Improved, High Yield Synthesis of 3H-Quinazolin-4-ones, the Key Intermediates of Recently Developed Drugs

Purine bases and their bioisosteric analogs are widely used as building blocks in combinatorial chemistry. Recently a great number of fused pyrimidine derivatives became known as potential drug molecules against various types of proliferative diseases, caused by over-expression of protein kinases [1]. One of the most important compound families are quinazolines : e.g. the best inhibitor of EGFR tyrosine kinase is PD153035 (6,7-dimethoxy-4-(3'- bromophenyl)amino-quinazoline) [2] and IRESSA™ (gefitinib, ZD1839) [3], developed from this compound family, is presently the only one approved and granted drug by the FDA for the treatment of advanced non-small-cell lung cancer (NSCLC). KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]- quinazoline-2-thione dihydrochloride) from this group, showed significantly higher inhibitory activity on cyclic GMP-specific phosphodiesterase compared with those of sildenafil (Viagra™) [4]. The synthetic procedures of the example compounds are based on imidoyl chloride intermediates that were prepared from the appropriate 3H-quinazoline-4-ones. Although the key intermediates, quinazoline-4-ones, have been known since more than hundred years, their synthetic procedures have been improved much only in the past ten years. In this paper we reviewed the efficient synthetic methods of quinazolin-4-ones, and presented a novel, reliable method for their synthesis. There was no considerable effect of microwave-, or traditional thermal activation on the yield and compound purity.