Synthesis of thioether phosphocholine analogues |
| |
Authors: | Elmar Bosies Dieter B. J. Herrmann Uwe Bicker Rudi Gall Wulf Pahlke |
| |
Affiliation: | (1) Department of Immunopharmacology and Cancer Research, Boehringer Mannheium GmbH, Sandhofer Strasse 116, 6800 Mannheim 31, Federal Republic of Germany |
| |
Abstract: | The synthesis of thioether phospholipids, which represent a new class of antitumor agents, is reported here. In particular, the route of synthesis of 3-hexadecylmercapto-2-methoxymethylpropyl-2′-trimethylammonio-ethyl phosphate (BM 41.440, Ilmofosine), one of the most potent cytostatic/cytotoxic derivatives, is described in detail. Starting with diethylbis-hydroxymethylmalonate, ethyl 2-phenyl-1,3-dioxane-5-carboxylate is formed via diethyl 2-phenyl-1,3-dioxane-5,5-dicarboxylate and 5-ethoxycarbonyl-2-phenyl-1,3-dioxane-5-carboxylic acid. Reduction of ethyl 2-phenyl-1,3-dioxane-5-carboxylate with LiAlH4 affords 5-hydroxymethyl-2-phenyl-1,3-dioxane. Alkylation with dimethyl sulfate gives 5-methoxymethyl-2-phenyl-1,3-dioxane. The ring structure then is opened byN-bromosuccinimide, resulting in the formation of 3-bromo-2-methoxymethylpropyl benzoate. Reaction of 3-bromo-2-methoxymethylpropyl benzoate with the sodium salt of hexadecanethiol leads to 3-hexadecylmercapto-2-methoxy-methylpropanol, which is reacted with a cyclic chlorophosphate to give the corresponding phosphorylated 3-hexadecylmercapto-2-methoxymethylpropanol. Treatment with trimethylamine yields BM 41.440. This compound already has been tested in clinical phase I/II trials in West Germany. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|