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Synthesis of 4‐[(1,3‐diaminopyrrolo[3′,4′:4,5]pyrido[2,3‐ d ]‐pyrimidin‐8‐yl)benzoyl]‐L‐glutamic acid as a potential antifolate
Author(s) -
Su TsannLong,
Yang YuKun,
Huang JaiTung,
Ren WuYun,
Watanabe Kyoichi A.,
Chou TingChao
Publication year - 1993
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.5570300542
Subject(s) - chemistry , saponification , antifolate , hydrolysis , derivative (finance) , tricyclic , stereochemistry , bicyclic molecule , organic chemistry , antimetabolite , toxicity , financial economics , economics
This paper is dedicated to the memory of Professor Roland K. Robins The synthesis of 4‐[(1,3‐diaminopyrrolo[3′,4′:4,5]pyrido[2,3‐ d ]pyrimidin‐8‐yl)benzoyl]‐L‐glutamic acid ( 18 ), a potential antifolate and anticancer agent, has been achieved starting from 1,4‐dibromobutan‐2‐ol with alkyl p ‐aminobenzoic acids. Condensation of these two agents gave 1‐(4‐alkoxycarbonylphenyl)pyrrolidin‐3‐ols 7a,b , which were oxidized to the corresponding pyrrolidin‐3‐one derivatives 8a,b . Compounds 8a,b were converted into 1,3‐diamino‐8‐(4‐alkoxycarbonylphenyl)‐7,8‐dihydro‐9 H ‐pyrrolo[3′,4′:4,5]pyrido[2,3‐ d ]pyrimidines 12a,b in 4 steps. Saponification of 12b the benzoate ester and coupling with di‐ tert ‐butyl glutamate afforded a mixture of 7,8‐dihydro product 16 and its aromatized derivative 17 . Finally hydrolysis of esters 16 or 17 gave only the title compound 18 . The 7,8‐dihydro tricyclic derivatives were easily air‐oxidized to form their fully aromatized compounds. The title compound 18 was one tenth less active than MTX against HL‐60 cells in culture.