Bromination and Suzuki reaction towards purine-based CSF-1R inhibitors

Abstract

The aim of this master thesis was to develop a suitable synthetic procedure towards 6-amino-8-arylpurines as potential CSF-1R inhibitors. The chosen three-step route entailed thermal amination of 6-chloropurine with various amines, yielding 6-aminopurines. These compounds were further reacted with elemental bromine in electrophilic aromatic substitution reactions giving 6-amino-8-bromopurines. The brominated aminopurines were then reacted in Suzuki cross-coupling reactions with various arylboronic acids to obtain the desired 6-amino-8-arylpurines. Ten new compounds were synthesized.

The thermal aminations were investigated in a pre-master project, and although two aminations were performed, the primary focus of this master thesis has been the bromination and Suzuki reactions. An optimized procedure for the brominations was developed and was successful in increasing the yield of compounds 6 and 9 with 20-40 %. The lack of success for the two other bromination-products were mainly due to purification difficulties.

In the Suzuki cross-coupling reactions, Pd(PPh3)4 was identified as the most suitable catalyst for the coupling between compounds 6-9 and various arylboronic acids. High conversion of the starting materials was acquired, but due to extensive purification difficulties, the target compounds 10-19 were only obtained in low to moderate yields (12-59 %).

Two of the target molecules were tested for activity against CSF-1R, alongside three of the 6-amino-8-bromopurines and compound 5. Their inhibition-activity towards the epidermal growth factor receptor (EGFR) were investigated as well. The most promising activity was displayed by compound 15, with 74 % inhibition of EGFR. Compound 10 displayed similar activity (67 %) towards CSF-1R.