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Analogs of 3‐(1‐phenyl‐3‐oxobutyl)‐4‐hydroxycoumarin (warfarin) prepared from substituted salicylic acids
Author(s) -
Obaseki Andrew O.,
Steffen James E.,
Porter William R.
Publication year - 1985
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570220264
Subject(s) - chemistry , 4 hydroxycoumarin , salicylic acid , substituent , diethyl malonate , formic acid , coumarin , amine gas treating , medicinal chemistry , organic chemistry , yield (engineering) , ring (chemistry) , malonate , acetic anhydride , catalysis , biochemistry , materials science , metallurgy
Some derivatives of salicylic acid containing substituents meta to the carboxyl group were used to prepare analogs of the anticoagulant drug warfarin, 3‐(1‐phenyl‐3‐oxobutyl)‐4‐hydroxycoumarin, containing substituents in either the 6‐or 8‐position of the courmarin ring. When the substituent was the hydroxyl group, the resulting products are previously identified metabolites of warfarin. The substituted salicylic acid is first acetylated with acetic anhydride, then either converted to the acid chloride and condensed with diethyl malonate in the presence of sodium hydroxide or converted to the mixed anhydride with formic acid and condensed with ethoxymagnesium diethyl malonate to yield, in either case, the corresponding 3‐carbethoxy‐4‐hydroxycoumarin substituted in the 6‐ or 8‐position of the coumarin ring. These compounds readily condense with benzalacetone to form the corresponding substituted warfarin in the presence of 5 mole % tertiary amine catalyst. This method offers an improved route for the synthesis of 8‐hydroxywarfarin.