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Topics in Current Chemistry (2019) 377:2
Cyclopentyl mandelic acid (CMPA), a key intermediate in the synthesis of
glycopyrronium bromide (glycopyrrolate), is a synthetically challenging inter‑
mediate to prepare. The existing manufacturing routes utilize Grignard rea‑
gents to afford CPMA in 28–56% yield. Kappe, Luisi and co‑workers devised
a flow protocol for the sequential α‑lithiation and subsequent hydroxylation of
α‑phenylcyclopentylacetic acid by aerobic oxidation (Scheme 19) [73]. Hexyllith‑
ium was utilized as a cost‑effective and industrially safe base. A multistep con‑
tinuous flow protocol was developed that afforded CPMA in 50% isolated yield
under homogeneous and mild conditions (atmospheric pressure and room tem‑
perature). However, it was difficult to further improve this process and very chal‑
lenging to prevent decomposition of the desired product, with excess O 2 resulting
in the formation of the undesired ketone product. The reaction was very sensitive
to changes in the input parameters, including temperature, pressure and residence
time, thus demonstrating the importance of having precise control over the reac‑
tion parameters.
7 Membrane Technologies
A membrane acts as a gas permeable contact interface between the liquid phase
and gas phase to enable the liquid phase to be saturated with dissolved gas [74].
Membranes have been used to pre‑load the liquid phase with O 2 before a reac‑
tion or to continuously introduce O 2 to the liquid phase throughout the duration
of a reaction. The nature of the contacting method ensures the process is inher‑
ently safe because the liquid phase and gaseous O 2 are in different channels, thus
flammable organic solvents are never in the presence of gaseous O 2 . In addition,
this method also enables better control over residence time at different gas flow
rates compared to flow regimes containing undissolved O 2 , such as a segmented
gas–liquid flow regime, within a single microchannel. Membranes are designed to
have a large interfacial area to minimize mass transfer effects.
Scheme 19 Continuous flow α‑lithiation and aerobic oxidation to synthesize cyclopentyl mandelic acid
89
Reprinted from the journal
Topics in Current Chemistry (2019) 377:2
Cyclopentyl mandelic acid (CMPA), a key intermediate in the synthesis of
glycopyrronium bromide (glycopyrrolate), is a synthetically challenging inter‑
mediate to prepare. The existing manufacturing routes utilize Grignard rea‑
gents to afford CPMA in 28–56% yield. Kappe, Luisi and co‑workers devised
a flow protocol for the sequential α‑lithiation and subsequent hydroxylation of
α‑phenylcyclopentylacetic acid by aerobic oxidation (Scheme 19) [73]. Hexyllith‑
ium was utilized as a cost‑effective and industrially safe base. A multistep con‑
tinuous flow protocol was developed that afforded CPMA in 50% isolated yield
under homogeneous and mild conditions (atmospheric pressure and room tem‑
perature). However, it was difficult to further improve this process and very chal‑
lenging to prevent decomposition of the desired product, with excess O 2 resulting
in the formation of the undesired ketone product. The reaction was very sensitive
to changes in the input parameters, including temperature, pressure and residence
time, thus demonstrating the importance of having precise control over the reac‑
tion parameters.
7 Membrane Technologies
A membrane acts as a gas permeable contact interface between the liquid phase
and gas phase to enable the liquid phase to be saturated with dissolved gas [74].
Membranes have been used to pre‑load the liquid phase with O 2 before a reac‑
tion or to continuously introduce O 2 to the liquid phase throughout the duration
of a reaction. The nature of the contacting method ensures the process is inher‑
ently safe because the liquid phase and gaseous O 2 are in different channels, thus
flammable organic solvents are never in the presence of gaseous O 2 . In addition,
this method also enables better control over residence time at different gas flow
rates compared to flow regimes containing undissolved O 2 , such as a segmented
gas–liquid flow regime, within a single microchannel. Membranes are designed to
have a large interfacial area to minimize mass transfer effects.
Scheme 19 Continuous flow α‑lithiation and aerobic oxidation to synthesize cyclopentyl mandelic acid
89
Reprinted from the journal