ChemInform Abstract: Structural Studies on Bioactive Compounds. Part 5. Synthesis and Properties of 2,4-Diaminopyrimidine Dihydrofolate Reductase Inhibitors Bearing Lipophilic Azido Groups.
Abstract
The readily accessible pyrimidine derivative (Ia), which can be converted, for example, to other derivatives (Ib) by standard methods, is reduced by several methods, e.g. as shown in the scheme, in good yields affording the amine (IIIa) which is subsequently transformed to the azide (IIIb).
ChemInform Abstract
The readily accessible pyrimidine derivative (Ia), which can be converted, for example, to other derivatives (Ib) by standard methods, is reduced by several methods, e.g. as shown in the scheme, in good yields affording the amine (IIIa) which is subsequently transformed to the azide (IIIb). Similarly, other azidoarylpyrimidines (IV) are prepared. (IIIb) can be reduced by thiol reagents to the corresponding amine (IIIa), but reductive deazidation occurs when (IIIb) or (IVc) are heated with hydrazine. Degradation of (IIIb) in a TFA-trifluoromethanesulfonic acid mixture affords a means of introducing the bulky trifluoromethanesulfonyloxy substituent into the hindered ortho position of the 5-aryl substituent (→ (VIII)). The products formed from thermolysis and photolysis of (IIIb) (→ e.g. (IX)) derive from the triplet nitrene reactive intermediates. The chemistry of the quinazoline (X) is very similar to that of (IIIb). - The azides (IIIb) and (IV) are potent inhibitors of rat liver dihydrofolate reductase although not as active as metoprin (XI). The azide (IIIb), as its ethanesulfonic acid salt, is selected for clinical trials. - (In part no yields given or in g).
