Síntese Contínua de Benzocaína

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Two step continuous-flow synthesis of benzocaine
Alexandre de S. França1 & Raquel A. C. Leão1,2
& Rodrigo O. M. A. de Souza1
Received: 2 April 2020 /Accepted: 21 April 2020
# Akadémiai Kiadó 2020
Abstract
Benzocaine (ethyl p-aminobenzoate), ethyl ester of p-aminobenzoic acid, is an anesthetic acting as a blocker of the nerve
impulses and reducing the permeability of neuronal membrane to sodium iodide, it has become widespread in the pharmaceutical
industry having applications as an anesthetic prior to exams such as endoscopy or as a “retarding” agent when inserted in
condom. Due to the wide insertion in the pharmaceutical market, the methodologies for obtaining this molecule have already
been elucidated and published in the literature, however the application of traditional reactions in refined systems, such as
continuous flow are a technological bottleneck that allow approaches aimed at the optimization of productivity. Thus, the present
work aimed to apply the reduction and esterification of p-nitrobenzoic acid in one step continuous flow systems, optimizing the
reaction time and sequences, in order to add relevance and technology to the process as a whole. The model applied in a
continuous flow system generated extremely positive values compared to the present literature, which include results with high
conversion (> 99%) and selectivity (> 99%), in residence times that reach up to a minimum of 12 s.
Keywords Benzocaine . Continuous flow . Esterification . Reduction
Introduction
Benzocaine, an ethyl ester of p-amino benzoic acid (1), is a
local anesthetic generally used as a topic pain reliever, which
can also be found inmany other anesthetic preparations. It was
first synthesized in 1888 by the German chemist/pharmacist
Eduard Ritsert. As early as 1888, Ritsert had been working on
the production of an antipyretic to replace the toxic and harm-
less phenacetin when he synthesized p-aminobenzoic acid
ethyl ester which did not presented any antipyretic activity,
but it did have a local anesthetic effect. Ritsert left the new
substance to the Hoechst company, where it was marketed
under the name “anesthetic”, which became of outstanding
importance in medicine as local anesthetics, with special men-
tion being made of “Novocaine” (diethylaminoethyl p-
aminobenzoate) invented by Alfred Einhorn in 1905 (Fig. 1)
[1, 2].
Chemical synthesis of the ethyl ester of p-amino benzoic
acid is quite simple and straightforward being accomplished
by several groups during the past years. Two different ap-
proaches can be used starting from the esterification of p-nitro
benzoic acid to its ethyl ester followed by nitro reduction or it
could start with nitro reduction leading to p-amino benzoic
acid, followed by formation of the related ethyl ester product
(Scheme 1) [3].
The esterification reaction is quite simple and any protocol
for a Fischer esterification would in the end lead to the forma-
tion of the desired ester with small differences on yields.
Aromatic nitro reduction has already been well investigated
over literature and many metal catalysts and biocatalysts can
be found over literature with different reaction times and con-
version profiles. Despite the simplicity of the chemical reac-
tions behind this important molecule, continuous-flow tech-
nology has not yet explored its potential in order to deliver a
simple and fast methodology to obtain such compound [4].
Compared to batch technology, continuous-flow process
has several advantages [5–9]. The precise control of reaction
parameters as temperature, residence time, pressure and stoi-
chiometry are more effective [10]. This perfect precision
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s41981-020-00098-2) contains supplementary
material, which is available to authorized users.
* Rodrigo O. M. A. de Souza
rodrigosouza@iq.ufr.br
1 Biocatalysis and Organic Synthesis Group, Chemistry Institute,
Federal University of Rio de Janeiro, Rio de Janeiro 21941909,
Brazil
2 Pharmacy Faculty, Federal University of Rio de Janeiro, Av. Carlos
Chagas Filho, 373, Rio de Janeiro, RJ 21941-170, Brazil
https://doi.org/10.1007/s41981-020-00098-2
/ Published online: 6 July 2020
Journal of Flow Chemistry (2020) 10:563–569
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http://orcid.org/0000-0002-6422-4025
https://doi.org/10.1007/s41981-020-00098-2
mailto:rodrigosouza@iq.ufr.br
increases the selectivity with high reproducibility and allows
the scale-up and better reaction yields. Plus, the continuous
flow system minimizes the hazard and improves the heat
transfer efficiency due to smaller volume of reactor, so that
the thermal unstable molecules are prevented to decomposi-
tion [11–14].
Furthermore, speaking specifically about hydrogenation re-
actions, traditional batch hydrogenation protocols—in partic-
ular on a large scale—offers an operational hazard due to the
use of hydrogen gas, often requiring dedicated high-pressure
resistant reactors and autoclave conditions [15]. This kind of
reaction is also naturally exothermic, so necessitates of an
effective cooling. Therefore, the use of continuous-flow hy-
drogenation methods employing immobilized catalysts has
increased expressively, favoring the researches of continuous
flow processes performed in microreactors [16].
In our continuous-work towards the development of
continuous-flow process to the synthesis of important active
pharmaceutical ingredients (APIs), here in we report our study
on the continuous-flow synthesis of benzocaine on a fast and
efficient single step [17–19] cascade process, delivering the
desired p-amino benzoic acid ethyl ester in excellent yields
and very short reaction times.
Material and methods
Chemicals and solvents were purchased from commercial
suppliers and used as received [Merck: absolute ethanol and
sulphuric acid (99%); Riedel de Haën: p-nitro benzoic acid
(99.5%); Aldrich: catalyst cartridge (L × diam. 30 mm × 4
mm, 10% Pd/C) for H-Cube®].
Chromatography analysis
Samples were prepared by diluting 20 μL of reaction crude in
980 μL of ethyl acetate. Conversion percentages were ana-
lyzed by chromatogram areas using the Shimadzu GC2010
GC-MS – SLB-5MS column 30 m. Injection temperature
250 °C, injection split ratio 20.0, carrier gas was He, pressure
100.0 kPa, column flow 1.61 mL min−1. The oven tempera-
ture setting was: 100 °C for 2 min, heated at 15 °C min−1 to
190 °C and remained for 1 min. Conversion percentages were
analyzed by chromatogram area based on a calibration curve.
Mass ion source temperature 250 °C, interface temperature
300 °C, solvent cut time 3.5 min and scan acquire mode.
Esterification in batch conditions
According to a reported literature procedure, [20] the esterifica-
tion reaction was realized initially in batch conditions adding in
50 mL round-bottom flask the p-nitro benzoic acid (3.12 g,
0.018 mol) in 15 mL of ethanol. The mixture was cooled in ice
bath and 1.0 ml (0.018 mol) of concentrated sulfuric acid were
slowly added. A large amount of precipitate formed, but slowly
dissolved when the mixture was heated. A reflux condenser con-
nected with a cooler adjusted to 4 °C was attached and the mix-
ture was heated under 150 °C for 3 h. (monitored by TLC eluted
with 30:70 ethyl acetate:hexane). Additional ethanol was added
to the reaction vessel in order to keep solvent volume during the
experiment. The reaction mixture was cooled at room tempera-
ture and the precipitated solid was filtered and washes with hex-
ane (3 × 5 mL) to give the 4 (98% yield). A 20 μL aliquot was
transferred to a new vial and 980 μL of ethyl acetate was added
and analyzed in the GC-MS.
Scheme 1 Synthesis of the ethyl
ester of p-amino benzoic.
Fig. 1 Benzocaine, Novocaine
and its start material (1)
564 J Flow Chem (2020) 10:563–569
https://www.sigmaaldrich.com/catalog/product/aldrich/ths02141?lang=pt&region=BR
https://www.sigmaaldrich.com/catalog/product/aldrich/ths02141?lang=pt&region=BRunder continuous flow conditions
A solution containing p-nitro benzoic acid (3.12 g, 0.018 mol)
in 15 mL of ethanol and 1 mL of sulphuric acid was pumped
(Asia Syringe Pumps) through a 10.5 mL PTFE-coil (1/16), in
a 1 mL.min−1 flow, where reaction temperature was screened
(80–120 °C). Asia back pressure regulator was used to keep
reaction at the desired pressure. The reaction mixture was
cooled at room temperature and the precipitated solid was
filtered and washes with hexane (3 × 5 mL) to give the 3
(96% yield). A 20 μL aliquot was transferred to a new vial
and 980 μL of ethyl acetate was added and analyzed in the
GC-MS to monitor the reaction.
Reduction of ethyl-4-nitrobenzoate in H-cube mini
reactor
The ester produced in the first step (ethyl 4-nitrobenzoate
3.0 g, 0.015 mol,) was pumped (Thalesnano pump) in ethanol,
through a 10% Pd/C catalyst cartridge (CatCart®) in a
1 mL.min−1 flow (12 s residence time) at 45 bar and 50 °C
to give the 4. The reaction mixture was cooled at room tem-
perature and the precipitated solid was filtered and washes
with hexane (3 × 5 mL) to give the 4 (92% yield). A 20 μL
aliquot was transferred to a new vial and 980 μL of ethyl
acetate was added and analyzed in the GC-MS to monitor
the reaction.
Reduction of p-nitro benzoic acid in H-cube mini
reactor
A solution containing p-nitro benzoic acid (3.12 g, 0.018 mol)
and sulphuric acid (3.0 mL, 0.054 mol) in ethanol (100 mL)
was pumped (Thalesnano pump) through a 10% Pd/C catalyst
cartridge (CatCart®) at 45 bar and 50 °C in different flow
rates, testing 0.5, 1.0, and 2.0 mL.min−1 with the 0.6, 0.12,
and 0.24 s residence time respectively to give the 3 (99%
yield). Aliquots of 20μLwere collected and diluted with ethyl
acetate to 1.0 mL and analyzed by GC-MS to monitor the
reaction.
Cascade reduction/esterification of p-nitro benzoic
acid in H-cube mini reactor
A solution containing p-nitro benzoic acid (3.12 g, 0.018 mol)
and sulphuric acid or trifluoroacetic acid in absolute ethanol
(100 mL) was pumped (Thalesnano pump) through a 10% Pd/
C catalyst cartridge (CatCart®) in a 1 mL.min−1 flow (12 s
residence time) at 45 bar and 50 °C to give the 4 (99% yield).
A 20 μL aliquot was transferred to a new vial and 980 μL of
ethyl acetate was added and analyzed in the GC-MS to mon-
itor the reaction.
We began our studies following the original synthetic route
which begins with the esterification of p-nitro benzoic acid (2)
followed by H2 / Pd/C reduction of nitro group arriving at p-
amino benzoic acid ethyl ester (4) in two steps under batch
conditions (Scheme 2).
The esterification step was screened at different reaction
temperatures, but good conversions were observed only above
150 °C, being the best condition a temperature of 180 °C for
3 h. Reduction of nitro group can be performed by different
heterogeneous catalysts, we have chosen Pd/C since is a cheap
and readily available catalyst which can afford the desired
product under mild conditions on moderated reaction time.
Both steps are simple and reproducible on gram scale. p-
Amino benzoic acid ethyl ester (4) can be obtained after re-
crystallization with 92% of purity.
After the initial assessment of the synthetic protocol, we
decided to translate reaction conditions to continuous-flow
environment, in a two-step process. First, Fischer esterifica-
tion was implemented on our continuous flow apparatus
where reaction temperature was again screened since the fast
heat transfer of our meso flow reactor could allow us to reduce
reaction temperature (Table 1).
Reaction conditions: p-nitro benzoic acid (3.12 g,
0.018 mol) and sulphuric acid (1 mL, 0.018 mol) in ethanol
(15 mL) in a 1 mL.min−1 continuous flow, measured by GC-
MS method.
Results presented on Table 1 shows that very good conver-
sion can be obtained after 10.5 min of residence time under
lower temperatures when compared to the batch process.
Shorter reaction times do not allow further improvement on
reaction conversion and very similar results could be observed
on reaction carried out at 110 and 120 °C, leading to satisfac-
tory results with 96% conversion (Entries 4 and 5, Table 1).
Temperatures below 100 °C did not lead to satisfactory results
to conversion (Entry 3, Table 1).
Next step was the reduction of nitro group on p-nitro
benzoic acid ethyl ester using H-Cube mini reactor which
allow the screening of several reaction parameters. Specially
in this case, the most important parameter in order to reduce
reaction time, is reaction pressure. As we were aiming for a
cascade process, we decided to use the product solution ob-
tained from previous step as a starting material for optimizing
the continuous-flow protocol for nitro reduction. Results are
presented on Table 2.
Reaction conditions: Ethyl-4-nitrobenzoate (3 g,
0.015 mol) in ethanol (100 mL) using a 10% Pd/C catalyst
cartridge at 25–45 bar and 50 °C, measured by GC-MS
method.
Taking into account that we were looking for a cascade
process, we need to use 1 mL.min−1 as a standard flow rate
since this is was used on the previous step, allowing us a very
Temperature screening of the esterification reaction 565Results and discussion (2020) 10:563–569
short residence time (12 s). As shown on Table 2, higher
pressure values lead to conversion improvements arriving at
90% at 45 bar.
These results corroborate with previous literature, about
reduction of aromatic nitro compounds to the corresponding
amines in microreactors. Heterogeneous catalytic hydrogena-
tion reactions under continuous flow conditions has been in-
vestigated as a standard hydrogenation protocol by a number
of research groups, using Pd on different supports as a catalyst
[21–23]. However, there is no global specific parameter re-
sponsible for the efficiency, so hydrogen pressure, tempera-
ture and residence time have been studied in great detail to
each system [24].
With this results in hands we decided to evaluate a
change on the reaction sequence, starting from the p-
nitro benzoic acid (2) reduction followed by the
Fischer esterification protocol. Taking into account the
experience previously obtained with the reduction of p-
nitro benzoic acid ethyl ester (3) we decided to use the
best reaction condition as a first guess to our experi-
ment. Results obtained are shown on Table 3 for differ-
ent residence times.
Reaction conditions: p-nitro benzoic acid (3.12 g,
0.018 mol) and sulphuric acid (3 mL, 0.054 mol, pH 1) in
ethanol (100 mL) using a 10% Pd/C catalyst cartridge
(CatCart®) at 45 bar and 50 °C, measured byGC-MSmethod.
Under the reaction conditions used, only two products were
observed after the residence time studied, the p-amino benzoic
acid ethyl ester (3) and p-dimethylamino benzoic acid ester
(5). The esterification of carboxylic acids under such condi-
tions is already know over literature but we have not seen yet
the alkylation of the amino group, which can occur probably
through an imine formation derived from the coupling be-
tween acetaldehyde and the amino group with subsequent
H2 reduction. Longer residence times lead to reduction of nitro
group followed by amino group alkylation (Table 3, entry 1),
Scheme 2 Two-step batch protocol for the synthesis of p-amino benzoic acid ethyl ester (4).
Table 1 Temperature screening for the Fisher esterification of p-nitro benzoic acid
Entry T (
o
C) Conv. (%)
1 80 35
2 90 46
3 100 62
4 110 96
5 120 96
566 J Flow Chem (2020) 10:563–569
reducing the residence time also reduce the undesired
alkylated product (Table 3, entry 2). A further reduction on
residence time do not lead to an increase on the desired prod-
uct since unreacted p-amino benzoic acid can be found on the
reacted solution.
In order to try to improve the results presented on Table 3,
we decided to perform the same experiment in the presence of
acid, not to perform the Fischer esterification but to protonate
the p-amino benzoic acid ethyl ester (4) and avoid the alkyl-
ation step. The results are presented on Table 4.
Table 2 Pressurescreening on the reduction of p-nitro benzoic acid towards benzocaine synthesis
Entry Pressure (bar) Conv. (%)
1 25 3
2 30 18
3 35 76
4 40 76
5 45 90
Table 3 Reduction of p-nitro benzoic acid by continuous-flow hydrogenation
Entry Flow Rate (ml.min
-1
) Conv (%) Selectivity to (3) (%)
1 0.5 >99 45
2 1.0 >99 72
3 2.0 >99 61
567J Flow Chem (2020) 10:563–569
Reaction conditions: p-nitro benzoic acid (3.12 g,
0.018 mol) and sulphuric acid or trifluoroacetic acid in ethanol
(100 mL) using a 10% Pd/C catalyst cartridge (CatCart®) in a
1 mL.min−1 flow at 45 bar and 50 °C, measured by GC-MS
method.
In order to achieve the desired results sulfuric acid (Table 4,
entry 1) and trifluoro acetic acid (Table 4, entries 2 and 3) were
evaluated at different pHs. Results shows that at same pH, TFA
present a slight improvement on conversion when compared to
sulfuric acid (Table 4, entries 1 and 2). A decrease on reaction pH
lead to full conversion towards the desired product with a 12 s
residence time (Table 4, entry 3). Under the conditions studied
we could perform the reaction up to 12 mg.mL−1 without any
change on conversion and selectivity.
Conclusion
In this work we have explored the continuous-flow benzocaine
synthesis using different approaches aiming for a cascade two-
step process consisted in Fischer esterification followed by nitro
group reduction under hydrogenation conditions. The results ob-
tained were good with excellent conversions and moderate
selectivity’s with short residence time. During our optimization
step, we have found that we could perform a single step synthesis
of benzocaine by performing the hydrogenation step under acidic
conditions. After optimizing reaction parameters we were able to
find reaction conditionswhich could afford the desired product in
quantitative conversion (> 99%) and selectivity (> 99%), after a
residence time of 12 s.
Acknowledgments Authors thanks CAPES, FAPERJ and CNPq for fi-
nancial support.
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Table 4 Cascade reduction/esterification of p-nitro benzoic acid by continuous-flow hydrogenation under acidic conditions
Entry Acid Conv. (%) Selectivity (4) (%)
1 H2SO4 (pH 2) 61 >99
2 TFA (pH 2) 87 >99
3 TFA (pH 1) >99 >99
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569J Flow Chem (2020) 10:563–569
	This link is 10.1007/s41981-00098-,",
	Two step continuous-flow synthesis of benzocaine
	Abstract
	Introduction
	Material and methods
	Chromatography analysis
	Esterification in batch conditions
	Temperature screening of the esterification reaction under continuous flow conditions
	Reduction of ethyl-4-nitrobenzoate in H-cube mini reactor
	Reduction of p-nitro benzoic acid in H-cube mini reactor
	Cascade reduction/esterification of p-nitro benzoic acid in H-cube mini reactor
	Results and discussion
	Conclusion
	References