Over the past two decades, there have been major developments in transition metal-catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for C–N bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Herein, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event.
With the development of new photocatalytic methods over recent decades,t he translation of these chemical reactions to industrial-production scales using continuous-flow reactors has become at opic of increasing interest. In this context, we describe our studies towarde lucidating an empirically derived parameter for scaling photocatalytic reactions in flow. By evaluating the performance of ap hotocatalytic CÀNc ross-coupling reaction across multiple reactor sizes and geometries,i tw as demonstrated that expressing product yield as afunction of the absorbed photon equivalents provides apredictive,empirical scaling parameter.Through the use of this scaling factor and characterization of the photonic flux within each reactor,t he cross-coupling was scaled successfully from the milligram scale in batch to am ultikilogram reaction in flow.
In an effort to discover a noninvasive method for predicting which cancer patients will benefit from therapy targeting the EGFR and HER2 proteins, a large body of the research has been conducted toward the development of PET and SPECT imaging agents, which selectively target these receptors. We provide a general overview of the advances made toward imaging EGFR and HER2, detailing the investigation of PET and SPECT imaging agents ranging in size from small molecules to monoclonal antibodies.
The gas‐liquid biphasic photochemical [2+2] cycloaddition of maleic anhydride with ethylene was identified as a desirable strategy for the divergent synthesis of cyclobutane derivatives. To address the challenge of utilizing this transformation on a larger scale, studies toward the development of a stable process with sufficient productivity were undertaken. These studies revealed the importance of several reaction parameters to enhance both the gas solubility in solution and the efficient utilization of photons from various types of light sources.
Gefapixant citrate (MK-7264) is a
P2X3 antagonist for the treatment
of chronic cough. The second generation manufacturing route developed
for the Step 3A/3B formylation–cyclization reaction to generate
the key intermediate diaminopyrimidine (1) (AF-072) required
a significant excess of ethyl formate (EF), potassium tert-butoxide (KOt-Bu), and guanidine•HCl (G•HCl)
when both steps were run as batch processes. It was imperative to
develop an alternative process that required less of each reagent
and generated less carbon monoxide byproducts, as the annual production
of the final active pharmaceutical ingredient (API) is expected to
be over 50 MT. In addition, the second generation process was misaligned
with our company’s strategy of having the best science in place
at the first regulatory filing. The final flow–batch process
described herein, which features a flow-based formylation combined
with a batch cyclization, has been performed on a 500 kg scale and
now requires 35% less EF (leading to a 70% reduction in waste carbon
monoxide), 38% less KOt-Bu, and 50% less G•HCl.
These improvements, along with a twofold increase in concentration,
have resulted in a 54% reduction in the step process mass intensity
(step-PMI) from the second generation two-step batch–batch
process (PMI of 17.16) to the flow–batch process (PMI of 7.86),
without sacrificing reaction performance.
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