New route development activities toward ceralasertib (AZD6738) have resulted in the discovery of an efficient, acid additive-free, photoredox Minisci reaction. Mechanistic understanding resulting from LED-NMR reaction profiling, quantum yield measurements, and Stern−Volmer quenching studies have enabled optimization of the catalyst system, resulting in a significant enhancement in the rate of reaction. A large-scale continuous photoflow process has been developed, providing encouraging proofof-concept data for the future application of this technology in the clinical manufacture of ceralasertib.

This article details the approach to large-scale production of cyclobutane 2 by the continuous-flow [2 + 2] photocycloaddition of maleic anhydride and ethylene, including (1) focused reaction optimization and development of a robust isolation protocol, (2) the approach to equipment design and process safety, and (3) the results of commissioning tests and production runs delivering the target compound at throughputs exceeding 5 kg/day.

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.

A multistep continuous manufacturing process to synthesize (1R,2R)-2-amino-1-methylcyclopentan-1-ol (2) was developed. The step 1/2 flow process mitigated the safety hazard associated with high exothermicity during epoxidation, the epoxide-opening reaction, and the low onset of the epoxide intermediate. Process improvements included a hybrid plug flow reactor (PFR)/continuous stirred tank reactor (CSTR) reaction and a continuous quench/work-up process in step 1; a continuous reaction, extraction, washing, and thin-film distillation work-up in step 2; and a continuous trickle bed hydrogenation in step 3, which provided the desired product with high purity and high ee. The end-to-end continuous process provided significant advantages of cost-saving, minimization of manufacturing space and utilities, and reduction of the cycle time.

Some microfluidic lab-on-chip devices contain modules whose function is to mix two fluids, called reactant and buffer, in desired proportions. In one of the technologies for fluid mixing the process can be represented by a directed acyclic graph whose nodes represent micro-mixers and edges represent micro-channels. A micro-mixer has two input channels and two output channels; it receives two fluid droplets, one from each input, mixes them perfectly, and produces two droplets of the mixed fluid on its output channels. Such a mixing graph converts a set I of input droplets into a set T of output droplets, where the droplets are specified by their reactant concentrations. The most fundamental algorithmic question related to mixing graphs is to determine, given an input set I and a target set T , whether there is a mixing graph that converts I into T . We refer to this decision problem as mix-reachability. While the complexity of this problem remains open, we provide a solution to its natural sub-problem, called perfect mixability, in which we ask whether, given a collection C of droplets, there is a mixing graph that mixes C perfectly, producing only droplets whose concentration is the average concentration of C. We provide a complete characterization of such perfectly mixable sets and an efficient algorithm for testing perfect mixability. Further, we prove that any perfectly mixable set has a perfect-mixing graph of polynomial size, and that this graph can be computed in polynomial time.One of the most fundamental functions of LoC devices is mixing of different fluids. In particular, in applications related to sample preparation, the objective is to produce desired volumes of pre-specified mixtures of fluids. In typical applications only two fluids are involved, in which case the process of mixing is often referred to as dilution. The fluid to be diluted is called reactant and the diluting fluid is called buffer. For example, in clinical diagnostics common reactants include blood, serum, plasma and urine, while phosphate buffered saline is often used as buffer [16].There is a variety of different technologies that can be used to manufacture microfluidic devices for fluid mixing. In our work, we consider microfluidic chips that involve a collection of tiny components called micro-mixers connected by micro-channels. In such chips, input fluids are injected into the chip using fluid dispensers, then they travel, following appropriate micro-channels, through a sequence of micro-mixers in which they are subjected to mixing operations, and are eventually discharged into output reservoirs. We focus on droplet-based chips, where fluids are manipulated in discrete units called droplets. In such chips each micro-mixer has exactly two input and two output channels. It receives one droplet of fluid from each input, mixes them perfectly, producing two identical droplets on its outputs. Specifically, if the input droplets have (reactant) concentrations a, b, then the produced droplets will have concentration 1 2 (a + b). It foll...