Pyridine <i>N</i>‑Oxide vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C–H Bond Functionalization

The origin of the high reactivity and site selectivity of pyridine <i>N</i>-oxide substrates in <i>O</i>-pivaloyl hydroxamic acid-directed Rh­(III)-catalyzed (4+2) annulation reactions with alkynes was investigated computationally. The reactions of the analogous pyridine derivatives were previously reported to be slower and to display poor site selectivity for functionalization of the C(2)–H vs the C(4)–H bonds of the pyridine ring. The <i>N</i>-oxide substrates are found to be more reactive overall because the directing group interacts more strongly with Rh. For <i>N-</i>oxide substrates, alkyne insertion is rate-limiting and selectivity-determining in the reaction with a dialkyl alkyne, but C–H activation can be selectivity-determining with other coupling partners such as terminal alkynes. The rates of reaction with a dialkyl alkyne at the two sites of a pyridine substrate are limited by two different steps: C–H activation is limiting for C(2)-functionalization, while alkyne insertion is limiting for C(4)-functionalization. Consistent with the observed poor site selectivity in the reaction of a pyridine substrate, the overall energy barriers for functionalization of the two positions are nearly identical. High C(2)-selectivity in the C–H activation step of the reaction of the <i>N</i>-oxide is due to a cooperative effect of the C–H Brønsted acidity, the strength of the forming C–Rh bond, and intramolecular electrostatic interactions between the [Rh]­Cp* and the heteroaryl moieties. On the other hand, some of these forces are in opposition in the case of the pyridine substrate, and C(4)–H activation is moderately favored overall. The alkyne insertion step is favored at C(2) over C(4) for both substrates, and this preference is largely influenced by electrostatic interactions between the alkyne and the heteroarene. Experimental results that support these calculations, including kinetic isotope effect studies, H/D exchange studies, and results using a substituted pyridine, are also described

Rh(III)-Catalyzed C–H Activation and Double Directing Group Strategy for the Regioselective Synthesis of Naphthyridinones

A general Rh­(III)-catalyzed synthesis of naphthyridinone derivatives is described. It relies on a double-activation and directing approach leveraging nicotinamide <i>N</i>-oxides as substrates. In general, high yields and selectivities can be achieved using low catalyst loadings and mild conditions (room temperature) in the couplings with alkynes, while alkenes require slightly more elevated temperatures

Telescoped Process to Manufacture 6,6,6-Trifluorofucose via Diastereoselective Transfer Hydrogenation: Scalable Access to an Inhibitor of Fucosylation Utilized in Monoclonal Antibody Production

IgG1 monoclonal antibodies with reduced glycan fucosylation have been shown to improve antibody-dependent cellular cytotoxicity (ADCC) by allowing more effective binding of the Fc region of these proteins to T cells receptors. Increased in vivo efficacy in animal models and oncology clinical trials has been associated with the enhanced ADCC provided by these engineered mAbs. 6,6,6-Trifluorofucose (<b>1</b>) is a new inhibitor of fucosylation that has been demonstrated to allow the preparation of IgG1 monoclonal antibodies with lower fucosylation levels and thus improve the ADCC of these proteins. A new process has been developed to support the preparation of <b>1</b> on large-scale for wide mAb manufacture applications. The target fucosylation inhibitor (<b>1</b>) was synthesized from readily available d-arabinose in 11% overall yield and >99.5/0.5 dr (diastereomeric ratio). The heavily telescoped process includes seven steps, two crystallizations as purification handles, and no chromatography. The key transformation of the sequence involves the diastereoselective preparation of the desired trifluoromethyl-bearing alcohol in >9/1 dr from a trimethylsilylketal intermediate via a ruthenium-catalyzed tandem ketal hydrolysis–transfer hydrogenation process

A Continuous Process for Manufacturing Apremilast. Part I: Process Development and Intensification by Utilizing Flow Chemistry Principles

Herein, we report the development of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance (DS) of the commercial product Otezla. This development effort was motivated by the desire to create an alternative manufacturing configuration with a significantly smaller footprint and to impart intensification resulting in a more sustainable process. Three primary aspects of the existing batch process had to be addressed to achieve this goal: (1) long reaction time, (2) low solubility of the starting materials and intermediates in the primary reaction solvent (THF), and (3) extensive postreaction unit operations contributing to significant solvent waste. Key features of the intensified CM process include the following: (1) use of a plug-flow reactor (PFR) to access increased reaction temperatures (130 °C), resulting in a shorter reaction time to reach the target conversion (>18 h in batch to 30 min in flow); (2) replacement of THF with DMSO to solve solubility issues related to starting materials and reaction intermediates, and (3) development of a multistage continuous MSMPR (mixed-suspension, mixed-product removal) crystallization upon addition of water as antisolvent to the end-of-reaction stream containing apremilast. This intensified CM process reduced the number of primary unit operations from nine to three (67% reduction). Moreover, it can be executed at commercial scale using a compact manufacturing skid. Part I of this manuscript series highlights the effort to develop the novel process and the corresponding kg-scale demonstration of the optimized process. Part II describes the process characterization and development of a control strategy in detail to ensure process efficiency and robustness of the small-footprint continuous skid

Oxopyrido[2,3‑<i>d</i>]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

In nonsmall cell lung cancer (NSCLC), the threonine⁷⁹⁰–methionine⁷⁹⁰ (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido­[2,3-<i>d</i>]­pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound <b>24</b> which potently inhibits gefitinib-resistant EGFR^L858R,T790M with 100-fold selectivity over wild-type EGFR. Compound <b>24</b> displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR^L858R,T790M driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR