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Synthesis of thioether phosphocholine analogues
Author(s) -
Bosies Elmar,
Herrmann Dieter B. J.,
Bicker Uwe,
Gall Rudi,
Pahlke Wulf
Publication year - 1987
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/bf02535561
Subject(s) - chemistry , thioether , medicinal chemistry , hydroxymethyl , carboxylate , alkylation , stereochemistry , organic chemistry , catalysis
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 diethyl bis ‐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 LiAlH 4 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 by N ‐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.