Photon Equivalents as a Parameter for Scaling Photoredox Reactions in Flow: Translation of Photocatalytic C-N Cross-Coupling from Lab Scale to Multikilogram Scale.

With the development of new photocatalytic methods over recent decades, the translation of these chemical reactions to industrial-production scales using continuous-flow reactors has become a topic of increasing interest. In this context, we describe our studies toward elucidating an empirically derived parameter for scaling photocatalytic reactions in flow. By evaluating the performance of a photocatalytic C-N cross-coupling reaction across multiple reactor sizes and geometries, it was demonstrated that expressing product yield as a function of the absorbed photon equivalents provides a predictive, empirical scaling parameter. Through the use of this scaling factor and characterization of the photonic flux within each reactor, the cross-coupling was scaled successfully from the milligram scale in batch to a multi-kilogram reaction in flow.

STILLE CROSS-COUPLING REACTIONS OF ARYL MESYLATES AND TOSYLATES USING A BIARYLPHOSPHINE BASED CATALYST SYSTEM.

A catalyst system for the Stille cross-coupling reactions of aryl mesylates and tosylates is reported. Using the combination of Pd(OAc)2, XPhos, and CsF in t-BuOH an array of aryl and heteroaryl sulfonates were successfully employed in these reactions. Morever, heteroarylstannanes, such as furyl, thiophenyl, and N-methylpyrrole, which are often prone to decomposition, were efficiently coupled under these conditions. Ortho-substitution on the stannane coupling partner was well tolerated; however, the presence of ortho substituents on the aryl sulfonates greatly reduced the proficiency of these reactions.

A Next Generation Synthesis of BACE1 Inhibitor Verubecestat (MK-8931).

The development of a commercial manufacturing route to verubecestat (MK-8931) is described, highlights of which include the application of a continuous processing step to outcompete fast proton transfer in a Mannich-type ketimine addition, a copper-catalyzed amidation reaction, and an optimized guanidinylation procedure to form the key iminothiadiazine dioxide core.

Preclinical Experimental and Mathematical Approaches for Assessing Effective Doses of Inhaled Drugs, Using Mometasone to Support Human Dose Predictions.

BACKGROUND: Understanding the relationship between dose, lung exposure, and drug efficacy continues to be a challenging aspect of inhaled drug development. An experimental inhalation platform was developed using mometasone furoate to link rodent lung exposure to its in vivo pharmacodynamic (PD) effects. METHODS: We assessed the effect of mometasone delivered directly to the lung in two different rodent PD models of lung inflammation. The data obtained were used to develop and evaluate a mathematical model to estimate drug dissolution, transport, distribution, and efficacy, following inhaled delivery in rodents and humans. RESULTS: Mometasone directly delivered to the lung, in both LPS and Alternaria alternata rat models, resulted in dose dependent inhibition of BALf cellular inflammation. The parameters for our mathematical model were calibrated to describe the observed lung and systemic exposure profiles of mometasone in humans and in animal models. We found that physicochemical properties, such as lung fluid solubility and lipophilicity, strongly influenced compound distribution and lung retention. CONCLUSIONS: Presently, we report on a novel and sophisticated mathematical model leading to improvements in a current inhaled drug development practices by providing a quantitative understanding of the relationship between PD effects and drug concentration in lungs.

Augmentation of postswelling surgical sealant potential of adhesive hydrogels.

Two-component hydrogels formed with star polyethylene glycol amine and linear dextran aldehyde polymers (PEG:dextran) show promise as tissue-specific surgical sealants. However, there is a significant loss of adhesion strength to soft tissues following PEG:dextran swelling, which may limit material ability to appose disjoined tissues and prevent leakage from surgical sites. We covalently incorporated the modified amino acid L-3,4-dihydroxyphenylalanine (L-DOPA) into PEG:dextran to enhance postswelling sealant performance. L-DOPA is an essential component of marine animal adhesive plaques and has been used to confer wet adhesion in synthetic materials. As both PEG:dextran cohesion and adhesion are mediated by aldehyde-amine interactions, L-DOPA side-groups make it a potent network modulator with potential to affect multiple material properties. Following 1-h submersion in aqueous media, PEG:dextran doped with 3 mM L-DOPA/M aldehyde on average swelled 50.3% less, had 287.4% greater stiffness, and had 53.6% greater functional adhesion strength compared to the neat hydrogel. Increased concentrations of L-DOPA up to 11 mM L-DOPA/M aldehyde similarly curtailed swelling and mitigated property loss with hydration, but sacrificed initial functional adhesion strength, material modulus, and biocompatibility. Taken together, these data support tailored L-DOPA conjugation as a promising approach to enhance the clinical performance of PEG:dextran sealants.