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 ...
