aeruginosa is an antibiotic-resistant pathogen that demonstrates cooperative behaviours and communicates using small chemical molecules in a process termed quorum sensing. A variety of C-3 analogues of the quorum sensing molecules used by P. aeruginosa were synthesised. Expanding upon previous research within the group, investigations were carried out into alternative protecting group strategies of 2-heptyl-4-(1H)- quinolone with the aim of improving the yields of products of cross-coupling reactions. In the third section, investigations into fluorination and trifluoromethylation of 2-pyrones, pyridones and quinolones is reported. The incorporation of a fluorine atom or a trifluoromethyl group into a molecule is important in pharmaceutical drug discovery programmes as it can lead to increased lipophilicity and bioavailability, however late-stage incorporation is rarely reported. Both direct fluorination and trifluoromethylation were attempted. Eight trifluoromethylated 2-pyrones, five trifluoromethylated 2-pyridones and a trifluoromethylated 2-quinolone were obtained in a late-stage synthesis from their respective iodinated precursors using methyl fluorosulfonyldifluoroacetate as a trifluoromethylating reagent.