Synthesis of fluorinated derivatives of glutethimide and aminoglutethimide

Aminoglutethimide (1), used in the treatment of hormone dependent breast cancer, interacts with enzyme complexes desmolase and aromatase. Its action is not specific and its metabolism gives rise to toxic and non-inhibitory metabolites. The work described here explores the impact of fluorine substitution within the glutethimide (2) framework, on the enzyme inhibitory properties of aminoglutethimide. Four new fluorinated derivatives (5), (6), (8) and (9) have been prepared, in which fluorine substituents have been introduced into the phenyl ring and the ethyl side chain. 4-Fluoroglutethimide (5) and 3-trifluoroglutethimide (6) were synthesised from the corresponding fluorophenylacetonitriles (10) and (14) via sequential monoethylation, Michael addition to methyl propenoate and cyclisation. An alternative strategy, devised for the synthesis of (8), involved the monoarylation of ethyl cyanoacetate, and gave rise to the intermediate (29). Incorporation of fluorine was carried out by SF₄ fluorination of the cyanoketoester (33), which was subsequently converted to the difluoroaminoglutethimide (8). For the synthesis of trifluoromethyl glutethimide (9), the trifluoromethyl group was introduced by alkylation of phenylcyanoacetate (16) with 2-iodo-1,1,1,-trifluoroethane. Preliminary enzyme inhibition results have been obtained for compounds (5), (6) and (8).