Synthesis of the lipophilic antifolate piritrexim via a palladium(0)-catalyzed cross-coupling reaction |
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Authors: | Chan David C M Rosowsky Andre |
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Institution: | Dana-Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA. |
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Abstract: | 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. |
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