Development and Scale-up of a Route to ATR Inhibitor AZD6738

Abstract

AZD6738 is currently being tested in multiple phase I/II trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine, and an azaindole, make it a challenging molecule to synthesize on a large scale. We describe the evolution of the chemical processes, following the manufacture of AZD6738 from the initial scale-up through to multikilos on plant scale. During this evolution, we developed a biocatalytic process to install the sulfoxide with high enantioselectivity, followed by introduction of the cyclopropyl group first in batch, then in a continuous flow plate reactor, and finally through a series of continuous stirred tank reactors. The final plant scale process to form AZD6738 was operated on 46 kg scale with an overall yield of 18%. We discuss the impurities formed throughout the process and highlight the limitations of this route for further scale-up.

The rise of continuous flow biocatalysis – fundamentals, very recent developments and future perspectives

“…Finally, a process on a plant scale with a CSTR cascade with four reactors was established and operated on a 46 kg scale with a total yield of 18%. 99 Very recently, Tamborini and co-workers investigated the chemo-enzymatic flow synthesis of selected APIs butacaine, Reaction Chemistry & Engineering Review procaine and procainamide. 100 The amide and ester intermediates were prepared in gram scale using a PBR with acyltransferase from Mycobacterium smegmatis immobilized on glyoxyl-agarose and inline purification with polymerbound sulphonyl chloride.…”

Flow Biocatalysis: A Challenging Alternative for the Synthesis of APIs and Natural Compounds

“…Therefore, developing a multistep continuous manufacturing process that includes biocatalytic steps will lead to highly productive and cost-efficient industrial plants with a lighter environmental footprint as well as meeting the principle of quality by design (QbD), which are all highly desirable aspects that pharmaceutical companies are seeking. While it is true that some biotransformations have been translated into "continuous-mode" pilot-plants by using continuously-stirred tank reactors (CSTRs) in series [146], the application of plug-flow microreactor technology for the scale-up of multistep API synthesis is currently understudied. An initial example was recently reported by Ho et al, who designed an end-to-end continuous flow system that included a biocatalyzed step for the synthesis of the antidiabetic drug sitagliptin (62, Scheme 18) [147].…”

Continuous flow asymmetric synthesis of chiral active pharmaceutical ingredients and their advanced intermediates

“…As demonstrated by these examples, one-flow multienzyme approaches hold significant potentials in improving atom as well as step-economy, whilst reducing the configurational complexity of multistep continuous chemoenzymatic flow systems. Although, there are recent examples for biocatalytic processes being realized in pilot-plants by employing a series of continuously-stirred tank reactors, 125 the utilization of continuous flow biocatalytic approaches at a manufacturing-scale is currently very limited. In an interesting recent example, Wang and co-workers designed and modelled an end-to-end continuous-flow system comprising an asymmetric chemoenzymatic key step for the manufacture of the antidiabetic drug, sitagliptin.…”

“…Although, there are recent examples for biocatalytic processes being realized in pilot-plants by employing a series of continuously-stirred tank reactors, 125 the utilization of continuous flow biocatalytic approaches at a manufacturing-scale is currently very limited. In an interesting recent example, Wang and co-workers designed and modelled an end-to-end continuous-flow system comprising an asymmetric chemoenzymatic key step for the manufacture of the antidiabetic drug, sitagliptin.…”