An optimized route to an iodo-imidazole intermediate in the synthesis of 4-ethynyl-2,5-dimethyl-1-aryl-1H-imidazoles (6) was devised. Important data for the optimization work was obtained by carrying out a DOE study to gain understanding of the parameters that affect the key intramolecular cyclization to build the imidazole ring. Additional information on the reaction mechanism of this step was obtained by carrying out a flow NMR experiment. In order to complete the proof of concept, the iodo-imidazole intermediate was converted to two ethynyl imidazoles (6a, b) using metal-catalyzed reactions.

The application of two Process Analytical Technology (PAT) tools was studied and implemented for the safe and reliable synthesis of an advanced intermediate (4S,5R-7) of a member of the dihydro-1H-imidazole (1) class of compounds. Real time data were generated using ReactIR to track the complete breakdown of phosgene precursors (2) to phosgene (3) and confirm the absence of these hazardous materials prior to batch transfer operations. In addition, the chiral resolution by crystallization of rac 7 was monitored by a Lasentec FBRM probe-based system. Implementation of the latter helped to track the crystallization process to minimize the risk of cocrystallization of undesired isomer 4R,5S-7.

This paper develops a case for more studies to assess the impact of discharges upon receiving aquatic systems and thereby allow closer tailoring of control measures. General approaches for conducting such studies are described. One approach includes methodology to allow predictions of where in the environment a key effluent constituent will be transported, the rate and extent of its transformation, and its effect on organisms and environmental processes at expected ambient levels.