Folate Analogues. 24. Syntheses of the Antitumor Agents 10-Deazaaminopterin (10-DAAM) and 10-Ethyl-10-deazaaminopterin (10-EDAAM)

Article abstract of DOI:10.1021/jo00211a019

Methods have been developed for the chemical synthesis of two recently described potent antitumor agents.They are 10-deazaaminopterin (10-DAAM) (2) and 10-ethyl-10-deazaaminopterin (10-EDAAM) (3).The methods described in this paper have general applicability for the synthesis of a variety of hitherto difficulty accessible 10-substituted-10-deazafolic acids and analogues.Reaction of methyl p-formylbenzoate (7) with the Wittig reagent 6 derived from N-(3-bromo-2-oxopropyl)phtalimide (5) and triphenylphosphine gave the common intermediate 8, which was used for the synthesis of both 2 and 3.This enone was reduced with Zn/HOAc to 15 and was used for the synthesis of 2.Alternately 8 was reacted with ethylmagnesium bromide in the presence of cuprous bromide to obtain the conjugate addition product 16.Both 15 and 16 were converted to the masked α-amino ketones 20 and 21 reacted with 6-chloro-2,4-diamino-5-nitropyrimidine to obtain 22 and 23.These pyrimidine intermediates were subsequently elaborated to the pteroic acid analogues 26 and 27 by multistep procedures previously described from this laboratory.The target compounds 2 and 3 were prepared from 26 and 27 by standard coupling procedures involving isobutyl chloroformate and diethyl L-glutamate.