At the recent ‘Scale Up of Chemical Processes Conference’ in Baveno, Italy, Charles Papageorgiu of Eisai described the optimization of a borylation process to prepare boronic acid ML-826 (see Scheme 1).

Scheme 1 July2016

Scheme 1: Preparation of boronic acid ML-826

The original method using B2Pin2 and Pd(PPh3)2Cl2 as catalyst was extremely inefficient (9.25 day batch cycle time!) and suffered from variable yield, purity and reaction kinetics.

Pd 168 July2016

The presentation centered on the development of new borylation reaction conditions using bis-boronic acid (BBA). Two equivalents of BBA were required for good conversion and to minimise homo-coupling. The problem was caused by the sensitivity of BBA to oxygen and mixing. Faster mixing is detrimental and has two effects – faster dissolution of BBA and faster mass transfer of O2 in the headspace in to the reaction mixture.

Process safety studies on BBA using accelerated rate calorimetry (ARC) shows a catastrophic decomposition with onset at 85°C. Time to maximum rate (TMRAD) was calculated to be 165 hours at 35°C, but only 5 hours at 65°C. One of the main issues is the decomposition rate of BBA under the reaction conditions is comparable to the desired borylation reaction rate which is why 2 equivalents of BBA are required, so a screen of BBA stability in various solvents was undertaken. Oxygen solubility varies dramatically from solvent to solvent, with cyclohexane containing 138.56 ppm and water only 9.31 ppm (at 20°C under air). Ethylene glycol was found to stabilize BBA, through in situ boronate formation, and this also allowed the catalyst loading to be reduced.

With O2 levels ≥ 0.5% in the headspace a mixing dependency is still observed but this is now due solely to the change in kLa resulting in faster mass transfer of O2 into solution. In the final process 1.25 equivalents of BBA were required along with 0.05 mol % Pd-168, which resulted in a yield increase from 80% to 93% and purity increase in the product from 97.5% to 99.4%, as well as a 46% overall cost saving for the process.