Journal of Science and Technology

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[Link] DOI:[Link]

Flow Chemistry: Recent Developments in the Synthesis of

Pharmaceutical Products
Shiva kumar 1 |srikar reddy 2 |[Link] kumar3
1Department of MSC , Vaagdevi College Of Engineering, Warangal.
2AssistantProfessor, Department of Msc, Vaagdevi College Of Engineering, warangal.
3Professor& HoD, Department of Msc, Vaagedevii College Of Engineering, warangal.

To Cite this Article

Shiva kumar 1 |srikar reddy 2 |[Link] kumar3 “Flow Chemistry: Recent

Developments in the Synthesis ofPharmaceutical Products ” Journal of Science and
Technology, Vol. 7, Issue 11,- July 2022, pp1-17

Article Info
Received: 06-06-2023 Revised: 07-07-2023 Accepted: 10-07-2023 Published: 23-07-2023

INTRODUCTION
Synthetic organic chemists have lately shown a lot of interest in continuous flow techniques, as an
alternative to the standard batch approach of doing organic synthesis in closed vessels, test tubes, or round-
bottomed flasks.1 The use of dedicated continuous plants in the petrochemical and bulk chemicals industries
was the norm until very recently. However, these systems have recently gained popularity for the
preparation of fine chemicals, including natural products2 and Active Pharma-ceutical Ingredients (APIs),
particularly in academic institutions. There is clear interest in moving towards continuous flow manufacture
of APIs, even if the pharmaceutical sector currently uses multipurpose batch or semibatch reactors.3
The synthesis of organic compounds is not the only use of flow technologies, however. The remarkable
end-to-end continuous production of an API, aliskiren hemifumarate, was revealed in a groundbreaking
study by researchers from the Novartis-MIT Centre for Continuous production in Cambridge.4 From a
chemical intermediate, the procedure explains how to continuously carry out the reactions and extra
operations (such as quench, work up, isolation, and purification) that are necessary. This allows for a
completely automated continuous process that incorporates not only chemical transformations and
separations but also crystallisations, drying, and formulation. The Novartis-MIT pilot plant has two
synthetic steps—forming the API salt and crystallization—and delivers 100 g/hour of aliskiren, which is
[Link] with 112 mg of free aliskiren are the end result of this method. The work's continuous
reactor, with a capacity of 0.7 L, could prepare 0.8 tonnes of API every year. The continuous reactor
capacity needed to bring the method to a commercial scale of 188 tonnes of API/year is 136 L, which
compares well with the actual batch reactor volume of roughly 1500 L. In addition, the reactions in the
batch process take 48 hours at refluxing conditions, but the continuous process only takes 1 hour and doesn't
use solvents. In total, the batch process takes 300 hours and uses 21 unit operations, while the flow process
uses 48 hours and 13 unit operations. These figures lead to a smaller, more convenient environmental
element and a smaller footprint for the automated flow process.4
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There is a newfound interest in continuous flow processes, and the aforementioned example proves it. The
fundamental properties of flow reactors are to blame for this trend. On a laboratory scale, a continuous flow
process is usually carried out in a so-called "microreactor,"5 a small-diameter apparatus that contains a
contained space and subjected the reaction to very regulated conditions. A flow system's unique selling
point is its very efficient heat and mass transmission, which speeds up the reaction rate and, in comparison
to a batch system, typically improves productivity.6 Temperature alone isn't enough

Figure 1. Types of continuous flow systems.

The tiny size makes it simple to apply and remove a heating source, allowing for highly accurate temperature control along the
microreactor and preventing uncontrolled dangerous exothermic reactions. This not only promotes transfer but also allows for
exact monitoring of the heat exchange. Compared to a batch process, a continuous flow system makes it easier to set up and
monitor reaction parameters like temperature, pressure, and flow rate, leading to a more consistent and repeatable process.7
The minimal volume needed for flow processes allows for quick screening of reaction conditions; once optimised, the reaction
may be ramped up. There are a lot of potential issues that could develop when scaling up a chemical reaction, such as runaway
reactions, inefficient miXing, or the creation of byproducts. There are three ways to make a lot of chemicals in a microreactor,
and the first and simplest is to run the process for longer, which is known as scaling-out. In theory, this is simpler than in batch
reactions. Another option is to employ many reactors in simultaneously, which is called "numbering up," or to scale up to bigger
continuous reactors and run the process there.8 Some safety concerns may also be eliminated by using the microreactor, which
uses very tiny amounts of chemicals. For instance, the operator is kept safer by limiting their handling of potentially dangerous
or toxic items. It is also feasible to conduct reactions involving transitory and reactive substances in a microreactor because of
the short residence period.

Some examples of flow chemistry include microwave irradiation, photochemistry, inductive heating, electrochemistry, novel
solvent systems, microreactor technology, 3D printing, and assisted reagents or catalysts. A completely automated process
with enhanced throughput might be developed with this combination.
It is not unexpected that continuous processing is becoming a method that may greatly influence the synthesis of APIs (or API
intermediates) due to all these benefits. A recent study by Professor Kappe and colleagues thoroughly investigated the use of

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continuous flow conditions for the safe production of organic intermediates and APIs.10 Some previously
forbidden synthetic steps may now be carried out under flow circumstances with little danger, as pointed
out by the authors. These steps include the employment of potentially toxic or explosive intermediates,
reactions operated under high pressures, or above the boiling point of the solvent. This is why flow
chemistry is a cutting-edge field that paves the door for more efficient ways to produce important
chemicals.

Figure 1 shows the four main categories into which the continuous flow systems described in the literature
so far fall, according to Kobayashi and colleagues.11 Type I reactions include flowing all chemicals through
the reactor and collecting the result at the end. The second sort of reactor involves connecting one of the
reactants to a solid and then passing the substrate through it. If the process proceeds to

processing steps that would be too difficult to manage or store in

finalisation, the departing response

conventional batch processing. In addition, the amount of solvents and reagents needed is much less, making
it easy and cost-effective to screen reaction conditions. This opens the door to automated library synthesis
and faster processing times. This would make it easier to find a prospective medicine and produce it in bigger
quantities for use in biological testing.
To further boost efficiency, continuous flow synthetic techniques are also readily combinable with other
supporting technologies.9 Common enabling technologies coupled with
just the thing you want. Catalysts are not necessary for reactions of types I and II. A homogeneous catalyst
is used in type III reactions; the catalyst flows through the reactor with the reactants, therefore a separation
step is needed at the end to retrieve the product without the catalyst (and any byproducts). In type IV, the
catalyst is housed within the reactor and the reagents pass through it. A solid support is needed for catalyst
immobilisation, but in theory, the product and catalyst don't need to be separated. Additionally, the catalyst
could be easily

Scheme 1. Continuous Flow Synthesis of Diphenhydramine Hydrochloride

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recycled. Since catalytic techniques are currently crucial for the development of sustainable and efficient
processes, the latter kind is often thought of as the most convenient way to carry out a reaction under
continuous-flow circumstances.12 All four reactor typologies are used or combined in the cases discussed
in this study. Finally, this study will go over type III and type IV flow systems, concentrating on how
stereoselective chiral organocatalysts are used.
One potential issue with using microreactors to synthesise APIs is the possibility of the reactor being
clogged, namely the channels becoming blocked owing to solid precipitation. For synthetic organic
chemists, dealing with the precipitation of inorganic salts or insoluble materials during reactions is a
regular occurrence. For example, when the reaction product separates from the reaction mixture and can be
easily purified, this may be a suitable scenario.

views, as well as potential and anticipated advancements in the field.

Here is a list of typical reactor materials and the acronyms used for them, as we will be describing many
kinds of continuous flow reactors: The acronyms FEP, PEEK, PFA, and PTFE stand for fluorinated
ethylene propylene, polyether ether ketone, perfluoroalkyl alkanes, and polytetrafluoroethylene,
respectively.

To clarify for the schemes, the following is a list of colours used to denote different components: red for
starting materials, green for products, yellow for isolated intermediate products, dashed yellow for
nonisolated intermediates, and light blue for catalysts.

1. MULTISTEP SYNTHESIS OF ACTIVE PHARMACEUTICAL INGREDIENTS IN FLOW

2. Here are a few instances of the continuous flow creation of APIs that have been shown in

process. In the context of a flow system, however, the issue this poses becomes immediately apparent.
This is why, despite the fact that more technological advancements are required, more advanced
methods for dealing with solids in continuous flow processes have been created in recent times.

Given the abundance of recent reviews covering the synthesis and manufacturing of APIs and related
advanced intermediates, we will narrow our focus to recent developments in the continuous flow
multistep synthesis of organic molecules that have found API applications. This will include
contributions described in the literature from 2013 to 2015, as well as unreported examples from this
time period. In an effort to help bridge the gap between pharmaceutical research and production, we
will provide a broad review of the many techniques, technologies, and synthetic methodologies that
have been employed so far.

Section 2 will focus on the most notable cases from 2013 and 2014 that emerged in the literature, while
Section 3 will explore in depth only the most recent works that have not been covered in any other
study.

Section 4 provides an overview of a new and mostly uncharted area of study: stereoselective
organocatalysis under flow conditions. We aim to show the many possibilities of this method and

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provide a foundation for future work in this area so that we can create better tools for the
stereoselective synthesis of chiral drugs.

Section 5 concludes with some suggested broad strokes on the subject and some thoughts on the

We will go over the literature from 2013 and 2014.13 The key synthetic pathway to the final target
molecule and the major advances in each case will be emphasised.

Over 100 tonnes of diphenhydramine hydrochloride are required annually to provide the global
demand for several popular drugs, including Benadryl, Zzzquil, Tylenol PM, and Unisom.

Jamison and colleagues came up with a continuous flow method for synthesising 3 in 2013, cutting
down on production time, waste, and purification stages compared to current batch synthetic
approaches (Scheme 1).14 A 720 μL PFA tube reactor (i.d. = 0.5 mm) was used in the optimised
process to mix chlorodiphenylmethane 1 and dimethylethanolamine 2, with a residence period of 16
minutes and at a temperature of 175 °C. A rapid rate of reaction was achieved by conducting the
reaction above the boiling point of water and in the absence of solvent. Unlike under batch
circumstances, Product 3 could be readily conveyed in the flow system when it was acquired as molten
salt, meaning it was above the salt's melting point.

The output of the reactor was then mixed with warmed

Ammonium salts may be neutralised using 3 M NaOH. The neutralised tertiary amine was removed
into an inline membrane separator using hexanes after quenching. Diphenhydramine hydrochloride 3
was precipitated with an overall yield of 90% and an output of 2.4 g/h after the organic layer was
treated with HCl (5 M solution in iPrOH).

Less side effects, such as extrapyramidal effects, bodily stiffness, and involuntary tremors, are a
characteristic of atypical antipsychotic medications compared to traditional antipsychotics. Among the
unusual ones, olanzapine 10,15, which is sold under the brand name of

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Scheme 2. Continuous Flow Synthesis of Olanzapine

Scheme 3. Continuous Flow Synthesis of Amytriptyline Hydrochloride

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Scheme 4. Continuous Flow Synthesis of Tamoxifen

Zyprexa is a medication that may help with bipolar illness and schizophrenia.
The multistep continuous flow synthesis of olanzapine 10 was created by Kirschning and colleagues in 2013
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with the use of inductive heating (IH), a method that significantly decreased reaction times and increased
process efficiency.16 Using magnetic nanoparticles and an electromagnetic field (operating at medium or
high frequency according to the size of the nanoparticles) to rapidly raise their temperature is the basis of
inductive heating, an unconventional method of heating.17 Using Pd2dba3 as a catalyst and Xantphos as a
ligand, the first synthesis step included combining aryl iodide 4 and aminothiazole 5, as shown in Scheme 2.
The Buchwald-Hartwig coupling process was carried out inside a PEEK reactor that was inductively heated
to 50 °C (15 kHz) and included 0.8 mm steel beads. Since AcOEt was compatible with some of the

stages in the response that follow. The Pd catalyst was removed by passing the crude mixture through a silica
cartridge after quenching with distilled water and in-line extraction in a glass column. Then, at 40 °C,
nitroaromatic compound 6 was reduced with Et3SiH in a fixed bed reactor that also included Pd/C. The
catalyst maintained its activity for over 250 hours after usage, and a nearly quantitative yield of aniline 7
was achieved. The output of the reactor was then mixed with hydrochloric acid (a 0.6 M methanol solution)
and subjected to high frequency heating (800 kHz) at 140 °C. The total yield of product 8, which was
obtained by acid catalysed cyclization, was 88%. The overall reactor capacity is just approximately 8 mL,
and it is remarkable that the three-step process did not need any solvent swap.
In a 3 mL PEEK reactor using MAGSILICA as the inductive material and silica-supported Ti-(OiPr)4 as the
Lewis acid, compound 8 was finally substituted with piperazine 9. Olanzapine 10 was produced in 83% yield
by inductively heating the reactor at 85 °C with a medium frequency of 25 kHz.
Tricyclic antidepressants like amitriptyline inhibit channels for potassium, calcium, and salt. Migraines,
tension headaches, anxiety attacks, and even some forms of schizophrenia are among the many medical
conditions that it may alleviate.

health problems. Synthesis of dibenzosuberone 13 from lithiated benzyl bromide 11 by Wurtz dimerization
and one-pot Parham cyclization using CO2 as an electrophile is the most common synthetic method for its
manufacture. After reacting ketone 13 with Grignard reagent 14, the next step was to remove water, which
yielded API target 16.
Following this well-established synthetic technique, Kirschning and Kupracz (2013) devised a novel
procedure for the continuous flow synthesis of Amitriptyline 16 (Scheme 3).18 Considering the utilisation
of gas phase reagents (CO2) and highly reactive intermediates (aryl- and alkyllithium compounds), doing
the multistep synthesis of 16 in continuo offers significant benefits over the typical batch technique. The first
lithiation reaction involving nBuLi and benzyl bromide 11 was carried out at -50 °C in a 0.5 mL steel reactor
coil with an inner diameter of 1.0 mm. The target aryl bromide 12 was successfully extracted in 79% yield
after just 5 seconds of quenching with MeOH. The optimal reaction conditions for initial Wurtz coupling
were determined, and then the telescoped synthesis of ketone 13 was investigated. Direct addition of CO2 to
the raw stream of reactants was made possible by using S. V. Ley's19 tube-in-tube reactor technique. 0.5 mL
of PFA reactor coil (i.d. = 0.8 mm) was used for the carboXylation phase, which was carried out at 25 °C.
Following the removal of gas, a second stream of nBuLi was introduced to the reaction mixture. The last
phase of cyclization was carried out at 25 °C using a 0.5 mL PFA reactor coil with an inner diameter of 0.8
mm. Upon adding MeOH, dibenzosuberone 13 was extracted with a 76% yield and a total residence time of
around 30 seconds. It is easy to understand the flow methodology's superior performance when one considers
that the 13-unit batch synthesis alone needed a 2-hour reaction time at -100 °C, with a yield of 56%.
A 0.5 mL PFA reactor coil (i.d. = 1.0 mm) was used to react with Grignard reagent 14 at 25 °C with a
residence period of roughly 30 s after the pure ketone 13 had been extracted from the multistep flow
synthesis. Using inductive heating technology, a 0.3 mL cartridge steel reactor (i.d. = 4.0) was used to
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eliminate water from the carbinol 15 that was produced after protonating the crude reaction mixture with
EtOH.

Scheme 5. Continuous Flow Synthesis of GABAA Inhibitors

mm) in a high-frequency field (810 Hz) that was filled with steel beads (i.d. = 0.8 mm). The initial
substance was entirely transformed into amitriptyline after 30 seconds of residence time at 200 °C. In order
to get the raw mixture down to room temperature, a heat exchanger had to be present. The 17-methyl
amitriptyline hydrochloride salt was finally obtained in 71% yield by recrystallization from an EtOH/Et2O
mixture and the addition of HCl (1 M solution in isopropanol).
Utilising organometallic reagents through flow chemistry technology has numerous advantages over
conventional batch procedures. These include the ability to precisely control the temperature of reactions
that could be exothermic, the safe handling of extremely reactive organometallic intermediates, and the
rapid and stoichiometric reaction of Weinreb amide 17 in a 10 mL PFA reactor coil at 60 °C. Isolation of
ketone 19 in 97% yield was achieved after 5 minutes of residence time and quenching with HCl aq. At -50
°C, using a 10 mL PFA reactor coil, aryl bromide 18 was simultaneously lithiated with nBuLi. Following a
7-minute reaction, the aryl lithium compound 20 was combined with a ketone 19 THF solution and fed into

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a 0.4 mL PFA reactor coil at -50 °C with a 10-second residence period. The mixture was then heated for a
second.

Cook the PFA reactor coil (5 mL) for 2 minutes at 30 °C. The 10 mL PFA reactor coil was heated to 25 °C
for 3 minutes after adding TFA to the crude lithium alkoXide 21. After that, trifluoroacetate 22 was
eliminated with triethylamine into two PFA reactor coils (10 mL) at 100 °C for a total of 5 minutes. The

mixing substrates and reagents, quantified.20 This being the case,

Tamoxifen 23 was produced as an E/Z mixture using telescoped synthesis.

Organolithium and Grignard reagents are examples of very reactive and air-sensitive chemicals; hence,
Steven Ley's lab investigated a novel flow platform based on fluoropolymer peristaltic pumps. The
multistep synthesis of the antagonist prodrug tamoXifen 23, which is used to treat breast cancer at all
stages, was shown in 2013 using this method.21 Schema 4 shows how this method reduced hazards
associated with handling organometallic reagents by combining four separate chemical processes into one
stream with little human participation.
The tetrasubstituted target alkene 23, which is produced using a flow synthesis, was first prepared by
Grignard addition of PhMgBr to

from aryl bromide 18 in a yield of 84% (25:75). With the flow process running continuously for 80
minutes, 12.4 g of pure API was obtained; this quantity is enough to treat one patient for more than 900
days, which is comparable to taking one dosage every 5 seconds.
When the chemical and biological sciences are not properly integrated, it may lead to inefficient drug
development processes and a loss of valuable data. The 2013 study by Ley's group looked at the possibility
of creating a technology that could combine chemical synthesis with biological assays22 for potential new
drugs. They used frontal affinity chromatography (FAC) as an inline screening tool and a flow chemistry
platform for chemical synthesis.23 In a modest collection of 22

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Scheme 6. Continuous Flow Synthesis of Meclinertant

GABAA inhibitor analogues were produced and evaluated in a continuous manner (Scheme 5). Two of
them are agonists of GABAA receptors that are utilised as active medicinal ingredients: alpidem for
anxiety and sleeplessness and zolpidem for certain brain problems. The imidazopyridines to which these
compounds belong are active against cancer, viruses, and microbes.
The synthesis of imidazopyridines in continuous flow started with the acid-catalyzed condensation of ethyl
glyoXalate 25 with ketone 24. A reactor containing 2 grammes of polymer-supported sulfonic acid was
used for the reaction, which was carried out at 120 °C with a residence duration of 25 minutes. A cartridge
containing 3 g of polymer-supported benzyl amine was used to scavenge the excess of 25 after the crude
mixture was run through it. With an excellent yield ranging from 76% to 85%, three products were
recovered without the requirement for workup or additional purifications. At 50 °C, three α,β-unsaturated
ketones 26 and three aminopyridines 27 were pumped into a reactor containing MgSO4 as a dehydrating
agent. The collection process was carried out using an auto sampler. The matching imines were quickly
produced under superheating conditions and then 5-exo cyclized into a 14 mL reactor coil at 120 °C. It was
possible to recover the excess aminopyridine 27 by injecting NH3 into MeOH to release the bound
material after the crude reaction mixture had gone through a column filled with polymer-supported sulfonic
acid. Eight imidazopyridines were obtained after in-line chromatographic purification using the Biotage
system. In the final stage of the synthetic process, molecular diversity was introduced into the
imidazopyridine scaffold through the use of an auto sampler to regulate two separate reactions. The first
reaction involved the saponification of 28 ester moieties with NaOH aq. in a 14 mL reactor coil at 90 °C.
The second reaction involved converting 28 esters into corresponding amides.

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Through the use of Me2AlCl and two distinct secondary amines (HN(R4)2). To eliminate Al compounds,
the reaction mixture was heated at 90 °C in a 14 mL reactor coil and then passed through a cartridge
containing IRA-743 polyol resin. It just took four days to get a library of twenty-two imidazopyridine
derivatives using this flow method. The synthetic platform ended with the introduction of a fraction
collector. After the appropriate dilution, 10 μL aliquots were automatically obtained for each reaction
output and submitted to FAC analysis.
The employment of machine-assisted flow methodologies24 allows for better efficiency and high
throughput, however batch methods are still the most common approach for executing chemical reactions.
Ley and colleagues published a study in 2013 (Scheme 6) that directly compared the flow multistep
synthesis of the selective neurotensine probe SR48692 (Meclinertant) with traditional batch preparation.25
The authors of this case study set out to determine if flow technology might solve several synthetic
problems—such as solid precipitation and the buildup of byproducts—and speed up a multistep synthesis
(i.e., improve yields or decrease reaction times). Product 32 is produced in 60% yield after 3 hours of
stirring in an initial Claisen condensation between ketone 31 and ethyl glyoXalate in the presence of
NaOEt as a base and EtOH as a solvent in a batch operated at room temperature. A speedier approach was
to superheat the reaction in flux, which involves heating the solvent over its boiling point. For example, a
52 mL PFA reactor coil was heated to 115 °C with a residence period of 22 minutes, yielding 32 of the
respective products in 74% yield. An impromptu pressurised stainless-steel tank was constructed to address
solid accumulation issues; this tank was meant to conduct the reaction constantly, without the risk of
precipitation or obstruction, using 5 bar of nitrogen.
In a DMF reaction, the following was carried out with 32 and a commercially available hydrazine 33:

5. OUTLOOK AND PERSPECTIVES

It is hardly surprising that pharmaceutical companies have also begun to focus on flow chemistry for the preparation
of active pharmaceutical ingredients (APIs) given the obvious benefits of continuous flow technologies in the
industrial process. The potential to integrate flow-based chemical synthesis with new analytical tools for in-process
monitoring and enabling technologies to expedite isolation and purification steps is driving this trend, which will
only grow stronger in the years to come.
Microreactors provide many benefits, including as tiny dimensions, improved mass and heat transfer coefficients by
1-2 orders of magnitude, high volumetric productivity, and laminar flow conditions, as well as high surface to
volume ratios. When considering potential uses in industrial synthesis, it is important to consider the following
factors: low power consumption; greater safety owing to minimal quantity of materials utilised in the process; and
cheap operating, maintenance, and manufacturing costs. Scalability in parallel is also an appealing characteristic.

Despite the availability of technology to produce micro-reactors from silicon, glass, steel, and other metals, their
widespread application is surprising. The need for an active, stable catalyst and very rapid reactions is a problem
because of the short residence durations involved. Recent research by a large pharmaceutical manufacturer found
that while continuous processing would improve approximately half of their synthesis reactions, 63% of those
reactions could not be done in a microreactor at the time because of solids. Finally, the most important thing is to
create microreactors that can handle solids and are adaptable enough to be employed in continuous plants with
several purposes. Some recent multistep synthesis flows are also included in this study, demonstrating the
tremendous development achieved in this field. It is possible to imagine many more significant technical
improvements in the future. When thinking about the economics of flow processes, it's important to keep in mind
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that it often takes more time and sometimes not trivial expenditures to construct such processes compared to batch
processes.
Furthermore, existing installations may be reluctant to be replaced because of the perceived high risk associated with
micro reactors, which is exacerbated by their tiny size, susceptibility to fouling and clogging, leakage between
channels, and the lack of information on their dependability and life on stream. Additional drawbacks of catalytic
reactors include the possibility of catalyst deactivation, the need to repack or reactivate the reactor often, and the
reactor's dependability over an extended period of time while operating.
One major advantage of in-flow processes, nevertheless, is the ability to realise very flexible modules that can carry
out on-demand synthesis. The result will be a regional distribution and manufacturing network that can adapt more
quickly to changes in demand thanks to "ad hoc" tailoring of industrial processes that alter production size and
timing. For instance, (micro)reactors technology has made it possible to synthesise unique molecules with less risk
of medicine shortages, and in-situ preparation of explosive and dangerous chemicals is now a real possibility.
Lastly, our capacity to carry out catalytic, enantioselective reactions in flow is an important and likely to be the focus
of future research. All of the reaction sequence examples reported in the last few years pertain to the synthesis of
achiral compounds or the racemic form of a chiral product; there is a lack of development in the stereoselective
synthesis of chiral products. The utilisation of chiral catalytic reactors to produce pharmaceutically relevant
enantiomerically pure compounds was only made possible in 2015 thanks to the Kobayashi report on Rolipram11.
But

A successful use of catalytic reactors in an applied process requires optimisation and study of various subjects,
including activation, efficiency, longevity, degradation, and probable reactivation of supported chiral catalysts.
Future difficulties may include integrating the whole manufacturing process into a single, all-in-continuo process, in
addition to the synthesis of complicated compounds. There are a number of potential benefits: moving directly
from research to manufacturing will reduce overall process timelines and speed up time to market. In addition, by
integrating and colocating production processes in one facility, one may get savings on COGS (cost of products
sold), have more flexibility, have a smaller footprint, and reduce inventory. According to reference 4, the
astounding outcome for the manufacturing of alkiskiren's final tables has
opened new avenues in this area; however it should be noted that the whole in flow manifacturing of aliskiren tablets was
accomplished by studying only the two final steps of the synthesis, a condensation reaction starting from an advanced precursor of the
final product where the absolute configuration of all four stereocenters has been already established. The future challenge is to
accomplish efficient synthesis of enantiomerically pure products under continuous flow conditions and integrate the in flow
synthesis in a single “allin flow” process featuring also in line analysis, purification, and crystallization steps, and leading to the production
of the final, ready for the market drug. The road is long and full of obstacles, but, considering the impressive progress made in the
continuous flow technologies in the past few years, the final goal might be accomplished in shorter times than expected.

REFERENCES
(41) (a) Flow Chemistry by Darvas, F., Hessel, V., and Dorman, G., Berlin: De Gruyter, 2014. (b) In Lab Chip
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Microreactors in Preparative Chemistry by W. Reschetilowski. (d) Microreactors in Organic Synthesis
and Catalysis, 2nd ed., Wirth, T., Wiley-VCH: Weinheim, 2013. Green Chemistry 2012, 14, 38 (e) Wiles,
C.; Watts, P.
(f) „Wagener, Ceylan, and Kirschning“ (2011) in „Chemistry Communicatons“, volume 47, issue 4583.
(g) In the 2011 issue of Angew. Chem., International Edition, Hartman, R. L., McMullen, J. P., and
Jensen, K. F. published a paper with the DOI 50, 7502. (h) The Chem. Commun. of 2011 was 47, 6512,
according to Wiles and Watts. (i) V. Hessel, Chemical Engineering Technology, 2009, 32, 1655.
(2) Pastre, J. C.; Browne, D. L.; and Ley, S. V. Chem. Soc. Rev. 2013, 42, 8849 provides a thorough
overview of flow synthesis of natural products. See, for instance, Newton et al. (2014) in Angew. Chem.,
Int. Ed. 53, 4915 for a more recent example, also see Carter et al., Pearson et al., de C Alves et al., Lange
et al., Thansandote and Ley.
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Article cited as (3) "Continuous Manufacturing in the Pharmaceutical Industry" may be found in (a)
"Journal of Medical Chemistry 2012, 55, 4062" by Malet-Sanz and Susanne. (b) In the article "Org.
Process Res. Dev. 2013, 17, 1472," the authors included Poechlauer, Colberg, Fisher, Jansen, Johnson,
Koenig, Lawler, Laporte, Manley, Martin, and O'Kearney-McMullan.
(c) Organised Process Research and Development (2011) 15, 900, by Jimenez-Gonzalez, C., Poechlauer,
P., BroXterman, Q. B., Yang, B.-S., am Ende, D., Baird, J., Bertsch, C., Hannah, R. E., Dell'Orco, P.,
Noorman, H., Yee, S., Reintjens, R., Wells, A., Massonneau, V., and Manley, J. (d) In this article
published in 2015 in the Journal of Pharmaceutical Science, Baxendale et al. discuss many topics related
to pharmaceuticals.

(a) In the 2013 issue of Angew. Chem., the authors Mascia, Heider, Zhang, Lakerveld, Benyahia, Barton,
Braatz, Cooney, Evans, Myerson, and Trout published a paper with the DOI 52, 12359. (a) In the article
"Org. Process Res. Dev. 2014, 18, 402," the authors include many names and affiliations: Heider, Born,
Basak, Benyahia, Lakerveld, Zhang, Hogan, Buchbinder, Wolfe, Mascia, Evans, Jamison, and Jensen.
(a) Rodrigues, T., Schneider, P., and Schneider, G. Ann. of Chemical Engineering, International Edition
2014, 53, 5750. b) Elvira, K. S., Solvas, X. C., Wootton, R. C. R., and deMello, A. (2013, 5, 905) in the
Journal of the National Chemistry.
6. (a) Plouffe and Macchi (2014) Organic Process Research and Development 18, 1286.
"Green Chemistry" (2013), 15, 1456, written by S. G. Newman and K. F. Jensen. Wegner, J., Ceylan, S.,
and Kirschning, A. were published in Chem. Commun. 2011, 47, 4583.
Chemical Engineering Communications 2007, 194, 760 (Wu, H.; Khan, M. A.; Hussain, A. S.).
Anderson, N. G. Organised Process Research and Development (2012), 16, 852–869.
the ninth(a) In ChemSusChem 2013, 6, 746, Hessel, V., Kralisch, D., Kockmann, N., Noel, T., and Wang,
Q. published a study. b) In Adv. Synth. Catal. 2012, 354, 17, Wegner, Ceylan, and Kirschning were
authors.
In their 2015 article published in the International Edition of the Journal of Chemical Engineering,
Gutmann, Cantillo, and Kappe cited a reference number of 54, 6688.
Nature 2015, 520, 329. Tsubogo, T., Oyamada, H., and Kobayashi, S.
(12) The Green Chemistry Textbook by Anastas, P. T., published by Oxford University Press in 2004 in
New York.
(13) Refer to: (a) Pinho, V. D.; Gutmann, B.; Kappe, C. O. RSC Adv. 2014, 4, 37419 for a few cases that
aren't included in this study.
(b) In the Organ. Process Res. Dev. 2014 article, LaPorte et al. cite Spangler, Hamedi, Lobben, Chan,
Muslehiddinoglu, and Wang as sources: 18, 1492. c) Sterk, D.; Jukic, M.; Casar, Z. Organic Process
Research and Development 2013, 17, 145. (d) As published in the Chemical Communications article by
Hopkin, Baxendale, and Ley (2010, 46, 2450). (e) In the article "Org. Biomol. Chem. 2010, 8, 1798," the
authors Venturoni, Nikbin, Ley, and Baxendale discuss the topic. (f) In the article "Org. Process Res.
Dev. 2010, 14, 432," Bedore, Zaborenko, Jensen, and Jamison were cited.
(g) Comm. — Eur. J. 2010, 16, 12342, by Qian, Z., Baxendale, I. R., and Ley, S. V.
Chemical Science 2013, 4, 2822 (Snead & Jamison, 2014).
The thieno[1,5]benzodiazepines were patented in 1986 by Chakrabarti and Tupper of Lilly Industries Ltd.
(15).
(16) In the 2013 issue of the Angew. Chem. International, Hartwig, Ceylan, Kupracz, Coutable, and
Kirschning published their findings in article 52, 9813.
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[Link] DOI:[Link]

(17) In an article published in 2008 in the International Edition of the Journal of Applied Chemistry,
Ceylan et al.
(a) Kupracz and Kirschning (2013) published in Adv. Synth. Catal. 355, 3375.
(19) In the International Edition of Angew. Chem. published in 2011, Polyzos, A., O'Brien, M., Petersen,
T. P., Baxendale, I. R., and Ley, S. V. reached a result of 50, 1190.
(20) Published in 2007 in Journal of the American Chemical Society, this article was written by Usutani,
Tomida, Nagaki, Okamoto, Nokami, and Yoshida.
(21)Researchers Murray, Browne, Pastre, Butters, Guthrie, and Ley published a paper in Organic Process
Research and Development in 2013 with the DOI: 17.1192.
(22)In a recent publication, Werner et al. provided an example in their article published in 2014 in the
International Edition of the Journal of Chemical Education (Angew. Chem., 53, 1704).
Chemical Science 2013, 4, 764 (Guetzoyan, L., Nikbin, N., Baxendale, I. R., & Ley, S. V.).
Twenty-fourth, in Ley, S. V., Fitzpatrick, D. E., Myers, R. M., Battilocchio, C., and Ingham, R. J., 2015,
54, 2.
The authors of the article "Battilocchio et al. (2013) 19:7917" are Battiloco, Deadman, Nikbin, Kitching,
Baxendale, and Ley.
Lange et al. (2011) published a paper in the Journal of Chemical Science with the DOI 2, 765.
Huisgen, R., 1961, Proc. Chem. Soc. 357.
The authors of the article "Org. Process Res. Dev. 2014, 18, 1567" are Zhang, P., Russell, M. G., and
Jamison, T. F.
Lev́esque and Seeberger published an article in Angew. Chem., International Edition, 2012, 51, 1706.
(30) As published in the 2014 issue of Chem. Commun., the authors Gilmore, Kopetzki, Lee, Horvath,
McQuade, Seidel-Morgenstern, and Seeberger discuss the topic in length.

(31) Check out this article published in 2015 by Poh, J.-S.; Tran, D. N.; Battilocchio, C.; Hawkins, J. M.;
and Ley, S. V. for some instances of continuous flow synthetic techniques.
(b) As published in the European Journal of Chemistry in 2015, Fabry, Ronge, and Rueping were the
authors of the article with the DOI name 21, 5350. (c) In the article "Chem. Sci. 2015, 6, 1120," the
authors Tran, Battilocchio, Lou, Hawkins, and Ley discuss the work of their colleagues. (d) In the
European Journal of Organic Chemistry (2015), Vukelic et al. published a paper with the DOI: 2015,
3036. The authors of the article "Org. Biomol. Chem. 2015, 13, 7633" are Alves, L. C., Desidera, A. L.,
de Oliveira, K. T., Newton, S., Ley, S. V., and Brocksom, T. J. (f) Britton et al. (2015) published in the
Chem. — Eur. J. 21, 10660. (g) In an article published in 2015 in Organic Letters, Gauthier, D. R., Jr.,
Sherry, B. D., Cao, Y., Journet, M., Humphrey, G., Itoh, T., Mangion, I., and Tschaen, D. M. discuss
many topics. (h) “RSC Adv. 2015, 5, 1268” by Viviano, Milite, Rescigno, Castellano, and Sbardella. , in
Souto, J. A., Stockman, R. A., and Ley, S. V., et al., Organic Biomol. Chemistry 2015, 13, 3871. [j] In
RSC Advances 2015, 5, 58798, He, W., Fang, Z., Yang, Z., Ji, D., and Guo, K. "Journal of Organic
Chemistry" from 2015, volume 80, issue 4590, authored by Salvador, Pieber, Neu, Torvisco, Andrade,
and Kappe.
(32), Flow by Martin, A., Siamaki, A., Belecki, K., and Gupton, B. J. Chemistry 2015, 5, 145. (33).(a) In
a 1993 article published in the Journal of Medical Chemistry, Ries et al. (36, 4040) discuss several
compounds that have been found in medicinal chemistry. (b) The authors of the article "Org. Process Res.
Dev. 2007, 11, 81" are Reddy, K. S., Srinivasan, N., Reddy, C. R., Kolla, N., Anjaneyulu, Y.,
Venkatraman, S., Bhattacharya, A., and Mathad, V. T.
the work of Gottessein and Knauber, L. J., Organ. Chem. 2008, 73, 8631.
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[Link] DOI:[Link]

(d) Beilstein, Kumar, Ghosh, and Mehta Organometallic Chemistry 2010, 6, 25.
The authors of the article "Org. Process Res. Dev. 2015, 19, 551" are Pellegatti and Sedelmeier.
The authors of the article are: Alfonsi, K., Colberg, J., Dunn, P. J., Fevig, T., Jennings, S., Johnson, T. A.,
Kleine, H. P., Knight, C., Nagy, M. A., Perry, D. A., and Stefaniak, M. Green. Chemistry 2008, 10, 31.
In their 2015 article published in Organic Letters, Lau et al. (36) cite Galvań, A., Merchant, R. R.,
Battilocchio, C., Souto, J. A., Berry, M. B., and Ley, S. V.(37) Research in Organic Processes, published
in 2014, 18, 1560 by Ouchi, Battilocchio, Hawkins, and Ley.38) Snead and Jamison's 2015 article in the
International Edition of Angew. Chem., volume 54, page 983(39) Bogdan et al. published an article in
2009 with the DOI 48, 8547 in the International Edition of the Journal of Chemical Engineering.. forty(a)
Pierce et al. (1998) (Journal of Organic Chemistry, 63, 8536)The authors of the publication "Synth.
Commun. 1997, 27, 4373" are Radesca, Lo, Moore, and [Link] sentence is paraphrased from a
publication by Dai, Long, Luo, Kulesza, Reichwagen, and Guo (Lonza Ltd.) in [Link] for cyclization-
based efavirenz synthesisForeign application WO2012097510, 2012 PCTAngew. Chem., International
Edition 2015, 54, 4945 (42), Correia, C. A., Gilmore, K., McQuade, D. T., and Seeberger, P. H.(43)
Ghislieri, D.; Gilmore, K.; Seeberger, P. H. Angew. Chem., Int. Ed. 2015, 54, 678.(44) In Comprehensive
Asymmetric Catalysis, Supplement 1, edited by Jacobsen, Pfaltz, and Yamamoto, published by Springer
in 2004 in New York, it is mentioned by Okhuma and Noyori.(b) Trindade and Afonso (2009) published
in the Chemical Review, volume 109, page [Link] (a) Tsubogo, T., Ishiwata, T., and Kobayashi, S.
Angew. Chem., Int. Ed. 2013, 52, 6590 for a few reviews on continuous flow stereoselective catalytic
methods (45).(b) ACS Catal. 2013, 3, 928 (Zhao, D.; Ding, K.).c) In their 2009 article "Beilstein Journal
of Organic Chemistry," Mak, X. Y., Laurino, P., and Seeberger, P. H. published at 10.3762/bjoc.5.19, the
authors acknowledge their [Link] authors Andrade, Kroutil, and Jamison published an article in 2014
describing continuous flow enzymatic catalysis (d) in Organic Letters, 16, [Link], K., Kumagai,
N., and Shibasaki, M., "Org. Lett. 2014, 16, 3496," provides some instances of chiral organometallic
compounds in flow chemistry that were published not long ago.(f) "Gree" Castano, Gallo, Cole-Hamilton,
Dal Santo, Psaro, and Caselli co-authored the following:the journal "Nature Chemistry" in 2014, 16,
[Link] with Enantioselectivity (46a)In: Dalko, P. I. (Ed.), Reactions and Experimental
Procedures, Weinheim, 2007: Wiley VCH.(a) Organocatalysis of Inverse ForcesWith List, B., ed.,
Springer, New York, 2009, Vol. 291, in Materials in Current Chemistry..

See (a) Atodiresei, I.; Vila, C.; Rueping, M. ACS Catal. 2015, 5, 1972 for a few recent studies on
continuous flow stereoselective organocatalysis (47). The authors of the article "Current Organocatalysis
2015, 2, 79" are Puglisi, Benaglia, Porta, and Coccia. (c) Finelli, F. G.; Miranda, L. S. M.; and de Souza,
R. O. M. A. (2015, 51, 3708) in Chem. Commun.
in ChemCatChem 2014, 6, 3286 (48) Cantillo, D., & Kappe, C. O. Green Chemistry 2015, 17,
2012−2026, Gursel, I. V., Noel, T., Wang, Q., and Hessel, V.
four digits(a) The article "Adv. Synth. Catal. 2015, 357, 1093" was written by Munirathinam, Huskens,
and Verboom. (b) In the article "Eur. J. Org. Chem. 2015, 6, 1173," Rodríguez-Escrich and Pericas̀ are
cited. (c) "Green Chemistry" (2013), 15, 1790, Puglisi, Benaglia, and Chiroli, authors. go to reference 45a
for more information.
(50)(a) In a 2013 article published in the Journal of Flow Chemistry, Carroccia, Musio, Degennaro,
Romanazzi, and Luisi (Papers 3, 29). (b) In the article "Beilstein J. Org. Chem. 2011, 7, 1671," the
authors Opalka, S. M., Longstreet, A. R., and McQuade, D. T. discuss the compound. in Angew. Chem.,
Int. Ed. 2009, 48, 2699 (c) Odedra, A.; Seeberger, P. H.
(51)"Beilstein Journal of Organic Chemistry 2013, 9: 2457" (a) by Sugiono and Rueping. (b) In the article
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ISSN: 2456-5660 Volume 7, Issue 11 (July -2022)
[Link] DOI:[Link]

"Beilstein J. Org. Chem. 2012, 8, 300," Rueping, Bootwicha, and Sugiono (2012) were cited. in Angew.
Chem., Int. Ed. 2011, 50, 9467, with contributions from S. Fritzsche, S. Ohla, P. Glaser, D. Giera, M.
Sickert, C. Schneider, J. Belder.
The authors of the article "J. Flow Chem. 2015, 5, 17" are Rossi, Benaglia, Puglisi, De Filippo, and
Maggini (52).
(53) Symmetry 2015, 7, 1395, Porta, R., Benaglia, M., Coccia, F., Rossi, S., and Puglisi, A.
Xie et al. (2007) published an article in Organic Letters, volume 9, pages 413, with co-authors Yue, Du,
Zhu, Deng, and Chen.
(55)Refer to (a) Su, Y.; Straathof, N. J. W.; Hessel, V.; Noel, T. Chem. - Eur. J. 2014, 20, 10562 for a few
recent reviews on photochemistry in flow. (b) In Chem. Rec. 2014, 14, 410, Gilmore and Seeberger were
recognised.
publication: Chem. — Eur. J. 2014, 20, 15226, by Booker-Milburn, K. I., et al.
(d) In the article "Isr. J. Chem. 2014, 54, 351," the authors Garlets, Nguyen, and Stephenson discuss the
topic.
Ref. 56: Neumann and Zeitler's article in Organic Letters (2012), 14, 2658.
(57)(a) Org. Lett. 2000, 2, 3963, by Hafez, A. M., Taggi, A. E., Wack, H., Drury, W. J., III, and Lectka,
T. b) Published in the Journal of the American Chemical Society in 2001, volume 123, pages 10853, by
Hafez, A. M., Taggi, A. E., Dudding, T., and Lectka, T.
In 2013, the authors Chiroli, Benaglia, Cozzi, Puglisi, Annunziata, and Celentano published an article in
Organic Letters with the DOI number 15, 3590.
Journal of Industrial Chemistry 2014, 54, 381 (59) Porta, R., Benaglia, M., Chiroli, V., Coccia, F., and
Puglisi, A.
(60) In Green Chemistry (2014), 16, 2798, Chiroli, V., Benaglia, M., Puglisi, A., Porta, R., Jumde, R. P.,
and Mandoli, A. were authors.
(61 )(a) In a 1996 article published in Chemistry of Materials, Viklund, Svec, Frechet, and Irgum raised
the subject. in Adv. Mater. 1999, 11, 1169, Peters, E. C., Svec, F., and Frećhet, J. [Link] authors of the
article "ChemSusChem 2014, 7, 3534" are Porta, Benaglia, Puglisi, Mandoli, Gualandi, and Cozzi.. (63(a)
In the 2009 issue of Angew. Chem. (International Edition), pages 1313–1314, Cozzi, Benfatti, and Zoli
were named as authors.(b) Benfatti, F., Benedetto, E., and Cozzi, P. G. (2010, 5), Chemical - Asian
Journal, 2047.. (64(a) Duan and Li (2014) in Catal. Sci. Technol., 4, 311.(b) Melchiorre, P. Chemical
Engineering: International Edition 2012, 51, 9748c) Alkaloids in Synthesis and Catalysis from Cinchona
by Song, C. E. Wiley-VCH, Weinheim, [Link] is a single article that mentions using a supported
amino-Cinchona derivative to enhance aldol reactions in water, specifically in batch processes, as far as
we are aware (65).(a) Journal of Organic Biomolecular Chemistry (2012), 10, 4179; Zhou, J., Wan, J.,
Ma, X., Wang, [Link] outb) Wang, W., Ma, X., Wan, J., Cao, J., and Tang, Q. (2012, 41, 5715) Dalton
[Link] Letters 2007, 9, 599 (66) McCooey, S. H.; Connon, S. [Link] authors of the article "Adv.
Synth. Catal. 2015, 357, 377" are Porta, Benaglia, Coccia, Cozzi, and [Link], R.; Benaglia, M.; and
Puglisi, A. (68)undisclosed findings69) In the Organic Biomolecular Chemistry article from 2015, J.
Izquierdo, C. Ayats, A. H. Henseler, and M. A. Pericas̀ were [Link] authors of the article "Chem. -
Eur. J. 2014, 20, 2367" are Osorio-Planes, L., Rodríguez-Escrich, C., and Pericas̀, M. A..

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