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

Abstract

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.