An Integrated Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS) for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors

Article abstract of DOI:10.1021/acs.oprd.9b00212

Integrated continuous manufacturing has emerged as a promising device for the rapid manufacturing of active pharmaceutical ingredients (APIs). We herein report a newly designed continuous flow micro-total process system platform for the rapid manufacturing of celecoxib, a selective nonsteroidal anti-inflammatory drug. This approach has been proven generally for the synthesis of several alkyl and aryl substituted pyrazoles. In order to minimize the tedious work-up process of potential reaction intermediates/products, we have developed a continuous flow extraction and separation platform to carry out the entire reaction sequence resulting in a short residence time with good yield. The present process was further extended to gram-scale synthesis of the COX-2-related API, viz. celecoxib, in the continuous flow process.

Full text of DOI:10.1021/acs.oprd.9b00212

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Full Paper
An Integrated Continuous Flow Micro-Total Ultra-Fast Process System (µ-
TUFPS) for the Synthesis of Celecoxib and other Cyclooxygenase Inhibitors
Sthalam Vinay Kumar, Ajay K. Singh, and Srihari Pabbaraja
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00212 • Publication Date (Web): 01 Jul 2019
Downloaded from http://pubs.acs.org on July 2, 2019
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An Integrated Continuous Flow Micro-Total Ultra-Fast
Process System (-TUFPS) for the Synthesis of Celecoxib
and other Cyclooxygenase Inhibitors
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Sthalam Vinay Kumar, a,b Ajay K. Singh, a*, Srihari Pabbaraja,a,b,*
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aDepartment of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of
Chemical Technology, Hyderabad-500007, India.
bAcademy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource
Development Centre (CSIR-HRDC) Campus, Ghaziabad-201002, Uttar Pradesh
E-mail: ajaysingh015@gmail.com; srihari@iict.res.in
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ABSTRACT: Integrated continuous manufacturing has emerged as a promising device
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for the rapid manufacturing of an active pharmaceutical ingredients (APIs). We herein
report a newly designed continuous flow micro-total process system platform for the
rapid manufacturing of celecoxib, a selective non-steroidal anti-inflammatory drug
(NSAID). This approach has been proven general for the synthesis of several alkyl and
aryl substituted pyrazoles. In order to minimize the tedious work up process of potential
reaction intermediates/products, we have developed a continuous flow extraction and
separation platform to carry out the entire reaction sequence resulting in short residence
time with good yield. The present process was further extended to gram scale synthesis
of COX-2 related active pharmaceutical ingredient (API), viz. celecoxib in the
continuous flow process.
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Keywords: Pyrazoles API, Integrated Continuous flow, Ultra-fast Synthesis, COX-2
inhibitor, In-line IR.
Introduction
Pyrazoles have
a
wide range of applications in the field of natural
products/pharmaceutical therapeutic agents, including anti-inflammatory and anti-
diabetic etc and thus attracted attention from both academia and industry. (Fig. 1).1-13
Celecoxib is a non-arylamine benzene sulfonamide derived cyclooxygenase-2 (COX-2)
inhibitor that can be used for the treatment of many human diseases (e.g., rheumatoid
arthritis, osteoarthritis, acute pain and painful menstruation) in addition to cancer.14-22
Pyrazole derivatives are conventionally prepared by condensation of a diketone with
hydrazine using ethanol or water as solvent under reflux conditions.7,22 API
manufacturing is usually performed at multiple locations in non-continuous or “batch”
synthesis involving extraction, product separation and formulation.23-29 The main
disadvantages of the batch approach include long production times, the high cost of
transportation and the potential disruption of the supply chain.23,24
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H2NO2S
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N
N
CHF2
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MeO
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H2NO2S
Deracoxib
MeO
COX inhibitor
N
N
CF3
N
N
CF3
Br
SC-558
R3
Cl
F2C
Human Lungs Cancer
Suppression
COX inhibitor
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R2
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R1
ra
Py
le
zo
H2NO2S
H2NO2S
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CF3
CF3
Cl
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Celecoxib
COX inhibitor
Mavacoxib
COX inhibitor
CF3
MeO
SC-560
COX inhibitor
Fig. 1: Biologically active 3-fluoro methyl pyrazole motif containing selective non-
steroidal anti-inflammatory drug (NSAID) inhibitors.
Recently, Taran et al. have devised an approach for pyrazole synthesis using transition
metal-catalyzed (Cu) cycloaddition of terminal alkynes and less economical sydnones
that proceed under milder conditions (60 °C). However, the process suffers by longer
reaction time (16 h) due to the reactive Cu-acetylide intermediate which becomes
insoluble aggregate.30
Rutjes group has produced pyrazoles employing newly
31,32
emerging flow technique to overcome the above disadvantages. However, his protocol
involved high temperature (140 C) with moderate regioselectivity.33 “Steven ley’s”
o
group also reported the multi-step continuous flow process system with amine-redox
cycle followed by hydrolysis of the hydrazine surrogate in industrial unfavorable solvent
o
and ensuing cyclo-condensation at high temperature (140 C) with a moderate
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residence time (28 min.) resulting in poor pyrazole (celecoxib) yield (48%).34, 35 Micro-
total process system (μ-TPS) involving quenching, extraction and a separation system
which does not involve extra workup procedure. The system completely addresses the
tedious problems related to the organic synthesis.23,24,26-29,36-38 To understand and
further improve the concept of a -TUFPS, herein we describe the integrated
continuous flow process for pyrazole synthesis via cyclo-condensation of substituted
diketone (2) and 4-hydrazinylbenzenesulfonamide hydrochloride (1) in a combination of
methanol or industrial favorable Isopropanol and water as the green solvents. The
strategy was further extended to minimize the tedious work up process of potential
reaction intermediates by a way of continuous flow extraction and separation resulting in
a short residence time with good yield.
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Results and Discussion
Initially, we proceeded with the precursors 4,4,4-trifluoro-1-p-tolylbutane-1,3-dione (2a)
and 4-hydrazinylbenzenesulfonamide hydrochloride (1) to yield pyrazole (3a) as a
model reaction (table 1). To optimize the reaction conditions / parameters for the
continuous flow process system, the reaction was initiated by infusing the solution
containing reactants with the solvent(s) under stoichiometric molar ratio [2a: 1: MeOH :
H2O (1: 1: 277: 45)]. The continuous flow reaction performance was found to be
dependent on the infusion flow rate (residence time), reaction pressure, temperature
and the concentration of reactants as depicted in Table 1. It was observed that the
o
optimal yield (of 85%) for 3a was obtained at 120 C temperature with 32 bar pressure
o
(table 1, entry 3). We noticed that under lower temperature (60-100 C), no isolated
yield was observed (table 1, entries 6-8) which may be due to the insufficient energy of
o
activation of reactant molecules to react. However, when high temperature (120 C)
and low pressure (10-17 bar) were applied, the yield of the desired product (3a) was
found to be decreased (table 1, entries 9-10), which may be attributed to
uncontrollability of the flow rate of low boiling solvent methanol. Further, when the
feasibility of industrial favourable solvent isopropanol was investigated, similar yield for
celecoxib was obtained (table 1, entry 11).
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Table 1. Optimization for pyrazole formation with continuous flow technique to
synthesize celecoxib (3a).
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Entry
Flow
rate
l/min
1000
2000
600
Retention
time (Min.)
Temperature (oC)
Pressure
(Bar)
% Yieldb
3a
1
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8.0
4.0
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120
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600
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11a
600
600
Reaction condition: Feed solution molar ratio (4,4,4-trifluoro-1-p-tolylbutane-1,3-dione
2a: 4-hydrazinylbenzenesulfonamide hydrochloride 1: MeOH: H2O; 1: 1: 277: 45); SS
tubing (id: 1 mm and length 10.2 meter); (a) isopropanol (IPA) was used in place of
methanol (MeOH); (b) Yield is based on isolated yield; NA = yields are less than 2%.
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Table 2. Comparative pyrazole synthesis performance of batch and continuous flow
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process.
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Entry
Process
Time (h)
Yield (%)
Ref.
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Batch
Batch
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Batch
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Batch
Batch
-TPS
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90
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0.22
This study
After investigating several reaction conditions, 85% yield (optimized condition) of 3a
was obtained in 13.3 min (0.22 h) of residence time at 120 °C and 32 bar, resulting
in ca. 0.33 mmol h–1 productivity (table 2, entry 12). The reaction in -TPS was
observed to be ~90 times faster than the batch process7,39-41 (see comparative table
2, entries 1-4).
After optimizing the reaction parameters for the synthesis of celecoxib, we became
interested to develop the total integrated process strategy (reaction, quenching,
extraction and separation) to reduce the tedious workup procedures.37,38,49-52 During
workup for this reaction process, we had to use strong base NaOH, which becomes
unfavourable for the polyimide film based micro-channel that is used generally for
separation.50,52,53 Keeping this drawback in mind, we have fabricated a micro separator
with a stainless steel body Fig. 2, part 1 (60 mm length x 60 mm width x 10 mm
thickness).
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Fig. 2. Illustration of a fluoropolymer PTFE membrane micro separation joined between
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microseparator.
The second teflon (60 mm length x 60 mm width x 2 mm thickness) layer was made
with a laser cutter, to (fig. 2, part 2 and 3) protect the stainless steel from the corrosive
acid/base. The third layer consists of a laser grooved teflon film (60 mm x 60 mm x 1
mm thickness) zig-zag groove with rectangular shape (2 mm x 80.0 mm). To align the
film patterns, the 4-corners of each two teflon film were drilled to make a hole (1 mm
diameter). Thereafter, a polypropylene coated polytetrafluoroethylene (PTFE)
membrane (Whatmann, 0.45 μm pore, 47 mm dia.) was sandwiched between two teflon
sheets with identical dimensions to fit the groove channels and coupled to each other by
inserting metal pins through the holes at the film corners. Finally, the metal holder was
tightly screwed to pack all the layers of the device, to ensure no leaks.
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Table 3. Solvent screening for extraction using Micro-separator.
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Entry Solvent Solvent flow
rate (mL/min)
Aq. NaOH Extraction time Separation % Yield
flow rate
(mL/min)
1.0
(min.)
time (sec)
3a
1
2
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DCM
DCM
DCM
DCM
Toluen
e
1.0
0.8
0.6
0.5
1.0
0.80
0.9
9.0
11.0
13.6
15.3
9.0
NA
NA
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NA
NA
0.8
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0.5
1.0
1.1
1.20
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Toluen
e
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0.5
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0.5
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1.1
1.2
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13.6
15.3
NA
NA
NA
Toluen
e
Toluen
e
9
DEE
DEE
DEE
DEE
DEE
MTBE
1.0
1.5
1.0
1.0
0.8
0.6
8.0
6.0
5.0
8.0
7.9
7.9
80
50
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85
85
84
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1.0
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0.5
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1.25
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0.60
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Extraction condition: Aq. NaOH solution (0.001 N). Yields reported are based on
isolated yields.; NA = yields are less than 2%.
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Prior to an integrated continuous one flow arrangement for pyrazole syntheses, we
optimized the reaction process for extraction and separation of celecoxib. Since the high
boiling polar protic mixture (MeOH + water) was utilized in the reaction, we have used
aprotic low boiling solvent (dichloromethane (DCM)/ diethyl ether (DEE)/ t-butyl methyl
ether (MTBE)) for the extraction purpose following the completion of the reaction. In the
first step, aqueous NaOH solution was introduced into the out flowing product mixture
along with the organic solvent used for extraction through the X-junction with the
desired flow rate in order to extract the product mixture (table 3).
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In the second step, extraction takes place at the X-junction where the MeOH solvent in
the reaction mixture was progressively moved to the aqueous phase in a droplet form
and the real time extraction occurred in the course of a PFA capillary (id = 1000 m,
length = 2.6 m, vol. = 2 mL). In the final step, the product was extracted into the organic
phase, which wet the thin polypropylene coated PTFE membrane and permeated to the
opposite channel of the separator. Whereas, the aqueous phase containing the waste
did not wet the membrane when maintained at the desired flow stream (supporting
video S1). The extracted product was analyzed by LC-MS and NMR analysis (1H and
13C NMR spectra of 3a) to get the desired isomer exclusively. After the investigation for
the extraction (0.6 min) and separation process (7.9 sec), it was observed that DEE was
the best solvents (table 3, entries 13) for product extraction without contamination. It is
important to note that this process involves no additional workup procedure such as
washing of the product or acid/base treatment and drying over anhydrous Na2SO4. The
organic extract (diethyl ether layer) was concentrated and the resulting residue was
purified by column chromatography (hexane/ethyl acetate) to further purify the product
3a. DEE has some significant handling issue (chronic exposure) for the batch process
chemistry,54 to minimize that issue we were replaced with industrial favorable MTBE
(table 3, entries 14) and obtained similar result. As shown in Figure 3, we have
successfully developed the celecoxib synthesis (13.3 min) including its
extraction/separation (0.6 min) as a better alternative process in shorter duration with
good yield (85% yield).
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After the development of a fully automated and integrated system for the synthesis of
pyrazole celecoxib, we were interested to extend and check further scope and limitation
of this strategy in the continuous flow system.55 Towards this, few electron-rich and
electron-neutral substituent diketones (2b-2i) (fig. 3) were synthesized and utilized for
pyrazole synthesis in continuous flow system. Notably, the alkyl, fluoro, alkoxy, and
phenyl substituted diketones 2b, 2c, 2d, 2f, 2g, 2h, 2i (fig. 3) underwent the cyclization
in short reaction time to afford the corresponding pyrazoles (3b-d, f-i) in an excellent
yield (75-85%) compared to bromo 3e, which was obtained in 65% yield. In general, for
the synthesis of substituted pyrazoles, the batch process system involved longer
reaction times and poor yields.7,39-48
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Fig. 3. Synthesis of pyrazoles; Reaction condition: feed solution molar ratio (2: 1:
MeOH: H2O; 1: 1: 277: 45); SS tubing (id: 1 mm and length 10.2 meter); pressure 32
bar at 120 oC; Yields are based on the isolated yield.
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Lastly, to assess the sustainability benefits of operating the celecoxib synthesis with
process intensification reactor in comparison to the conventional batch reactor(s), the
scale-up synthesis of 3a using two reactors parallelized by the SS tubing in stack was
examined (fig. 4). The parallelized SS tubing reactors were heated to maintain the
o
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desired temperature (120 C) and the solution of 2a and hydrazine compound 1 were
supplied to each reactor with the flow rate of 1.2 mL/min while maintaining 32 bar
pressure (see fig. 4) to produce celecoxib 3a in an excellent yield (obtained in 13.9 min
residence time, resulting in ca. 0.66 mmol h–1 productivity (table 1, entry 3)). Thus, we
were able to produce 3.0 g of celecoxib after running the reaction for 12 h. The out-
flowing product mixture was monitored for a long time by in-line IR to see the steady
state of the celecoxib synthesis, wherein the spectral absorption of corresponding -S=O
asymmetric str. (1164 cm-1) and -NH str., of primary amine (3350 cm-1) were found to be
homogenous (fig. 5). Furthermore, the product quality was also confirmed by HPLC,56 to
be 99% of desired product and further the structure was elucidated by NMR
spectroscopy (2D NMR study nuclear Overhauser effect spectroscopy (NOESY)).56 This
method can also be extended to a parallelized version (numbering-up principle) by
simply wrapping several SS tube reactors into the cylinder to obtain ton level
production.
Fig. 4. Parallel reactor for gram-scale synthesis
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Fig. 5. (a) IR absorption spectra of pure 1a, 2a and 3a; (b) continuous inline IR spectra
of out-flowing solution containing -S=O asymmetric str.; (b) continuous inline IR spectra
of out-flowing solution containing -NH str., primary amine.
Conclusion
In summary, we have developed an improved, scalable and time-effective, μ- TUFPS for
real-time, Ultra-fast API synthesis. This total integrated continuous manufacturing
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system produced on-demand pyrazoles in excellent yields (65-85%), including
enantiopure APIs. This is a first integrated reaction operated at ultra-fast manner (0.22 h
with 85% yield), and the product quality remaining steady throughout the run. The
production rate for celecoxib was found to be 0.66 mmol h–1. This μ-TPS platform can
be easily applied to other modern small-molecule pharmaceuticals involving multi-step
cascade reactions, poisonous or hazardous reagents. This would also enable a
potential automation of an academic laboratory and industry to generate on-demand
enantiopure APIs including extraction and separation units for hospitals, health care
organizations, pharmaceutical development, and humanitarian aid.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgments
S.V.K. is thankful to Sai Life Sciences Limited, Hyderabad, for providing opportunity to
pursue Ph.D. course at CSIR-IICT through AcSIR. A.K.S. thanks Department of Science
and Technology, New Delhi (Govt. of India) (DST), New Delhi, for the INSPIRE Faculty
Award and Early Carrier Research Award. Financial assistance received from the DST
and Science and Engineering Research Board (SERB) by sponsoring project no.
ECR/2017/000208 are gratefully acknowledged. We gratefully acknowledge Director,
CSIR-IICT for his support and encouragement. CSIR-IICT, Hyderabad, has filed a
patent on the design of a reactor and micro separator for an integrated continuous flow
micro-total process system for synthesis of cyclooxygenase-2 reported herein. IICT
manuscript communication no. IICT/Pubs./2018/311.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the ACS Publications website
at DOI:xxx. The general materials and methods, analysis, experimental procedures and
analytical data including the 1H and 13C NMR of the compounds prepared (PDF). Video
of
the
experimental
setup
(MP4).
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