Development of a Microreactor for Solid Phase Synthesis

1.2
Solid Phase Organic Chemistry
One of today's most effective and reliable methods for the preparation of large libraries is based on the use of solid phase organic synthesis due to the ease of its automation and the good purities of the final products. This technology - the build up of a molecule on a template which is covalently bonded via a linker to a polymer support, followed by cleavage of the bond to the linker - has been developed to a very reliable tool in parallel synthesis [5]. The main advantages are: • The ease of driving a reaction to completion by employing excess reagent which can be washed off after the reaction. • The avoidance of difficult purification steps such as chromatography, distillation or crystallization. SPOS needs only few repetitive unit operations which have to be realized under inert conditions: • Addition of liquid reagents / solvents • Agitation • Filtration • Heating / cooling
Abstract: Laser micro manufacturing is well suited for the fabrication of microreaction systems. The use of high performance polymers in combination with microstructuration and microjoining technologies allows us to develop sealed microreaction systems. These are suited for organic synthesis even with aggressive reagents and under inert atmospheres. The microreaction system presented in this paper will enable us to perform combinatorial solid phase chemistry very efficiently. The most striking novelty of our micro reactor matrix is the mixing of the reaction vessels by means of an oscillating membrane. That generates turbulence in the above suspension of a polymer resin. The addition of reagents and the work up / washing of the resin will be extremely fast and gentle. Keywords: laser microstructuration, microjoining, polymers, combinatorial solid phase synthesis, mixing, micro reaction system
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M. Matlosz et al. (eds.), Microreaction Technology © Springer-Verlag Berlin Heidelberg 2001
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1.1
Miniaturization of Combinatorial Chemistry
Combinatorial chemistry is a topic of great interest for microreaction technology due to high economic importance and the fact that single microreactors can easily produce sufficient amounts of substances for HTS purposes. Modern ultra High Throughput Screening systems (uHTS) can test up to 100.000 compounds per day, which is only accessible as a result of the miniaturization of all components in screening systems and a high degree of parallelization and automation. Within the last 5 years the standard micro titer plate used for screening has been redesigned twice. Starting from 96 well plates followed by 384 well plates, these are today replaced by state of the art 1536 well plates. The increased screening capacities lead to an exponential increase in the demand for new substances for testing while the needed amounts are decreasing at the same ratio. The increase in test wells per plate has led to a decrease in volume by a factor of 16. Following the decrease in the needed amounts of test substances, modern combinatorial/parallel synthesis does not need to produce several (10-20) milligrams of new compounds any more, less than one milligram will be satisfactory in the future to be used in several dozens of essays. This goal can be accomplished using the modern method of solid phase organic chemistry (SPOS) on less than 30 mg of resin. Today's technologies in SPOS do not offer any satisfactory solutions for this demand - more compounds in smaller amounts - in a fast and reliable automated synthesis yet.
Development of a Microreactor
for Solid Phase Synthesis
Elke Bremus-K6bberling, Arnold Gillner, Martin Wehner, Ulrich Russek, Fraunhofer Institute for Lasertechnology, Aachen, Germany Johannes K6bberling, Dieter Enders, Institute for Organic Chemistry, RWTH Aachen, Germany Siegfried Brandtner, Innolabtec GmbH, Stolberg! Rhld., Germany
1
Introduction
The trends of miniaturization, parallelization and automation are continuously gaining influence on modern fields of chemistry and life sciences. Chemical and biological micro total analysis systems (uTAS) are a subject of steady development since more than 10 years.[1,2] In the last few years advantages of miniaturization for chemical synthesis such as use of the high surface to volume ratio, good heat conduction and mass transport have drawn the attention to developing microreactors for single reactions, often as tools for optimization purposes. [3] The many applications of microreactors are reviewed by Ehrfeld et al.[4]