2-Bromo-3-(cyclohexyloxy)acrylaldehyde: An Isolable Enol Ether of Bromomalonaldehyde Suitable for Use in the Manufacture of Imidazolecarboxaldehydes

Enol ethers derived from 2-bromomalonaldehyde are useful intermediates for the preparation of functionalized imidazolecarboxaldehydes. Recent work in our group required that bromomalonaldehyde be converted to an enol ether on a large scale and be used in a campaign to generate a late-stage intermediate in the synthesis of an investigational active pharmaceutical ingredient (API). 2-Bromomalonaldehyde was converted into several enol ethers and each was evaluated with respect to its suitability for long-term storage and the temperature at which thermal decomposition was initiated. Although the highest onset temperature was measured with the ethyl enol ether (178 °C), the cyclohexyl enol ether was discovered to be an isolable solid (mp 66.5 °C). Other enol ethers examined in our hands could not be isolated as solids and storage as stock solutions did not offer the long-term stability required to support our campaign. A process safety hazards analysis revealed that the most potential for a hazardous event to occur was during the solvent exchange from processing solvent to isolation solvent. The total energy released during decomposition at this point would have exceeded the emergency vent relief capacity of the reactor set. The final concentration of reagent in solvent was adjusted so that the remaining solvent would function as a heat sink and diluent should decomposition occur, ensuring that the process did not exceed available vent relief capacity. The chemistry detailed in this communication was scaled up and produced a total of 1.1 MT of 2-bromo-3-(cyclohexyloxy)acrylaldehyde in four batches. Batch sizes ranged from 200 − 330 kg and the average yield was 80%.