Synthesis of thioether phosphocholine analogues

Publisher Website
Google Scholar
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.