A reaction sequence was described in which the reaction shown in the diagram produces an intermediate for the pharmaceutical Diclofenac. In this reaction, the 2,6-dichlorophenxoide is a weak nucleophile due to the electron withdrawing chlorine atoms ortho to the hydroxyl. This is likely why this etherification was performed at such a high temperature, which is very rare for PTC etherification of phenols, especially with an alkyl chloride that is as activated as this one in 2-chloro-N-phenylacetamide.
The inventors used PEG-400 as the phase-transfer catalyst likely since it is thermally stable at this high reaction temperature. The PEG-K-phenoxide complex was the active reactant that enables the use of a non-polar solvent in this solid-liquid PTC system. The inventors note in the teachings that the reaction can be performed using triethyl benzyl ammonium chloride (TEBA) and tetrabutylammonium bromide (TBAB) as the phase-transfer catalyst. This may have been a feeble attempt to mislead the reader since if this high temperature is really needed, TBAB and especially TEBA are not sable at these temeperatures.
Refluxing xylenes (b.p. in the 140’s) was chosen as the inert solvent with a boiling point (in the 140’s) perceived by the inventors to be needed to perform this high-temperature reaction.
The base used was potassium carbonate and was likely chosen to be strong enough to neutralize the phenol without deprotonating the NH that would have resulted in N-alkylated by-products. The inventors may have been able to reduce the solids in the system by working with less base since the low pKa of dichlorophenol should not need excess carbonate.
When your company needs low-cost high-performance etherifications, especially if selectivity challenges must be overcome, now contact Marc Halpern of PTC Organics to achieve your performance targets in the minimum number of experiments to avoid wasting valuable R&D resources.
