Keywords
Antimicrobial - Cetylpyridinium chloride - Continuous flow - High-
T
-
High-T and neat continuous flow synthesis of quaternary ammonium-based antimicrobial agent
and disinfectant: cetylpyridinium chloride (CPC)
-
Safe and efficient conversion within a smaller footprint with elements of sustainability
designed for large-scale manufacturing
-
A continuous flow protocol with >50-fold space-time-yield (STY) enhancement as compared
to the conventional batch process
Introduction
Quaternary alkyl pyridinium salts form a widely known utilitarian class of compounds
as they exhibit promising antibacterial activity [1]. In particular, cetylpyridinium chloride (CPC) has wide application in FMCG (fast-moving
consumer goods) products such as mouthwashes, toothpastes, throat and nasal sprays
owing to its powerful antiseptic or antibacterial properties ([
Fig. 1
]) [2]–[3]. Further surfactant properties of CPC have been utilized for the disinfection of
poultry and medical devices [4].
Fig. 1 Biologically active quaternary ammonium salts.
CPC is projected as a multitonnage product globally, which makes it a product of major
commercial significance. Since the first report in 1938 by Knight et al. [5] for the preparation of dodecylpyridinium chloride, several synthetic protocols based
on this approach have emerged in literature discussing methods of improving the yield
of quaternary alkyl pyridinium salts [6]–[7].
Given the importance and large-scale requirement of CPC, several patents have been
filed [8]–[12], describing multiple approaches, namely (i) the synthesis with inexpensive cetyl
chloride and pyridine at 110 °C for 80 h, (ii) synthesis under pressure using an autoclave
followed by agitation at 180 °C, and (iii) synthesis in dry ethanol for reaction times
around 40 h. Improved processes disclosed in recently filed patents did not necessarily
address the relatively long reaction times as well as the requirement of a cumbersome
and time-consuming purification procedure.
Most of the processes disclosed for CPC operate using a batch reactor or a high-pressure
autoclave and have major limitations such as (a) longer reaction times (>10 h up to
80 h), (b) lower product yields, (c) excessive usage of pyridine (several fold excess,
typically >8 equivalents), (d) cumbersome work-up procedures, and (e) requirement
of high pressures.
Despite these variations in classical batch processes that have catered to the global
supply of CPC, there is a clear need to design an improved, efficient and sustainable
synthesis of CPC.
We were, therefore, interested in developing an approach that would not only address
the longer reaction times and tedious purification procedures but also ensure a robust
process potentially less prone to scale-dependency factors while ensuring consistent
yields and purities. We envisaged that continuous flow approach for synthesis of CPC
could be advantageous in the context of using a smaller footprint that could be robustly
translated from lab to manufacturing.
Over the past few years, advances in flow chemistry and continuous manufacturing have
prompted a re-look of current batch processes and have increasingly addressed often
encountered limitations therein [13]–[16]. Compared to the batch reactions, continuous flow processes provide major advantages,
such as increased yield and selectivity, help create a safe working environment (safe
handling of hazardous and reactive substrates), dramatic reduction in the process
time, etc. The possibility of precise and instrument-intensive control of process
parameters such as residence time, temperature, dosing, and pressure has imparted
greater reproducibility and consistency in flow-based processes as compared to the
classical batch reactions [13]. Advancements in flow technology (microreactor) have been driven by several research
groups, namely, Ley [17], Kappe [18], Noel [19], Jamison [20], and Hilton [21].
There is a significant emphasis on improving the ‘time-economy’ of a chemical conversion
[22]. Recently, Kapdi et al. have reported a Suzuki–Miyaura and Heck alkenylation reaction
sequence in plug flow conditions, which greatly improved the conversion time for the
cross-coupling of a series of C5-pyrimidine-substituted nucleosides [23]. As a part of ongoing interest on flow-based process development for large-volume
ingredients, our recent efforts have focused on the high-T (high-temperature) regimen [24].
We herein report the development of a neat and high-temperature-mediated continuous
flow process for the multigram-scale synthesis of CPC employing lower equivalents
of pyridine and a significantly reduced conversion time.
Results and Discussion
As described earlier, an improved approach to address several operational problems
such as long reaction times, excess requirement of pyridine, irreproducible yields,
and variable purity (several purification steps required) is needed to transform current
manufacturing of CPC to a more sustainable production. Our efforts were directed toward
the identification of the key process parameters that could be potentially investigated
for the development of a successful flow process for CPC. It should be mentioned at
this point that long conversion times (slower reaction kinetics) often preclude the
development of a viable flow process owing to long residence times and inordinately
slow flow rates.
As a first step toward preliminary screening and identification of the process parameters,
we performed a batch reaction using pyridine and cetyl chloride on a gram-scale in
a sealed-tube Radleys Carousel 12 Plus Reaction StationTM system at 100 °C. A schematic representation of the batch experimental protocol is
depicted in [
Fig. 2
]; the results thus obtained are tabulated in [
Table 1
]. Although a high yield of ~94% was obtained, the time needed to facilitate a complete
conversion was almost 2 days ([
Table 1
], Entry-1). Furthermore, when the equivalents of pyridine were reduced from 4.0 equivalents
to 2.0 equivalents, a significant reduction in the product yield was observed ([
Table 1
], Entry-2). Subsequently, a 5 g batch was carried out under the same conditions ([
Table 1
], Entry-3) to estimate the reproducibility of the process. In all the cases, the
crude product isolated was yellowish brown in color. Post this initial batch screening,
our efforts were directed toward development of an improved process capable of producing
a high yield within lesser reaction times in an inherently safe and efficient manner.
Fig. 2 Batch process for the synthesis of CPC.
Table 1
Batch process parameters for the synthesis of CPC.
|
No.
|
Stoichiometric equivalents
|
Temperature (°C)
|
Time (h)
|
Isolated yield (%)
|
|
Cetyl chloride
|
Pyridine
|
|
1
|
1.0[
a
]
|
4.0
|
100
|
48
|
94
|
|
2
|
1.0[
a
]
|
2.0
|
100
|
74
|
66
|
|
3
|
1.0[
b
]
|
4.0
|
100
|
54
|
89
|
Reaction was carried out on a 1.5 g scale
Reaction was carried out on a 5 g scale
Against this background, we contemplated the use of continuous flow chemistry approach
to CPC and exploit the intrinsic advantages of flow. In particular, we wanted to investigate
whether high surface-to-volume ratio, enhanced heat and mass transfer, better intermixing
of reactants, and the ability to safely explore temperatures higher than the boiling
points of the reactants will bring about an improvement in the current batch process.
With this knowledge, we set forth to conduct a few flow chemical trials to facilitate
a deeper insight into the nature of conversion and identify a set of reaction conditions
where conversion is complete within a reduced reaction time without compromising on
the yield of the compound.
A flow-based setup, comprising a 10-mL Hastelloy coil reactor (1/8″ OD) coupled to
a peristaltic or HPLC pump, was configured in-house ([
Fig. 3A
]) and various flow conditions were screened as part of optimization trials ([
Fig. 4
] and [
Table 2
]). It was observed that temperature in excess of 180 °C was typically required to
ensure complete consumption of cetyl chloride with a residence time less than 1 h.
All the runs carried out at 180 °C and 200 °C afforded CPC as an off-white to white
solid after work-up and isolation ([
Fig. 3C
]). Indeed, the best results were observed when the quaternization reaction was carried
out with 4.0 eq. of pyridine and 1.0 eq. of cetyl chloride at a temperature of 200 °C
with a residence time of 30 min to obtain CPC with an isolated yield of 96% and HPLC
purity of >99% ([
Table 2
], Entry-4).
Fig. 3 (A) Continuous flow setup for the synthesis of CPC; (B) Hastelloy coil reactor (1/8″ OD, 10 mL internal volume capacity) used for conducting
the experiments; (C) in-house CPC synthesized through continuous flow.
Fig. 4 Continuous flow setup and purification protocol for the synthesis of CPC.
Table 2
Optimization studies for continuous flow synthesis of CPC.
|
No.
|
Stoichiometric equivalents
|
Temperature (°C)
|
Time (min)
|
Yield (%)
|
HPLC purity (%)
|
Moisture content (%)
|
|
Cetyl chloride (1)
|
Pyridine (2)
|
|
1
|
1.0
|
2.0
|
160
|
30
|
39
|
98.71[
b
]
|
5.6
|
|
2
|
1.0
|
4.0
|
180
|
30
|
70
|
99.30[
b
]
|
5.6
|
|
3
|
1.0
|
4.0
|
200
|
15
|
78
|
99.28[
b
]
|
5.8
|
|
4
|
1.0
|
4.0
|
200
|
30[
a
]
|
96
|
99.23[
b
]
|
6.1
|
|
5
|
1.0
|
4.0
|
200
|
60
|
91
|
98.99
|
5.3
|
Similar conversion observed for a residence time of 45 min.
Off-white to white colored solid.
Compared to the batch reaction, the continuous flow process has thus provided us with
notable advantages: (a) short residence time <1.0 h for complete consumption of the
limiting reactant, namely, cetyl chloride (compared to 48 h for a batch process);
(b) very high yields, viz. >95%; (c) excellent HPLC purity (>99%) with adherence to
the physical appearance and nature of the product as per standard specifications obtained
via a simple work-up procedure; and (d) smaller footprint thereby enabling a more
efficient production-scale adaptability in comparison with a batch process ([
Fig. 3A and 3B
] show the setup). Most importantly, the flow conditions identified would help preclude
any impact of scale on the successful outcome of the reaction and meeting critical
quality attributes of the final product.
A meaningful implication of the current flow process in a manufacturing scenario can
be correlated with an assumed production capacity and throughput of CPC (approximated
extrapolation from the data reported in Ref. [12]). In a batch scenario, 1.0–1.2 MT (metric tons) per week would require a minimum
of three batch cycles involving a 2 kL batch reactor operating at 120–130 °C with
60% volume occupancy for a 24 h conversion time. In contrast, extrapolating our current
findings and 30 min residence time in a flow process involving a rig equipped with
a 20 L flow reactor can potentially generate 3.0–3.5 MT of CPC per week (see [
Table 3
] for a comparison between derived process metrics of batch vs flow). Given that the
batch reactions are typically performed at or slightly above the boiling points of
pyridine, the safety risk and energy efficiency would directly correlate with the
reactor footprint. Clearly, a continuous flow manufacturing approach of CPC would
be sustainable in the long term.
Table 3
Comparison of space-time-yield (STY) for synthesis of CPC in batch versus flow
|
No.
|
Parameter
|
Batch[
a
]
|
Flow[
b
]
|
|
1
|
STY (g.L-1 h-1)
|
8
|
1050
|
|
2
|
RME (%)
|
33
|
57
|
Approximated extrapolation from the data reported in the patent considering a non-catalyzed
process 12.
Extrapolated from in-house experiments conducted in flow.
Conclusions
We herein report an efficient and sustainable approach for the synthesis of CPC using
a continuous flow process in the high-T regimen. This approach addresses several shortcomings in the known route of synthesis,
including stoichiometric excess of pyridine, longer reaction times, and lower yields.
Experimental Section
Materials and Methods
1-Chlorohexadecane (cetyl chloride, 98% pure) was procured from BLD Pharmatech (India)
Pvt. Ltd. Pyridine (99% pure) was purchased from Avra Synthesis Pvt. Ltd. All solvents
procured from commercial sources were used without further purification. Melting point
was recorded on a POLMON melting point apparatus (Model Number: MP96). 1H and 13C NMR spectra were recorded on a Varian 400 MHz spectrometer. Chemical shifts (δ)
in ppm are reported relative to Me4Si (= 0 ppm) by using residual solvent signals as internal reference [CDCl3: δ = 7.26 ppm (1H NMR) and 77.0 ppm (13C NMR)]. HPLC was performed on an X-Bridge C18 150*4.6 mm 5 μm column with a mobile
phase of 0.1 % TFA in water and acetonitrile. Mass data were recorded on an Agilent
1200 Series liquid chromatography module hyphenated to a 6430 Triple Quad LC/MS system.
General procedure for the synthesis of CPC through conventional batch techniques
All batch experiments were carried out in a sealed tube or a Radleys Carousel 12 Plus
Reaction StationTM under inert atmosphere. Into a round bottom flask, a mixture of cetyl chloride and
pyridine at the specified equivalents was heated and maintained under stirring for
the specified reaction temperature and duration. Subsequently, the reaction mixture
was cooled to room temperature to yield a dense brown liquid. This was dissolved in
methyl tert-butyl ether MTBE (15 volumes) into which hexane (10 volumes) was further
added. The resultant mixture was stirred for 1 h and the supernatant liquid was decanted,
following which a further amount of hexane (20 volumes) was added to the residue.
The resultant mixture was stirred for 1 h. The suspension thus obtained was filtered
and the resultant solid was dried under reduced pressure to provide a yellowish-brown
solid (CPC).
Typical procedure for the synthesis of CPC through a continuous flow Hastelloy reactor
All continuous flow experiments were performed in a Hastelloy coil reactor (AmAr Equipment
Pvt. Ltd., India, 1/8″ OD, 10 mL)
maintained at desired temperatures using a silicone high-temperature oil bath. A mixture
of cetyl chloride (25.06 g, 29.0 mL, 0.096 moles) and pyridine (30.46 g, 31 mL, 0.385
moles) was sparged with Argon under stirring at 55–60 °C for 1 h. The reactant mixture
was pumped using an HPLC piston pump (Waters) at a flow rate of 0.333 mL/min to afford
a residence time (RT) of 30 min. Initially, about two reactor volumes (20 mL) were
discarded to let the reaction attain steady state, following which about one reactor
volume (10 mL) was collected. Once the collection was complete, the reaction mass
was worked-up and purified as followed in the procedure described above to obtain
a white to off-white solid (CPC; [
Fig. 3C
]).
Melting point: 80-84 °C; 1H NMR (CDCl3, 400 MHz): δ = 9.53 (d, J = 5.2 Hz, 2 H, Ar-H), 8.60-8.40 (m, 1 H, Ar-H), 8.25-8.00 (m, 2 H, Ar-H), 5.01 (t, J = 6.8 Hz, 2 H, N-C
H
2
-CH2-), 2.55-2.10 (br s, 2 H, H2
O), 2.10-1.92 (m, 2 H, N-CH2C
H
2
-), 1.5-1.05 (m, 26 H, N-CH2CH2(CH
2
)13CH3), 0.86 (t, J = 6.4 Hz, 3 H, N-CH2CH2(CH2
)13
CH
3
). 13C NMR (101 MHz, CDCl3): δ 145.20 (CH), 145.03 (CH), 128.45 (CH), 62.10 (CH2), 31.93 (CH2), 31.83 (CH2), 29.60 (CH2), 29.56 (CH2), 29.52 (CH2), 29.44 (CH2), 29.29 (CH2), 29.27 (CH2), 29.02 (CH2), 26.04 (CH2), 22.59 (CH2), 14.02 (CH3). Mass [m/z] calculated for [C21H38N]+: 304; found: 304.
Bibliographical Record
Kashyap Patel, Anant R. Kapdi, Manish Manohar Shinde, Karuna Veeramani, Srinivas Oruganti.
Continuous Flow Multigram-Scale Synthesis of Cetylpyridinium Chloride. Sustainability
& Circularity NOW 2024; 01.
DOI: 10.1055/a-2243-0268
