Angewandte
Chemie
DOI: 10.1002/anie.201409765
Flow Chemistry
Chemical Assembly Systems: Layered Control for Divergent,
Continuous, Multistep Syntheses of Active Pharmaceutical
Ingredients**
Diego Ghislieri, Kerry Gilmore, and Peter H. Seeberger*
Abstract: While continuous chemical processes have attracted
both academic and industrial interest, virtually all active
pharmaceutical ingredients (APIs) are still produced by
using multiple distinct batch processes. To date, methods for
the divergent multistep continuous production of customizable
small molecules are not available. A chemical assembly system
was developed, in which flow-reaction modules are linked
together in an interchangeable fashion to give access to a wide
breadth of chemical space. Control at three different levels—
choice of starting material, reagent, or order of reaction
modules—enables the synthesis of five APIs that represent
three different structural classes (g-amino acids, g-lactams, b-
amino acids), including the blockbuster drugs Lyrica and
Gabapentin, in good overall yields (49–75%).
similar benefits to the automobile industry and other
industries involving mass production, where assembly line
manufacturing has made products significantly more avail-
able to the world-wide community.
Establishing a synthetic system requires careful develop-
ment at the level of the individual transformations. While
each of three consecutive reactions can be optimized indi-
vidually in a rather straightforward manner, the general
reaction conditions such as solvent, pH, and byproduct
tolerance often differ from one step to another. When
approaching a synthesis on a systems level, conditions must
be chosen for each transformation that are compatible with all
subsequent reaction units. For example, the choice of solvent
for the first reaction module dictates the solvent for all
subsequent reactions.
C
hemical synthesis traditionally takes a linear approach,
An assembly system provides control on three different
levels and can be used to synthesize series of molecules with
similar structural cores (Figure 1). The first level of control
relates to the starting materials, which when exchanged, yield
different molecules that share the same core functionalities.
Control over the order of reaction modules provides access to
different families of compounds.Using a certain set of starting
materials and a given sequence of reaction modules, different
structural classes of molecules can be synthesized by exercis-
ing control over the reagents within specific modules. The
chemical space that can be accessed through an assembly
system based on different modules is determined by these
three levels of control (Figure 1). Herein, we describe the first
non-iterative[12] chemical assembly system in which control at
all three levels was exercised to prepare three classes of useful
molecules: b-amino acids, g-amino acids, and g-lactams. Five
APIs, including those present in the blockbuster drugs
Pregabalin (Lyrica) and Gabapentin, were prepared in good
yields with the presented system.
In taking on the conceptual challenge, flow reaction
modules should be developed that cover commonly used
transformations and can serve as proofs-of-principle for
coupling to additional modules. A series of fundamental
considerations were kept in mind while developing both the
modules and the system as a whole. In addition to solvent
compatibility throughout, the flow rate has to be maintained
throughout the system. Byproduct formation should be
minimized, although water-soluble byproducts that can be
removed by in-line workup are acceptable. When multiple
reagents are utilized for a particular transformation, they
should be compatible to allow for mixing prior to addition to
the system. Finally, the early reaction modules in the system
should ideally be robust and flexible enough to accommodate
a range of conditions. This flexibility is particularly important
developing both chemistries and technologies to achieve
novel and more efficient routes towards specific targets.[1–4] In
recent years, flow chemistry has emerged as a useful tool,[5–7]
allowing access to advanced structures and active pharma-
ceutical ingredients (APIs) in both stepwise and multistep
processes.[8–11] Conceptually, however, the field has not
advanced, since multistep synthetic processes remain target
oriented. Chemical assembly systems represent a novel
paradigm in non-iterative[12] chemical synthesis, in which
modular synthesis platforms are developed[13–15] that are
capable of being applied in an interchangeable fashion,
thereby allowing access to a wide breadth of chemical space.
This allows a multiply divergent approach to multistep
chemical synthesis, in which different targets, within one or
several structural classes, can be quickly accessed through
manipulation of the system, for example, by changing the
order of the reaction modules or the reagents/compounds
introduced. This conceptual advance represents the first step
towards the chemical and pharmaceutical industries enjoying
[*] Dr. D. Ghislieri, Dr. K. Gilmore, Prof. Dr. P. H. Seeberger
Department of Biomolecular Systems
Max-Planck Institute for Colloids and Interfaces
Am Mꢀhlenberg 1, 14476 Potsdam (Germany)
Institute for Chemistry and Biochemistry
Freie Universitꢁt Berlin
Arnimalle 22, 14195 Berlin (Germany)
E-mail: peter.seeberger@mpikg.mpg.de
[**] We gratefully acknowledge financial support from the Max-Planck
Society. We thank Dr. D. Kopetzki for helpful discussions, Dr. M.
Rasparini from providing a pure sample of Pregabalin and Thales
Nano for providing the H-Cube hydrogenator.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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