Instrument Design for Parallel Synthesis

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By Peter Gmeiner, PhD and Stefan Loeber, PhD

In the modern drug and materials research sectors, the parallel synthesis method is gaining more and more importance. In addition to liquid-phase synthesis, solid-phase-supported substance preparation can be used efficiently. With the help of recently developed instrument design, both variants can be implemented under both classical reaction conditions and highly demanding reaction conditions.

PARALLEL SYNTHESIS: CONCEPT AND ADVANTAGES
Parallel synthesis makes it possible to prepare and examine a variety of chemical compounds that are prepared by the same procedure, but that differ in the type or arrangement of the underlying synthetic building blocks. The goal here is fast and effective discovery of novel drugs, materials or catalysts, and optimization of chemical reactions. Such substance libraries are necessary in the modern pharma research sector since genomics and proteomics are constantly identifying new drug targets that can also be examined very quickly for their biological activity with the help of automated high throughput screening procedures.

Parallel synthesis differs from classical combinatorial procedures in that substance libraries are not produced in a mixture, but definite reaction products are formed in spatially separated reaction vessels. Besides the classical reaction in solution or by mixing educts and reagents with no solvents, parallel synthesis can also be used in the area of solid-phase-supported synthesis. This has its origin in peptide synthesis (solid-phase peptide synthesis, or SPPS) and has very recently been extended to non-peptide organic reactions (solid-phase organic synthesis, or SPOS). In both cases, the support is by means of a suitable resin on which synthetic building blocks or reagents are immobilized through chemical anchor groups (linkers).

INSTRUMENT DESIGN: AREAS OF USE AND SPECIAL FEATURES
Our collaboration helped develop an instrument designed to meet the multiple and individual requirements of parallel liquid- and solid-phase synthesis on a laboratory scale. Elements of the design included high variability to permit a variety of applications in the areas of pharma research, development of new molecular materials, and in the search for and optimization of chemical reactions and novel catalysts. Depending on the configuration of the instrument module, it can be used for parallel liquid- and solid-phase synthesis or for simultaneous evaporation. Other design factors included technical details to enable demanding reaction conditions such as exclusion of moisture or oxygen or precisely controlled low temperature.

The resulting instrument, Synthesis 1 from Heidolph Instruments GmbH & Co. KG (Schwabach, Germany), offers optimal visual reaction control, for both liquid-phase and solid-phase synthesis, by a circular arrangement of reaction vessels, which consist of glass or PTFE and PFA. Rotatable reaction platforms provide access to all samples. Individual seals on the reaction vessels have precluded the risk of contamination. Separate heating zones make it possible to set four different reaction zones. In this way, both elevated temperatures and low temperatures can be set precisely, with the assistance of a cryostat. Condensation zones permit the recondensation of solvents without requiring the use of reflux condensers.

The nature of the vessel material prevents resin from sticking to the inside of the solid-phase synthesis reaction vessels. The bottom section of the vessel accommodates the ground joint, a valve and the tubing connector to the suction drain. These are provided to collect rinse solvents in a beaker, or to isolate the products in test tubes after completion of the synthesis. This suction device can be controlled visually. The glass vessels for liquid-phase synthesis have standardized screw threads. Septum, valve, and vacuum or inert gas connectors are integrated into both vessel platforms. The instrument can be optionally equipped with a multivaporizer that makes simultaneous concentration in all of the connected reaction vessels possible.

Mixing in the reaction vessels is done with the help of especially rugged and low-vibration shaking technology. The frequency of the shaking apparatus can be adjusted continuously up to a maximum of 1,000 rpm.

The design provides for a modular principle. Thus, the base station can optionally be equipped with a platform for 16, 20 or 24 reaction vessels, each containing 42, 25 or eight millilitres, for solid-phase synthesis. The liquid-phase platform can be delivered for 12 50-millilitre reaction vessels, 16 25-millilitre vessels, or a maximum of 24 10-millilitre reaction vessels. The technology permits the instrument to be equipped not only with the maximum possible number of reaction vessels, but also with any smaller number of vessels.

INTO THE LABORATORY
In recent months we have used the instrument intensively for research activities in the field of liquid- and solid-phase-supported drug synthesis. Co-workers are pleased with the instrument’s multiple capabilities, and also by the stability of operation and precision of control.

Peter Gmeiner, PhD is a professor of pharmaceutical chemistry at Friedrich-Alexander University of Erlangen-Nuremberg (Erlangen, Germany). He is the recipient of the Johann-Wolfgang-Doebereiner Prize of the German Pharmaceutical Assoc., and a member of the board of directors of the Medicinal Chemistry Professional Group of the GDCh. His research interests are directed toward the design of solid-phase-supported and stereoselective drug synthesis and the in vitro testing of CNS-active receptor agonists and antagonists. In the teaching sector, Gmeiner co-ordinates the new Master Study program in Molecular Life Science in Erlangen, as well as the revised Pharmacy program.

Stefan Loeber, PhD was scientific assistant in pharmaceutical chemistry at Friedrich-Alexander University of Erlangen-Nuremberg from 2000-2003 and is now academic council z.A. His research interests are directed toward the solid and liquid-phase synthesis of potential CNS-receptor ligands and the development of new polymer-bound linkers.