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Optimisation de la synthèse de 3,3-difluoroazétidin-2-ones et de β-aminoesters α,α-difluorés : Application à la synthèse d'inhibiteurs du TAFIa

Abstract : With the collaboration of Servier Laboratories, we report the synthesis of a new family of thiol- and carboxyl-based inhibitors that were developed as antagonists of activated thrombinactivatable fibrinolysis inhibitor (TAFIa) for potential antithrombotic and thrombolytic therapy. The key step in the synthesis consists in the formation of gem-difluoro-β-lactam scaffolds. In this purpose, the chemoselective and stereoselective synthesis of gem-difluoro-β-aminoesters and gem-difluoro-β-lactams was investigated using a Reformatsky reaction between ethyl bromodifluoroacetate and imines. Influence of various reaction parameters, nature of the amine and aldehyde parts, nature of the chiral auxiliary were evaluated. High levels of stereoselectivity (up to 98%) were obtained for gem-difluoro-β-aminoesters and gem-difluoro-azetidin-2-ones using either (R)-phenylglycinol or (R)-methoxyphenylglycinol. We also developed a very efficient process to perform the synthesis of racemic gem-difluoro-β-lactams. These targets were obtained by a Reformatsky reaction between ethyl bromodifluoroacetate and p-methoxybenzylamine imines. The synthesis of racemic gem-difluoro-β- aminoester compounds was accomplished by Gilman-Speeter reaction between iminium salts generated using Katritzky's process and ethyl bromodifluoroacetate. After an effective deprotection of these gem-difluoro-β-aminoesters and gem-difluoro-β-lactams, we investigated N-alkylation and N-acylation reactions for the introduction of the zinc-chelating group, e.g. a group bearing a carboxylic acid or thiol functionality, and a spacer group. After deprotection, compounds were assayed for carboxypeptidase U inhibition by IdRS angiology group. Unfortunately, all of them have showed an IC50 superior to 33 rM. Nevertheless, we have developed an efficient and general method to synthesize gem-difluoro pseudopeptide derivatives as original building blocks with a wide range of use.
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https://tel.archives-ouvertes.fr/tel-00725419
Contributor : Nicolas Boyer <>
Submitted on : Sunday, August 26, 2012 - 5:56:53 PM
Last modification on : Tuesday, February 5, 2019 - 11:24:28 AM
Long-term archiving on: : Tuesday, November 27, 2012 - 2:50:10 AM

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  • HAL Id : tel-00725419, version 1

Citation

Nicolas Boyer. Optimisation de la synthèse de 3,3-difluoroazétidin-2-ones et de β-aminoesters α,α-difluorés : Application à la synthèse d'inhibiteurs du TAFIa. Chimie organique. INSA de Rouen, 2007. Français. ⟨tel-00725419⟩

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