Chemical synthesis in microreactors is a novel way of conducting chemistry in a highly controlled way with improved yields at impressive selectivities and with reduced overall effort. This paper describes recent technological progress with the potential as well as the application of the technology to chemical synthesis, discusses novel chemical optimization technology and reports on the transfer of the technology into production.

Continuous processing of liquid/liquid synthesis and microreaction technology are shown to reduce the cost of process development and manufacturing of active pharmaceutical ingredients and other functional molecules on a commercial scale. Combinatorial synthesis systems for continuous chemistry are introduced, and their applications are described. Reactions within these systems scale seamlessly in standardized commercial continuous synthesis equipment allowing rapid access to kilogram quantities of advanced intermediates. Chemical and process development within such systems are illustrated by a case study of a continuous multistep process. Additionally, another case study shows the benefit of microreaction technology in the manufacture of high value added functional chemicals.

The realm of combinatorial chemistry is strongly based on the concept of parallel chemistry and its ease of automation. Although this batch-type approach in general may be considered a success story, some limitations remain rarely addressable by conventional approaches. Particularly, scaling-up problems such as the re-synthesis of multigram amounts of active compounds as well as the synthesis of building blocks and scaffolds in large amounts may prove to be problematic. Our expertise in continuous chemistry prompted us to develop a microreaction system for sequential organic synthesis that should overcome these limitations. In the present contribution we describe this system as well as its application to the first library approach towards fluoro-quinolone antibiotics such as Ciprofloxacin solely using microreaction technology. A known one-pot batch procedure for the synthesis of this compound class was split in its individual reaction steps, which were successfully adapted to a continuous conduct. After some optimisation studies the overall sequence was suitable for chemical diversification. Particularly it was shown, that the first step of the synthesis -the acylation reaction of a b-dimethylamino acrylate with trifluoro-benzoic acid chloride -was accessible to synthesis of high quantities without any difficulties to yield a primary building block suitable for subsequent library synthesis. In a first diversification step, the Michael addition of a set of primary amines was followed by nucleophilic ring closure providing the difluoroquinolone system, which was subjected to a second diversification step by means of a nucleophilic aromatic substitution reaction. Thus, a number of Ciprofloxacin analogues could be synthesised in good overall yield and purity. Isolated yields ranged from 71 to 85% in the first diversification step and from 59 to 99% in the second step.

Only a few microreaction manufacturing plants are being operated to date. The performance of two different microreaction manufacturing plants is discussed, one in a dedicated application, the other in a multi-purpose environment. Strategies to address the major design and operating challenges for microreactor manufacturing plants to equipartition starting material streams into parallel reaction chambers throughout manufacturing operation are provided for demanding liquid/liquid-reactions. The importance of minimizing the pressure drop variances between different microreactors or channels by rigorous microreactor fabrication process control is described. A cost/performance balanced microreactor manufacturing strategy is suggested, and the ease of assessing trade-off decisions is addressed for different manufacturing systems by the use of a case study involving a diffusion controlled Grignard reaction.

Photolactonization: a Novel Synthetic Entry to Macrolides 0-Quinol acetates, hydroxyalkylated at C(6), are easily accessible from simple phenols by Wessely acetoxylation (preferentially catalyzed by BF,). On UV irradiation (in the presence of an appropriate tertiary amine), they are smoothly converted to macrocyclic lactones. Subtle conditions have been elaborated to lead to high overall yields, and the scope of the conversion of phenols to macrolides has been elucidated 1. Einleitung. -Der Begriff 'Photolactonisierung' kennzeichnet ein photochemisches Verfahren zur Herstellung von Makromonoliden C und/oder Makrodioliden D (s.