Synthesis of thioether phosphocholine analogues.
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'-trimethylammoni o-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-ethoxycar-bonyl-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 by N-bromosuccinimide, resulting in the formation of 3-bromo-2-methoxymethylproply 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.
Bosies
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E
Boehringer Mannheium GmbH, Department of Immunopharmacology and Cancer Research, Federal Republic of Germany.
Herrmann
D B
DB
Bicker
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U
Gall
R
R
Pahlke
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W
D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D008968:Molecular Conformation; D010755:Organophosphates / Q000138:chemical synthesis*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis*; D010742:Phospholipid Ethers / Q000138:chemical synthesis*
D000970:Antineoplastic Agents; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010742:Phospholipid Ethers; C043297:ilmofosine