A through-process was developed for the synthesis of a biaryl ether (BAE), an intermediate towards the synthesis of a phase III clinical candidate. The original, 2-step route to the BAE offered low PMI, however, suffered from a demanding quench of excess H2SO4, erroneous removal of MeOH in the ester synthesis with varying levels of hydrolysis in the subsequent SNAr (DMF and K3PO4) reaction. To mitigate these concerns, dimethyl carbonate (DMC) was employed as both co-solvent and desiccant. This modification allowed for H2SO4 lowering from superstiochiometric to a catalytic amount; enabling seamless quench and phase cut. In response to the variability of hydrolysis in the SNAr, a controlled amount of water was ascertained for optimal reaction efficiency (attributed to partial K3PO4 solubility), however, beyond these limits excessive hydrolysis was observed. These finding put water and DMC content expectations on the preceding esterification stream. The chalenges were collectively met by inclusion of stepwise distillative, azeotropic drying under reduced pressure to address water content from the esterification, succeeded by continuous distillation with DMF, to lower DMC content to usher in the SNAr chemistry. The SNAr proceeded to full conversion with hydrolysis of the BAE ester as only a minor side-reaction. Taken together, these process addendums afforded a reproducible and robust through-process with a relatively acceptable PMI , generating high quality, dry material for the moisture sensitive proceeding chemistry.

Overcoming challenges in the scale-up of a biaryl ether synthesis

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