The American Chemical Society (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable conducted a study to elucidate the value of continuous processing, which had been defined as a key research area for green engineering. In the course of defining the business case for continuous processing, individual cases were collected and evaluated to determine specific drivers to implement continuous processing and to find key success factors. The magnitude and timing of effects and the relation to the principles of green chemistry were investigated.

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.

For on-line monitoring of chemical reactions (batch or continuous flow), mass spectrometry (MS) can provide data to (1) determine the fate of starting materials and reagents, (2) confirm the presence of the desired product, (3) identify intermediates and impurities, (4) determine steady state conditions and point of completion, and (5) speed up process optimization. Recent developments in small footprint atmospheric pressure ionization portable mass spectrometers further enable this coupling, as the mass spectrometer can be easily positioned with the reaction system to be studied. A major issue for this combination is the transfer of a sample that is representative of the reaction and also compatible with the mass spectrometer. This is particularly challenging as high concentrations of reagents and products can be encountered in organic synthesis. The application of a portable mass spectrometer for on-line characterization of flow chemical synthesis has been evaluated by coupling a Microsaic 4000 MiD to the Future Chemistry Flow Start EVO chemistry system. Specifically, the Hofmann rearrangement has been studied using the on-line mass spectrometry approach. Sample transfer from the flow reactor is achieved using a mass rate attenuator (MRA) and a sampling make-up flow from a high pressure pump. This enables the appropriate sample dilution, transfer, and preparation for electrospray ionization. The capability of this approach to provide process understanding is described using an industrial pharmaceutical process that is currently under development. The effect of a number of key experimental parameters, such as the composition of the sampling make-up flow and the dilution factor on the mass spectrometry data, is also discussed.

The development of a continuous flow sulfoxide imidation protocol for a pharmaceutically relevant target molecule is described. Sulfoxide imidation is a key-step in the preparation of certain ATR kinase inhibitors. Reactions with NaN 3 or TMSN 3 and concentrated sulfuric acid under literature conditions provided slow reactions and poor selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target sulfoximine with a selectivity of ~90% after a reaction time of only 10 to 15 min at 50 °C.The imidation reaction using TMSN 3 as reagent was successfully performed in a flow reactor utilizing CH 2 Cl 2 /H 2 SO 4 biphasic conditions. The mixture was subsequently quenched in-line with H 2 O. Phase separation, neutralization and re-extraction with an organic solvent furnished the product in excellent purity and good yields, albeit with loss of chirality.

The development of a ruthenium-catalyzed continuous flow ester hydrogenation using hydrogen (H2) gas is reported. The reaction was utilized for the reduction of an important precursor in the synthesis of...