Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and Sustainable Fine-Chemical Manufacturing.

Process analytical technology (PAT) is a system designed to help chemists better understand and control manufacturing processes. PAT systems operate through the combination of analytical devices, reactor control elements, and mathematical models to ensure the quality of the final product through a quality by design (QbD) approach. The expansion of continuous manufacturing in the pharmaceutical and fine-chemical industry requires the development of PAT tools suitable for continuous operation in the environment of flow reactors. This requires innovative approaches to sampling and analysis from flowing media to maintain the integrity of the reactor content and the analyte of interest. The following Review discusses examples of PAT tools implemented in flow chemistry for the preparation of small organic molecules, and applications of self-optimization tools.

Intelligent Multidimensional Purity Analysis and Confirmation Tool for Multiple Attribute Analysis.

Chiral active pharmaceutical ingredients (APIs) are known to bind to chiral biological targets with better on-target specificity than achiral ones. However, the methods of synthesizing such APIs stereoselectively require the exhaustive optimization of multiple quality attributes of an asymmetric synthesis, wherein all critical quality attributes (for example, chemical and stereochemical purity of the API) are to be optimized in parallel and ideally from the beginning of the drug development program. A multidimensional liquid chromatographic tool capable of simultaneously measuring multiple quality attributes from a single analytical injection is reported. The tool is designed for the recirculation of chromatographic eluent bearing an analyte of interest through one or more stationary phases using a new and uniquely designed heart-cut valve. The iterative measurement of a target analyte from just one single injection will help scientists identify whether an unknown impurity is formed during reaction or during analysis. This chromatographic tool is particularly useful in the discovery of on-analysis artifacts, which is a resource-intensive exercise involving the identification, synthesis, and injection of impurity standards, all of which delay the drug development program.

The Synthesis of Warfarin Using a Reconfigurable-Reactor Platform Integrated to a Multiple-Variable Optimization Tool.

Optimization of the asymmetric synthesis of warfarin, an important anticoagulant, has been evaluated using a reconfigurable reaction platform capable of performing batch, continuous flow, and plug-flow synthesis. Further, this platform has been integrated with a novel, multidimensional, multiple variable analysis tool that can evaluate multiple critical quality attributes (CQA), percent conversion and enantiomeric excess in this case, from a single injection that is repeatedly recycled in a closed loop of chromatography columns, a detector and a heart-cut valve. Further, the new, integrated analysis system also facilitates validation of each QA, providing a high-level of confidence in analytical measurements, which are obtained without operator intervention.

Sterically demanding imidazolinium salts through the activation and cyclization of formamides.

A new protocol was developed for the synthesis of sterically demanding imidazolinium salts. This procedure was adopted for the synthesis of seven NHC salts, including ones that were demonstrated to be inaccessible using the conventional orthoformate ester type cyclization method.

The development of bulky palladium NHC complexes for the most-challenging cross-coupling reactions.

Palladium-catalyzed cross-coupling reactions enable organic chemists to form C-C bonds in targeted positions and under mild conditions. Although phosphine ligands have been intensively researched, in the search for even better cross-coupling catalysts attention has recently turned to the use of N-heterocyclic carbene (NHC) ligands, which form a strong bond to the palladium center. PEPPSI (pyridine-enhanced precatalyst preparation, stabilization, and initiation) palladium precatalysts with bulky NHC ligands have established themselves as successful alternatives to palladium phosphine complexes. This Review shows the success of these species in Suzuki-Miyaura, Negishi, and Stille-Migita cross-couplings as well as in amination and sulfination reactions.

An efficient low-temperature Stille-Migita cross-coupling reaction for heteroaromatic compounds by Pd-PEPPSI-IPent.

The reactivity of Pd-PEPPSI (Pyridine, Enhanced, Precatalyst, Preparation, Stabilization, and Initiation) precatalysts in the Stille-Migita cross-coupling reaction between heteroaryl stannanes and aryl or heteroaryl halides was evaluated. In general, Pd-PEPPSI-IPent (IPent=diisopentylphenylimidazolium derivative) demonstrated high efficiency over a variety of challenging aryl or heteroaryl halides with thiophene-, furan-, pyrrole-, and thiazole-based organostannanes when compared with Pd-PEPPSI-IPr (IPr=diisopropylphenylimidazolium derivative). The transformations proceeded at appreciably lower temperatures (30-80 degrees C) than triarylphosphine-based Pd catalysts, improving the scope of this useful carbon-carbon bond-forming process.

Pd PEPPSI-IPr-mediated reactions in metal-coated capillaries under MACOS: the synthesis of indoles by sequential aryl amination/Heck coupling.

A method has been devised for the microwave-assisted, continuous-flow preparation of indole alkaloids by a two-step aryl amination/cross-coupling sequence of bromoalkenes and 2-bromoanilines. This process requires both the presence of a metal-lined flow tube (a 1180 micron capillary) and the Pd PEPPSI-IPr catalyst; without either, the catalyst or the film, there is zero turnover of this catalytic process. A silver film has been shown to provide some conversion (48-62 %), but optimal results (quantitative) across a variety of bromoalkenes and bromoanilines were achieved by using a highly porous palladium film. Possible roles for the Pd film are considered, as is the interplay of the catalyst and the film.

A 2.13 A structure of E. coli dihydrofolate reductase bound to a novel competitive inhibitor reveals a new binding surface involving the M20 loop region.

Dihydrofolate reductase (DHFR) is a vital metabolic enzyme and thus a clinically prominent target in the design of antimetabolites. In this work, we identify 1,4-bis-{[N-(1-imino-1-guanidino-methyl)]sulfanylmethyl}-3,6-dimethyl-benzene (compound 1) as the correct structure of the previously reported DHFR inhibitor 1,4-bis-{(iminothioureidomethyl)aminomethyl}-3,6-dimethyl-benzene (compound 2). The fact that compound 1 has an uncharacteristic structure for DHFR inhibitors, and an affinity (KI of 11.5 nM) comparable to potent inhibitors such as methotrexate and trimethoprim, made this inhibitor of interest for further analysis. We have conducted a characterization of the primary interactions of compound 1 and DHFR using a combination of X-ray structure and SAR analysis. The crystal structure of E. coli DHFR in complex with compound 1 and NADPH reveals that one portion of this inhibitor exploits a unique binding surface, the M20 loop. The importance of this interface was further confirmed by SAR analysis and additional structural characterization.