High hydrostatic pressure assisted synthesis of 2-methylpyrimidine-4,6-dione as a key FOX-7 precursor: Experimental and molecular-level insights

ABSTRACT 2-Methylpyrimidine-4,6(1 H ,5 H )-dione (MPO) is a key intermediate for the synthesis of the insensitive energetic material FOX-7 and other high-value heterocyclic compounds. However, conventional MPO synthesis suffers from limited yield, and the effect of hydrostatic pressure on this cyclization reaction remains poorly understood. In this work, high hydrostatic pressure (HHP) was applied using a warm isostatic press to regulate MPO synthesis at 60 °C over a pressure range of 0.1-300 MPa. The MPO yield exhibited a nonmonotonic pressure dependence, increasing from 32.97% under atmospheric pressure to 70.04% at 200 MPa, followed by a decrease to 34.81% at 300 MPa. Product identity and purity were confirmed by HPLC, HPLC-MS, and DSC analyses. Density functional theory calculations were performed to establish a six-step cyclization pathway and identify the rate-determining and sub-rate-determining steps. Pressure-dependent calculations using the X-HCFF and GOSTSHYP models revealed that HHP selectively modulates the energy barriers of the sub-rate-determining steps rather than the rate-determining isomerization step. Specifically, the Step 2 barrier decreases under moderate pressure and then increases, whereas the Step 5 barrier increases monotonically. The competing pressure responses of these two steps provide a plausible molecular explanation for the observed yield maximum. Energy decomposition analysis further showed that pressure mainly acts through polarization energy in the X-HCFF model, whereas gas-phase electronic energy dominates in the GOSTSHYP model. These findings provide experimental evidence and molecular-level guidance for pressure-assisted synthesis of FOX-7 precursors and related energetic heterocycles.