New methods and reagents for small scale synthesis of phosphor organic compounds with focus on the phosphonic acids and their analogues

• Main Author: Wärme, Rikard
• Format: Doctoral Thesis
• Language: English
• Published: Umeå universitet, Kemi 2010
• Subjects: micro scale; phosphorus oxyacids; solid phase; chlorination; fluorination; radiolabelling; Organic synthesis; Organisk syntes
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-32904; http://nbn-resolving.de/urn:isbn:978-91-7264-991-0

The development of a synthetic method of radiolabelled methylphosphono-fluoridates on a milligram scale is presented. The aim of this method is, besides affording high yield, to choose reaction pathways and reagents so that handling and transfer of labelled toxic substances is minimised, thereby reducing the risk of exposure as much as possible. The only substituent that is stable enough to be labelled is the methyl group, directly bonded to phosphorus. A drawback when labelling the methyl group is that it requires the label to be introduced early in the synthesis since the carbon-phosphorus bond of the methyl substituent usually has to be synthesized a few steps ahead of the final product. Two new classes of reagents for halogenation of phosphorus oxyacids have been developed. Firstly, four different analogues of α-chloroenamines and α-fluoroenamines were evaluated. Secondly, cyanuric fluoride was assessed in solution, but more importantly, as a resin-bound reagent. The reagents are evaluated for halogenation of phosphinic, phosphonic and phosphoric acids. Cyanuric fluoride is also successfully loaded on a polystyrene resin and used as a solid-phase reagent. The reagents produce high yields and low levels of impurities on a milligram scale. Furthermore, a new method for the preparation of mono-alkylated phosphonic acids on a small scale has been developed. The new method utilises the crystal water bound to certain salts to liberate limited amounts of water in a controlled manner. Phosphonic dichlorides are in this way reacted with water to form anhydrides. The anhydride is then cleaved with an appropriate alcohol to produce mono-alkylated phosphonic acids. === Rikard Norlin = Rikard Wärme