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An alternative synthesis of piritrexim, a lipophilic inhibitor of human dihydrofolate‐reductase
Author(s) -
Troschütz Reinhard,
Zink Mario,
Gnibl Rainer
Publication year - 1999
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.5570360321
Subject(s) - chemistry , thionyl chloride , yield (engineering) , dihydrofolate reductase , dimethylformamide , sodium hydride , derivative (finance) , guanidine , cyanoacetamide , ketone , organic chemistry , chloride , enzyme , solvent , materials science , economics , financial economics , metallurgy
An alternative synthesis of the lipophilic antifolate piritrexim ( 1 ) is outlined. Starting from ketone 2 , treatment with phosphorus oxychloride and dimethylformamide gave the β‐chlorocrotonaldehydes 3 E/Z , which were reacted with cyanoacetamide ( 6 ) in the presence of sodium hydride to yield a 3‐cyano‐2‐pyridone derivative 7 . Chlorination of 7 with thionyl chloride and subsequent reaction with guanidine ( 9 ) gave rise to piritrexim ( 1 ). The reaction of β‐chlorocrotonaldehydes 3 E/Z , with 2,4,6‐triaminopyrimidine ( 4 ) yielded iso ‐piritrexim ( 5 ).
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