2,4-DIAMINOPYRIMIDINES . CYCLIZATION OF 6-PHENACYLTHIO AND RELATED DERIVATIVES TO THIENO[2,3-D]PYRIMIDINES AND THIAZOLO[3,2-C]PYRIMIDINES

2,4-Diamino-5-and -6-substituted thieno [2,3-d] pyrimidines have been prepared from 2,4-diamino-6-mercaptopyrimidine plus α-halo ketones. The ease of cyclization of the intermediate pyrimidyl sulfides (Pyr-SCHR'COR) varies dramatically with the R and R' substituents. When R = p-bromophenyl and R' = H, cyclization can be effected in low yield at 200° in inert medium. On the other hand, with R = methyl and R' = benzyl, cyclization proceeds spontaneously at room temperature in slightly acidic medium. In concentrated sulfuric acid, where R = p-bromophenj 1 and R' = H, the isomeric thiazolo[3,2-c]pyrimidinium sulfate is readily produced. This compound is stable only as the cation. In alkali, the pyrimidine ring opens with loss of its 2-carbon atom. The 2,4-diammotbieno [2,3-d] pyrimidines are -weak bases, with pKa values below 5. A bulky R' group and small R substituent favors activity as a dihydrofolate reductase inhibitor, but slightly acidic solutions are required for maximum activity. The low pKa values of these compounds militate against wide utility, since the protonated species is required for enzyme binding. © 1969, American Chemical Society. All rights reserved.