Chemistry Reference
In-Depth Information
attention and been implemented on a large scale in several instances (see
Section 15.2.11) for the manufacture of drug candidates containing large
rings, due in part to the increased availability of commercial Ru catalysts
with higher reactivity and selectivity.
The Suzuki-Miyaura cross-coupling is by far the most widely used reaction
in process chemistry. The commercial availability of a large number of
boronic acids and esters, their stability in general and the possibility of
coupling advanced intermediates due to outstanding functional group
compatibility have contributed to the success of this reaction. A second
group of reactions encompassing Heck, Sonogashira, Negishi, cyanation and
C-N bond formation follow by number of examples. The latter is seeing
increasing application on a large scale due to the prevalence of aromatic
amines in today's APIs. Lastly, several transformations have seen very lim-
ited use in large scale applications, such as Stille coupling, because of the
toxicity of organotin reagents, and Migita coupling, owing to the scarcity of
sulfides, sulfoxides and sulfones in drugs and drug candidates. Interest-
ingly, we have not found process applications of Hiyama coupling, despite
the advantages that organosilicon reagents possess, such as low toxicity and
excellent chemical stability.
6
A major factor in the widespread application of these chemistries in both
medicinal and process chemistry is the application of high-throughput ex-
perimentation (HTE) and design of experiments (DoE), which allows the
screening of hundreds of metal source, ligand, base and solvent combin-
ations in as quickly as a few days or weeks to solve a specific problem. Thus,
it is not unusual to find unprecedented and totally unexpected reaction
conditions which are highly substrate dependent and that otherwise would
have never been identified under more traditional laboratory approaches.
Further optimization of the metal and ligand loadings, metal-to-ligand ratio,
concentration, temperature and reaction time can then provide the key to a
clean, high-yielding and scalable process.
The best proof of the relevance of transition metal-catalyzed coupling re-
actions comes from the numerous applications to the synthesis of com-
mercial drugs, as exemplified in Table 15.2.
This chapter describes case studies that have been reported recently by
processgroupsinpharmaceuticalcompanies and that, in most cases, have
not been reviewed previously.
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In addition to describing bond-forming
processes, the examples contained in this chapter also pay special atten-
tion to work-ups and purifications that purge metal catalysts to provide
intermediates or APIs of sucient purity. These examples were selected
based on two criteria: (a) the transformation has been implemented on a
large-scale (4100 mmol) and (b) the article contains a detailed experi-
mental procedure. Representative examples for each type of coupling are
highlighted in the synthetic schemes. Finally, examples found exclusively
in the patent literature have not been covered in this review because spe-
cific experimental details within these legal documents are often dicult
to access and interpret.
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