Synthesis of the lipophilic antifolate piritrexim via a palladium(0)-catalyzed cross-coupling reaction.
[reaction: see text] A regiospecific and convergent route the lipophilic antifolate piritrexim (PTX) is described in which a key step is a Pd(0)-catalyzed cross-coupling reaction between 2-amino-3-cyano-4-methyl-5-bromopyridine and 2,5-dimethoxybenzylzinc chloride to form 2-amino-4-methyl-5-(2,5-dimethoxybenzyl)nicotinonitrile. To complete the synthesis, the amino group is replaced by a more reactive bromine atom via nonaqueous diazotization with tert-butyl nitrite, and the resultant bromo nitrile is cyclized with guanidine.
Chan
David C M
DC
Dana-Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Rosowsky
Andre
A
D002384:Catalysis; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry*
D005493:Folic Acid Antagonists; D011743:Pyrimidines; D010165:Palladium; C024530:piritrexim