5.1 Introduction: Batch Versus Flow
73
Moreover, a recent and detailed protocol describing the assembly and use of a
continuous flow system in an expeditious manner has been reported recently and
should help to eliminate fears and misconceptions on the adoption of this technology
(Britton and Jamison 2017).
5.2 Miniaturized Continuous Flow Systems: Some
Remarks
The term ‘flow chemistry’ usually applies to the adoption of continuous flow systems through the assembly of numerous parts in a modular fashion consisting of
single reactor coils, stainless-steel syringes, pumping systems, pressure and temperature regulators, and multiple junctions (see Fig. 5.1). Further implementation
can also include, among others, liquid–liquid separators, membranes, mixers, drying columns, packed-bed reactors, etc, and all in all contrasts with conventional and
traditional technology using round-bottomed flasks, stirrers, heaters and reflux condensers. Continuous flow systems now enable the preparation of numerous organic
compounds, especially active pharmaceutical ingredients. Typically, enhanced reaction kinetics and accurate levels of control and automation can be achieved in contrast with batch conditions. Additional benefits provided by the small path occupied
by liquids or gas in channels of microscopic diameters include improvements in
heat and mass transfers, homogeneization, facile penetration of external activation
sources such as microwaves, ultrasound, light or plasma (Bruggeman et al. 2016),
and improved reaction safety. The latter represents a key concern as continuous flow
allows the safe handling of hazardous compounds. Moreover, the sequential generation and consumption of such species, formed in small amounts, avoids risks
associated with their manipulation, isolation and storage. These pluses are not only
linked to increased reaction efficiency and reduced costs but also to sustainability
and low environmental impact.
A clear-cut illustration of how flow synthetic chemistry works is shown in Fig. 5.2,
where a commercially available aryl tribromide undergoes a cascade of couplings
involving toxic and hazardous organometallic reagents without any separation leading to a more elaborated structure, which is finally subjected to aqueous alkaline
treatment to afford the desired target (Yoshida et al. 2013). This fast strategy, often
tolerating a variety of functional groups, has become an ideal companion in the
pharmaceutical industry. In fact, numerous patents aimed at preparing active pharmaceutical ingredients (APIs) or bioactive substances in general have adopted flow
processes as routine protocols (Hughes 2018).
A dramatic advantage of miniaturized flow chemistry relative to batch technology
can be appreciated in the continuous synthesis of a key antibiotic, ciprofloxacin
hydrochloride. The overall transformation consists of six telescoped steps followed
by filtration and crystallization to give the ciprofloxacin salt in 60% yield (Lin et al.
2017). A telescoped route is that in which the flow is not interrupted for offline
purifications. Remarkably, the flow synthesis takes nine minutes, which contrasts
73
Moreover, a recent and detailed protocol describing the assembly and use of a
continuous flow system in an expeditious manner has been reported recently and
should help to eliminate fears and misconceptions on the adoption of this technology
(Britton and Jamison 2017).
5.2 Miniaturized Continuous Flow Systems: Some
Remarks
The term ‘flow chemistry’ usually applies to the adoption of continuous flow systems through the assembly of numerous parts in a modular fashion consisting of
single reactor coils, stainless-steel syringes, pumping systems, pressure and temperature regulators, and multiple junctions (see Fig. 5.1). Further implementation
can also include, among others, liquid–liquid separators, membranes, mixers, drying columns, packed-bed reactors, etc, and all in all contrasts with conventional and
traditional technology using round-bottomed flasks, stirrers, heaters and reflux condensers. Continuous flow systems now enable the preparation of numerous organic
compounds, especially active pharmaceutical ingredients. Typically, enhanced reaction kinetics and accurate levels of control and automation can be achieved in contrast with batch conditions. Additional benefits provided by the small path occupied
by liquids or gas in channels of microscopic diameters include improvements in
heat and mass transfers, homogeneization, facile penetration of external activation
sources such as microwaves, ultrasound, light or plasma (Bruggeman et al. 2016),
and improved reaction safety. The latter represents a key concern as continuous flow
allows the safe handling of hazardous compounds. Moreover, the sequential generation and consumption of such species, formed in small amounts, avoids risks
associated with their manipulation, isolation and storage. These pluses are not only
linked to increased reaction efficiency and reduced costs but also to sustainability
and low environmental impact.
A clear-cut illustration of how flow synthetic chemistry works is shown in Fig. 5.2,
where a commercially available aryl tribromide undergoes a cascade of couplings
involving toxic and hazardous organometallic reagents without any separation leading to a more elaborated structure, which is finally subjected to aqueous alkaline
treatment to afford the desired target (Yoshida et al. 2013). This fast strategy, often
tolerating a variety of functional groups, has become an ideal companion in the
pharmaceutical industry. In fact, numerous patents aimed at preparing active pharmaceutical ingredients (APIs) or bioactive substances in general have adopted flow
processes as routine protocols (Hughes 2018).
A dramatic advantage of miniaturized flow chemistry relative to batch technology
can be appreciated in the continuous synthesis of a key antibiotic, ciprofloxacin
hydrochloride. The overall transformation consists of six telescoped steps followed
by filtration and crystallization to give the ciprofloxacin salt in 60% yield (Lin et al.
2017). A telescoped route is that in which the flow is not interrupted for offline
purifications. Remarkably, the flow synthesis takes nine minutes, which contrasts