A novel solid-phase synthetic method for production of N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide library

5 years ago

A novel solid-phase synthetic method for production of N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide library

This work describes a solid-phase synthetic method for building a compound library of N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide derivatives, that are based on the biologically active 1-aryl-1H-pyrazolo[3,4-d]pyrimidine scaffold. In the first step of this synthetic sequence, condensation reactions of ethyl 5-amino-1-aryl-1H-pyrazole-4-carboxylates with methyl cyanoformate resulted in the formation of esters that underwent hydrolysis to give 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one-6-carboxylic acids. The coupling reaction of these carboxylic acids with primary alkylamine-loaded acid-sensitive methoxybenzaldehyde (AMEBA) resins was followed by amination reactions mediated by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). Subsequent cleavage from the solid support resulted in the formation of the target N-alkyl-4-alkylamino-1-aryl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide derivatives. The reaction conditions for solid-phase transformations were optimized using a solution-phase model study with 2,4-dimethoxybenzyl-protected isobutylamine as a reactant in place of the AMEBA resin-loaded isobutylamine. The progress of the solid-phase reactions was monitored by on-bead ATR-FTIR spectroscopy. Diversification experiments were performed by using 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one-6-carboxylic acids and a variety of primary and secondary amine building blocks to build the target compound library.

Publisher URL: www.sciencedirect.com/science

DOI: S0040402017308840