SYNTHESIS OF 6-SUBSTITUTED PYRIDO[3,4-D]PYRIMIDIN-4(3H)-ONES VIA DIRECTED LITHIATION OF 2-SUBSTITUTED 5-AMINOPYRIDINE DERIVATIVES

Directed lithiation of Boc or pivaloyl derivatives of 2-substituted 5- aminopyridines with BuLi-TMEDA in diethyl ether at -10 degrees C gave 4-lithio derivatives which were quenched with CO2 to give the analogou s C-4 carboxylic acids, Hydrolysis of the protecting groups with eithe r TFA or aqueous KOH gave 2-substituted 5-aminopyridine-4-carboxylic a cids which were converted to 6-substituted pyrido[3,4-d]pyrimidin-4(3H )-ones by reaction with formamide or, more optimally, formamidine acet ate, Boc protected aminopyridines provided the best overall results, w ith synthesis of these derivatives best achieved by direct reaction of the aminopyridine with di-tert-butyl dicarbonate in the absence of ad ded base.