Abstract
Ipatasertib is a potent small molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple negative metastatic breast cancer. In this paper an overview of the development achievements towards the commercial manufacturing process is given. The convergent synthesis consists of ten steps with eight isolated intermediates and utilizes a wide range of chemical techniques and technologies to build-up this complex drug. All three stereocenters are introduced using enzyme or metal catalysis.
Highlights
a potent small molecule Akt kinase inhibitor currently being tested in Phase III clinical trials for the treatment
The convergent synthesis consists of ten steps with eight isolated intermediates
Ipatasertib is a complex molecule with three stereo centers
Summary
Ipatasertib (1) is a potent small molecule Akt kinase inhibitor[1,2] currently being tested in Phase III clinical trials for the treatment of metastatic castration-resistant prostate cancer and triple negative metastatic breast cancer. One of the key steps is the coupling of the two main building blocks from the two branches of the synthesis, bicyclic pyrimidine 4 and chiral α-aryl-β-amino acid 2. The stereo centers are introduced by highly selective metal and enzyme catalysis (Fig. 2). Key achievements from the late stage process development are a reduction of the mass intensity (MI in kg per kg API) by factor 5 and an increase of the overall yield by factor 3 over the last three manufacturing campaigns (Fig. 8). The usage of ecofriendly process solvents, solvent regeneration, development of a direct bromination to yield intermediate 5, upscale of the very sensitive Grignard reaction to intermediate 9, and a more efficient coupling of the main building blocks 2 and 4 are reported
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