Commercial Manufacturing Process for Ipatasertib (2)

Chimia, 2021, 75, 605–613. DOI: 10.2533/chimia.2021.605

◆The second stereo center was introduced by absolute diastereoselective reduction of the keto function in intermediate 9 with an engineered ketoreductase and i-PrOH as hydrogen source and NAD as co-factor

◆With the initial crystallization protocol (addition of n-heptane at 25 °C, seeding, and then cooling to –10 °C), oiling was observed which resulted in crust formation. With that, an improved process was developed, where 1 equiv. of water is added and the order of the process steps was changed (cooling to –10°C, seeding, then addition of n-heptane).

◆The effect of the water was nicely demonstrated in one experiment where the stirring speed was set to a too low rate and frozen water droplets accumulated below the stirrer. The crystal growth did mainly take place at these droplets.

◆The last stereo center is introduced by stereo selective hydrogenation of starting material 3 with a highly active and selective ruthenium catalyst.

◆Both key building blocks 2 and 4 are then coupled in the next step to yield Boc-protected API 11

◆Classical HPLC or GC analytics to monitor the activation of 2 failed to show reliable results. Thus, by utilizing an online IR probe, it was possible to monitor the pivaloyl chloride conversion and formation of activated 2.

◆In the final chemical transformation, intermediate 11 is deprotected by HCl in n-propanol

◆The process performance and robustness has been successfully proven at commercial scale over all ten chemical steps and the final spray-drying step