Small-molecule therapeutic drug discovery has long been constrained by high cost and inefficiency. Such is the case with pyrido[4,3-d]pyrimidin-3(6H)-one (Figure 1), which has been shown to be an effective backbone for several small-molecule kinase-inhibiting drugs described in a number of patents over the last ten years. Currently, synthesis of this molecule described in the literature has five-to-seven steps in the synthetic plan, uses expensive starting materials, and/or utilizes solvents and reagents that are particularly harmful to the environment. The research conducted confirmed a four-step synthesis for the title compound using comparatively cheap and readily available starting materials, as well as an environmentally friendly solvent. The optimized synthetic plan was also found to be able to be run in a one-pot fashion with a total yield of 42%, similar to that of the accumulated yield of the individually optimized steps in the synthesis (48%). The synthetic plan was used to synthesize four different molecules with the backbone of the title compound. Alkyl and aryl substituents, which are undescribed in the previous literature, were incorporated. These compounds were saved for the purpose of future analysis as potential protein kinase inhibitors.

Exploration and optimisation of the synthesis of pyrido[4,3-d]pyrimidin-3(6H)-one, a useful backbone in small-molecule kinase inhibitors

ACS Spring 2022

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