title: Synthesis of thioether phosphocholine analogues.
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'-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.
authors.affiliation: Boehringer Mannheium GmbH, Department of Immunopharmacology and Cancer Research, Federal Republic of Germany.
authors.forename: E
authors.initials: E
authors.lastname: Bosies
authors.forename: D B
authors.initials: DB
authors.lastname: Herrmann
authors.forename: U
authors.initials: U
authors.lastname: Bicker
authors.forename: R
authors.initials: R
authors.lastname: Gall
authors.forename: W
authors.initials: W
authors.lastname: Pahlke
mesh_terms: 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*
chemical_list: D000970:Antineoplastic Agents; D010755:Organophosphates; D009943:Organophosphorus Compounds; D010742:Phospholipid Ethers; C043297:ilmofosine