A practicable two-step procedure for the preparation of a series of lactone-type bridged biaryls 7 as favorable substrates for subsequent atropisomer-selective ring-opening reactions is described. Due to the efficiency of the coupling step, which tolerates even a telt·butyl group next to the biaryl axis and avoids problems of regioselectivity, a variety of differentlyThe regio-and stereoselective construction of natural and unnatural hindered biaryl systems is a synthetic challenge that has successfully been approached only very recentlyP-4 1 . Exemplarily for the substitution pattern as in 1, which is found in many naturally occurring biaryls l 5 1 , we have developed a useful procedure in which the two formal partial goals of stereoselective biaryl synthesis are attained consecutively l 6-11 1 : The CC bond formation is performed by intramolecular aryl coupling of the ester-type prefixed aromatics as in 3, and the asymmetric induction at this biaryl axis is achieved by an atropdiastereo-or enantioselective ring opening of the resulting lactones 2. Hence, such bridged biaryls 2 play a crucial role in this concept: Although they already possess the biaryl axis, most of them are axially prostereogenicl6.7.12.IJJ, i.e. they do not occur as stable atropisomers (helimers) at the synthetically relevant temperatures. Apparently, the rotational barrier of 2 is drastically lower than that of the open-chain final target biaryls 1 and thus allows rapid helimerization (e.g. at room temperature).For a thorough investigation of the structures of such bridged biaryls, of their isomerization mechanism, and eso 2 00 n ~o V 3 substituted representatives is prepared. These cover a broad range of steric hindrance and thus molecular distortion. The structures are investigated mainly by NMR spectroscopy and X-ray diffraction, showing the lactones 7 to be helically distorted, depending on the size of the residues R. pecially of the unprecedented stereocontrolled ring opening process, there is a great need of appropriately substituted representatives of this stereochemically interesting class of bridged biaryls. In this paper, we describe a practicable synthetic pathway to a series of benzonaphthopyranones of the general type 7, with a broad variety of substituents of most different sizes next to the biaryl axis. Part of this work has recently been reported in preliminary form 1 9 • 10 1.The structural type 7 was chosen for different reasons: On the one hand, its substitution pattern (alkyl groups and oxygen functions in ortho-positions with respect to the axis) is similar to that of many naturally occurring biaryls. Also, the symmetrical structure of the variable phenolic component helps to avoid additional problems of regioselectivity in the intramolecular aryl coupling step. A further advantage of the lactones 7 was their supposed tendency to afford crystals suitable for X-ray structure analysis (see below). By contrast, the long-chain O-substituted derivative 7c was prepared because of its expected favorable solubility properties,...

The pharmaceutical industry is moving towards a profitability gap between increasing costs and decreasing prices. Finally, management has understood that mergers and acquisitions, high throughput screening, and biotechnology alone will not save the companies' earnings. Therefore, classical approaches like the optimization of production technologies for drug substances, that might help to increase profitability, are receiving increasing attention. This paper shows how the combination of innovative components will guide the way to very efficient and cost-effective production. The first component is the design and manufacturing of production facilities. The second component is a process streamlining of the production process. The key technologies discussed here are process control and miniplant technology. For these technologies a brief outlook on future trends is given.

The atropo-diastereoselective cleavage of lactone-bridged and thus configurationally unstable biaryls with chiral metal-activated 1-arylethylamines gives axially chiral biaryl amides in good yields and high atropo-diastereomeric ratios of up to 95:5. In this methodology, even the minor not desired rotational isomer can be recycled literally by recyclization back to the configurationally unstable lactone, and renewed stereoselective cleavage. Furthermore, by the use of the corresponding enantiomer of the N-nucleophile, the enantiomeric biaryl product is also attainable from the same lactone precursor (ªatropo-divergenceº). In addition, several methods have been developed to transform the amide function into a methyl or an aminomethylene group. All these options further enlarge the scope and the utility of the method elaborated.

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Die Pharmaindustrie befindet sich auf dem Weg in die Kostenfalle. Mehr und mehr setzt sich die Erkenntnis durch, dass klassische Stärken der Optimierung von Produktionstechnologien dort ansetzen können, wo Fusionen, Investitionen in High‐Through‐Put‐Screening und Biotechnologie bisher nicht die nötigen Erfolge gezeigt haben. Im vorliegenden Beitrag wird gezeigt, wie aus einer Kombination von innovativen Bausteinen eine leistungsfähige und deutlich kostengünstigere Produktion von Pharmawirkstoffen resultiert. Diese kann den Ausweg aus der Kostenfalle weisen. Ein erster Baustein, der betrachtet werden soll, ist der Anlagenbau, daneben ist eine deutlich stärkere Prozessorientierung als zweiter Baustein zu sehen. Die Technologien, die den dritten Baustein der neuen Produktionswege für Pharmawirkstoffe darstellen, sind die Miniplant‐Technologie und die Prozessanalytik. Zu letzterem technologischen Baustein werden anhand von Beispielen die Trends der Zukunft aufgezeigt.

Ein zunehmender Kostendruck wird die Pharmaindustrie drastisch verändern. Wo bisher nur die Innovationskraft eines Unternehmens zählte, wird in Zukunft zusätzlich eine schnelle Entwicklung und eine dauerhaft günstige Fertigung kombiniert mit attraktivem Kundenservice erheblich an Gewicht erlangen.

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