New Methodology for the Medium Scale Solid-Phase Synthesis of Small Drug Molecules

Hans Christian Rudbeck

Research output: Book/ReportPh.D. thesisResearch

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Abstract

The aim of this dissertation was to investigate the possibility of synthesising small nitrogen heterocycles using solid-phase techniques, exploiting the properties of the novel, hydrophilic solid phase Versabeads.

Chapter 1 contains a general introduction to solid-phase chemistry and describes how Process Chemistry has the potential to benefit from the employment of solid-phase techniques in the initial scale-up of a drug candidate. The scope and problems concerning the use of solid-phase chemistry on a larger scale in the synthesis of small organic molecules are discussed.

Chapter 2 is a description of the development of the synthesis and use of two known solid-phase linkers: the REM linker and the carbamate linker, as well as the use of these two linkers in syntheses of piperazine derivatives.

The development of a gram-scale synthesis protocol of a series of N-aryl and N-arylN’- methyl piperazines based on the immobilization of bis(chloroethyl)amine on resin through the carbamate linker is described in Chapter 3. The scale-up to 0.19 mol reaction scale of a synthesis of an aryl piperazine on resin is demonstrated, as well as the possibility for reuse of the resin.

During the work on the piperazine-forming reaction an interesting side reaction was discovered, which formed a previously unknown imidazolidin-2-one through cyclative cleavage. The investigations into the scope and mechanism of this reaction are reported in chapter 4.

Chapter 5 concerns the use of the solid phase as a support for mesotetraphenylmetalloporphyrins, a well-known class of catalysts in organic chemistry. Two different meso-tetraphenylporphyrins were successfully immobilized on the resin and metallated with manganese. When tested as catalysts in the aqueous oxidation of sulphur, good conversions were obtained but the catalytic complexes appear to be cleaved from the resin under the reaction conditions. Attempts to synthesise porphyrins directly on the resin proved unsuccessful.
Original languageEnglish
Place of PublicationKgs. Lyngby, Denmark
PublisherTechnical University of Denmark
Number of pages189
Publication statusPublished - Jun 2006

Projects

New Methodology for the Medium Scale Solid-Phase Synthesis of Small Drug Molecules

Rudbeck, H. C., Tanner, D. A., Dancer, R. J., Gotfredsen, C. H., Jensen, K. J. & Vedsø, P.

ErhvervsPhD-ordningen VTU

01/03/200312/06/2006

Project: PhD

Cite this

Rudbeck, H. C. (2006). New Methodology for the Medium Scale Solid-Phase Synthesis of Small Drug Molecules. Technical University of Denmark.