Example 5 of this patent describes three consecutive reactions of which two use PTC. The overall yield was good at 67% over the three steps that included two sets of chromatography and crystallization. In our opinion, all three reactions could use PTC with a single phase-transfer catalyst and a single solvent.
We would streamline the process by using an organophilic phase-transfer catalyst that would remain in the organic phase, such as methyl trioctyl ammonium chloride (MTOAC). MTOAC is known to be effective in PTC Suzuki reactions. After washing away the inorganic salts into water, MTOAC would remain ij the toluene phase and we would probably perform the demethylation without isolation of the first intermediate.
We would then add concentrated aqueous HCl or HBr to the toluene solution of the first intermediate to perform the demethylation. MTOAC would also be effective for the acidic demethylation in toluene.
Finally, without isolating the second intermediate, we would add the third reactant for the etherification in the final step. MTOAC should be very effective for the etherification and toluene would again be a good solvent for this PTC reaction. We could likely perform the etherification with 1.0 equivalent of NaOH to neutralize the phenol. This would eliminate the need to use calcium carbonate solid and DMF as the solvent that is often hard to recover.
Since MTOAC will continue with the toluene phase throughout all three steps, we would separate the MTOAC from the final product by chromatography and crystallization. We also would not have worry about entrainment of the product into DMF and the workup of the final step could start with an easy water wash to remove the inorganic NaBr salt byproduct formed in the etherification.
If your company would benefit from streamlining multi-step processes that involve 2 or more consecutive reactions in which phase-transfer catalysis excels, now contact Marc Halpern of PTC Organics to explore how to integrate PTC Organics’ highly specialized expertise in industrial PTC with your commercial process development goals.
