Novel Solid‐phase and Solution‐phase Synthetic Methods for Trisubstituted Thieno[3,2‐d]pyrimidine Derivatives

The coupling of 7-aryl-3,4-dihydro-4-oxothieno[3,2-d]pyrimidine-2-carboxylic acid with a primary alkylamine-loaded acid-sensitive methoxy benzaldehyde (AMEBA) resin, a benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP)-mediated amination reaction, and cleavage from the solid support yielded N-alkyl-4-(alkylamino)-7-arylthieno[3,2-d]pyrimidine-2-carboxamide derivatives. The progress of the reactions on solid phase was monitored through attenuated total reflectance-FTIR spectroscopy and was compared with representative solution-phase surrogates. Additionally, N-acylation (acid chloride, InF3 , CH3CN, room temperature) and cyclization (DBN, 1,4-dioxane, 80°C) of a 3-amino-4-(4-t-butoxycarbonylphenyl)thiophene-2-carboxamide intermediate under previously unreported conditions provided 2-substituted thieno[3,2-d]pyrimidin-4(3H)-one derivatives, which were subsequently converted to 2-substituted 4-alkylamino-7-[4-(alkylaminocarbonyl)phenyl]thieno[3,2-d]pyrimidine derivatives through a reaction sequence consisting of a BOP-mediated amination reaction, t-butyl deprotection, and amide formation.