An Integrated Continuous Flow Micro-Total Ultrafast Process System

Article Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

pubs.acs.org/OPRD

An Integrated Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS) for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors Vinay Kumar Sthalam,†,‡ Ajay K. Singh,*,† and Srihari Pabbaraja*,†,‡ †

Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India Academy of Scientific and Innovative Research (AcSIR), CSIR-Human Resource Development Centre (CSIR-HRDC) Campus, Ghaziabad 201002, Uttar Pradesh, India

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‡

S Supporting Information *

ABSTRACT: 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 gramscale synthesis of the COX-2-related API, viz. celecoxib, in the continuous flow process. KEYWORDS: pyrazoles API, integrated continuous flow, ultrafast synthesis, COX-2 inhibitor, in-line IR

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INTRODUCTION

Figure 1. Biologically active 3-fluoro methyl pyrazole motif containing selective nonsteroidal anti-inflammatory drug (NSAID) inhibitors.

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 a solvent under reflux conditions.7,22 Active pharmaceutical ingredient (API) manufacturing is usually performed at multiple locations in noncontinuous 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 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 from a longer reaction time (16 h) due to the reactive Cu-acetylide intermediate which becomes an insoluble aggregate.30−32 Rutjes’ group has produced pyrazoles employing a newly emerging flow technique to overcome the above disadvantages. However, this protocol involved high temperature (140 °C) with moderate regioselectivity.33 Ley’s group also reported the multistep continuous flow process system with an amine-redox cycle followed by hydrolysis of the hydrazine surrogate in an industrial unfavorable solvent and ensuing cyclo-condensation at high temperature (140 °C) with a moderate residence time (28 min) resulting in poor pyrazole (celecoxib) yield (48%).34,35 The micro-total process system (μ-TPS) involves quenching, extraction, and a separation system that does not involve an extra work-up procedure. The system completely addresses the tedious problems related to the organic synthesis.23,24,26−29,36−38

is a non-arylamine benzenesulfonamide-derived cyclooxygenase-2 (COX-2) inhibitor that can be used for the treatment of many

Received: May 6, 2019 Published: July 1, 2019

Pyrazoles have a wide range of applications in the field of natural products/pharmaceutical therapeutic agents, including anti-inflammatory, antidiabetic, etc., and thus have attracted attention from both academia and industry (Figure 1).1−13 Celecoxib

© XXXX American Chemical Society

A

DOI: 10.1021/acs.oprd.9b00212 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Table 1. Optimization for Pyrazole Formation with Continuous Flow Technique To Synthesize Celecoxib (3a)a

entry

flow rate μL/min

retention time (min)

temperature (°C)

pressure (bar)

% yieldc 3a

1 2 3 4 5 6 7 8 9 10 11b

1000 2000 600 500 50 600 600 600 600 600 600

8.0 4.0 13.3 16.0 160.0 13.3 13.3 13.3 13.3 13.3 13.3

120 120 120 120 120 60 80 100 120 120 120

32 32 32 32 32 32 32 32 10 17 32

78 75 85 85 83 NA NA NA NA NA 85

a

Reaction conditions: 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 m). bIsopropanol (IPA) was used in place of methanol (MeOH). cYield is based on isolated yield; NA = yields are less than 2%.

To understand and further improve the concept of a μ-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 industrially 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.

After several reaction conditions were investigated, 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 Table 2. Comparative Pyrazole Synthesis Performance of Batch and Continuous Flow Process

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RESULTS AND DISCUSSION Initially, we proceeded with the precursors 4,4,4-trifluoro-1p-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 a 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 concentration of reactants as depicted in Table 1. It was observed that the optimal yield (of 85%) for 3a was obtained at 120 °C with 32 bar pressure (Table 1, entry 3). We noticed that under a lower temperature (60−100 °C), no isolated yield was observed (Table 1, entries 6−8), which may be due to the insufficient energy of activation of reactant molecules to react. However, when a 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 the industrially favorable solvent isopropanol was investigated, a similar yield for celecoxib was obtained (Table 1, entry 11).

entry

process

time (h)

yield (%)

ref

1 2 3 4 5 6 7 8 9 10 11 12

batch batch batch batch batch batch batch batch batch batch batch μ-TPS

20 20 20 20 16 16 16 24 12 20 20 0.22

45 46 66 66 90 94 75 76 93 72 60 85

7 39 40 41 42 43 44 45 46 47 48 this study

reaction in μ-TPS was observed to be ∼90 times faster than the batch process7,39−41 (see comparative Table 2, entries 1−4). After the reaction parameters were optimized for the synthesis of celecoxib, we became interested to develop the total integrated process strategy (reaction, quenching, extraction, and separation) to reduce the tedious work-up procedures.37,38,49−52 During work-up for this reaction process, we had to use a strong base NaOH, which becomes unfavorable for the polyimide film based microchannel that is used generally for separation.50,52,53 Keeping this drawback in mind, we have fabricated a microseparator with a stainless steel body Figure 2, part 1 (60 mm length × 60 mm width × 10 mm thickness). B



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Figure 2. Illustration of a fluoropolymer PTFE membrane microseparation joined between two PTFE films with a laser cut channel; (A) microseparator model; (B) image of microseparator.

Table 3. Solvent Screening for Extraction Using Microseparatora

entry

solvent

solvent flow rate (mL/min)

aq. NaOH flow rate (mL/min)

extraction time (min)

separation time (s)

% yield 3a

1 2 3 4 5 6 7 8

DCM DCM DCM DCM toluene toluene toluene toluene

1.0 0.8 0.6 0.5 1.0 0.8 0.6 0.5

1.0 0.8 0.6 0.5 1.0 0.8 0.6 0.5

0.80 0.9 1.1 1.20 0.8 0.9 1.1 1.2

9.0 11.0 13.6 15.3 9.0 11.0 13.6 15.3

NA NA NA NA NA NA NA NA

C



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Table 3. continued entry

solvent

solvent flow rate (mL/min)

aq. NaOH flow rate (mL/min)

extraction time (min)

separation time (s)

% yield 3a

9 10 11 12 13 14

DEE DEE DEE DEE DEE MTBE

1.0 1.5 2.0 1.25 1.25 1.25

1.0 1.0 1.0 0.5 1.25 1.25

0.8 0.6 0.8 0.8 0.60 0.60

8.0 6.0 5.0 8.0 7.9 7.9

80 50 20 85 85 84

a

Extraction condition: Aq. NaOH solution (0.001 N). Yields reported are based on isolated yields.; NA = yields are less than 2%.

Figure 3. Synthesis of pyrazoles. Reaction condition: feed solution molar ratio (2:1: MeOH/H2O; 1:1:277:45); SS tubing (i.d.: 1 mm and length 10.2 m); pressure 32 bar at 120 °C; yields are based on the isolated yield. D



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Figure 4. Parallel reactor for gram-scale synthesis.

The second Teflon (60 mm length × 60 mm width × 2 mm thickness) layer was made with a laser cutter, to (Figure 2, parts 2 and 3) protect the stainless steel from the corrosive acid/base. The third layer consists of a laser-grooved Teflon film (60 mm × 60 mm × 1 mm thickness) zigzag groove with rectangular shape (2 mm × 80.0 mm). To align the film patterns, the four corners of each two Teflon film were drilled to make a hole (1 mm diameter). Thereafter, a polypropylenecoated 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. 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 the aprotic low boiling solvent (dichloromethane (DCM)/ diethyl ether (DEE)/ t-butyl methyl ether (MTBE)) for extraction purposes following the completion of the reaction. In the first step, aqueous NaOH solution was introduced into the outflowing 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). 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 (i.d. = 1000 μm, 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 Information, 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 s), it was observed that DEE was the best solvent (Table 3, entries 13) for product extraction without contamination. It is important to note that this process involves no additional work-up 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 issues (chronic exposure) for batch process chemistry;54 to minimize that issue, we replaced it with industrially favorable MTBE (Table 3, entries 14) and obtained a similar result. As shown in Figure 3, we successfully developed the celecoxib synthesis (13.3 min) including its extraction/separation (0.6 min) as a better alternative process with a shorter duration and good yield (85% yield). After the development of a fully automated and integrated system for the synthesis of pyrazole celecoxib, we were interested to extend and determine further the scope and limitations of this strategy in a continuous flow system.55 Toward this, a few electron-rich and electron-neutral substituent diketones (2b−2i) (Figure 3) were synthesized and utilized for pyrazole synthesis in a continuous flow system. Notably, the alkyl-, fluoro-, alkoxy-, and phenyl-substituted diketones 2b, 2c, 2d, 2f, 2g, 2h, and 2i (Figure 3) underwent cyclization in a 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 Lastly, to assess the sustainability benefits of operating the celecoxib synthesis with a 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 (Figure 4). The parallelized SS tubing reactors were heated to maintain the desired temperature (120 °C), and the solution of 2a and hydrazine compound 1 were supplied to each reactor with a flow rate of 1.2 mL/min while maintaining 32 bar pressure (see Figure 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 outflowing 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 the corresponding -SO asymmetric str. (1164 cm−1) and -NH str., of primary amine (3350 cm−1) were found to be homogeneous (Figure 5). Furthermore, the product quality was also confirmed by HPLC56 to be 99% of desired product, and further the E



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Figure 5. (a) IR absorption spectra of pure 1a, 2a, and 3a; (b) continuous in-line IR spectra of outflowing solution containing -SO asymmetric str.; (c) continuous in-line IR spectra of outflowing solution containing -NH str., primary amine.

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.

enable 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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ASSOCIATED CONTENT

S Supporting Information *

CONCLUSION In summary, we have developed an improved, scalable, and time-effective, μ-TUFPS for real-time, ultrafast API synthesis. This total integrated continuous manufacturing system produced on-demand pyrazoles, including enantiopure APIs, in excellent yields (65−85%). This is a first integrated reaction operated in an ultrafast 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 multistep cascade reactions and poisonous or hazardous reagents. This would also

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.9b00212. 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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AUTHOR INFORMATION

Corresponding Authors

*(A.K.S.) E-mail: [email protected]. *(S.P.) E-mail: [email protected]. F



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ORCID

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Ajay K. Singh: 0000-0002-4065-7133 Srihari Pabbaraja: 0000-0002-1708-6539 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS S.V.K. is thankful to Sai Life Sciences Limited, Hyderabad, for providing the opportunity to pursue a Ph.D. course at CSIRIICT through AcSIR. A.K.S. thanks Department of Science and Technology, New Delhi (Government 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 is gratefully acknowledged. We gratefully acknowledge Director, CSIRIICT for his support and encouragement. CSIR-IICT, Hyderabad, has filed a patent on the design of a reactor and microseparator for an integrated continuous flow micro-total process system for the synthesis of cyclooxygenase-2 reported herein. IICT manuscript Communication No. IICT/Pubs./ 2018/311.

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An Integrated Continuous Flow Micro-Total Ultrafast Process System

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