Heterocyclic prostaglandins. VI. Synthesis of 11-deoxy-8,10-diazaprostaglandin E1 and its 10-methyl derivative.

Abstract

The synthesis of 11-deoxy-8, 10-diazaprostaglandin E1 (1a) starting from methyl 3-benzyloxycarbonyl-2-oxo-4-imidazolidinecarboxylate (3a) is reported. Alkylation of 3a with methyl 7-bromoheptanoate and NaH gave methyl 1-benzyloxycarbonyl-3-(6-methoxycarbonyl) hexyl-2-oxo-4-imidazolidinecarboxylate (9), which was converted into the 4-hydroxymethyl-imidazolidine derivative (10). The Moffatt oxidation of 10, and the Wittig reaction of the resulting aldehyde (11) with dimethyl 2-oxoheptylphosphonate provided an enone (12). Reduction of 12, and hydrolysis of a mixture of C15-epimeric alcohols (15) followed by re-esterification afforded 11-deoxy-8, 10-diazaprostaglandin E1 methyl ester (17a). Alkaline hydrolysis of 17a gave 1a as crystals in a good yield. The 10-methyl derivative (2a) was also synthesized. Methylation of 3a with methyl iodide and K2CO3 gave the 1-methylimidazolidine analog (7a), which was converted into methyl 3-(6-methoxycarbonyl) hexyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (20) after debenzyloxycarbonylation and alkylation with methyl 7-bromoheptanoate. Conversion of 20 into 2a was carried out by a synthetic sequence similar to that used for the elaboration of 1a.