Model Based Approach to Control Pinacol Precipitation Risk in in Telescoped Miyaura Borylation/Suzuki Cross-Coupling Process

Source: AIChE
  • Type:
    Conference Presentation
  • Conference Type:
    AIChE Annual Meeting
  • Presentation Date:
    November 9, 2015
  • Duration:
    30 minutes
  • Skill Level:
  • PDHs:

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The telescoped Miyaura borylation/Suzuki cross-coupling reaction is one of the most efficient methods used for the synthesis of a biaryl compounds in pharmaceutical industry. This reaction involves borylation of an aryl halide compound with a boron compound  (bis(pinacolato)diboron, BisPin) by palladium catalyst to form non-isolated intermediate, which is then telescoped in Suzuki coupling reaction with another aryl halide to form the biaryl compound. Pinacol precipitation is one of the problems faced during the development of this process in the laboratory and could possibly cause significant operational issues on commercial scale if not controlled. Pinacol is a by-product of the Suzuki reaction originating from hydrolysis of the boron pinacol species (BisPin, BisPin-OAc, etc.). It is a low melting (40-43 °C), high boiling (171-173 °C) compound.  Due to these physical properties it was undesirable to have pinacol in the wet cake.  While it could be removed by drying operation, it would crystallize upon cooling in the manufacturing equipment beyond the dryer (vent lines, catch pots, etc.) causing significant operational issues. In this contribution, we will show how solubility and distillation models were used to build the control strategy around pinacol. Specifically, we will show how the models were used to simulate the design space for the relevant parameters (BisPin equiv., solvent volume, distillation end volumes and final isolation temperature) and aided no pinacol precipitation, and a more robust and flexible process.

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