Upscaling and Risk Evaluation of the Synthesis of the 3,5-Diamino-1H-Pyrazole, Disperazol
Abstract
1. Introduction
1.1. Safety Assessment of the Active Compound
1.2. Synthetic Route
2. Results and Discussion
2.1. Step 1—Diazotisation
2.2. Step 2—Ring Closure of Pyrazole
2.3. Step 3—Formulation as a Salt
2.4. Summary
3. Materials and Methods
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Andersen, J.B.; Hultqvist, L.D.; Jansen, C.U.; Jakobsen, T.H.; Nilsson, M.; Rybtke, M.; Uhd, J.; Fritz, B.G.; Seifert, R.; Berthelsen, J.; et al. Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosa biofilms. Npj Biofilms Microbiomes 2021, 7, 59. [Google Scholar] [CrossRef]
- Hultqvist, L.D.; Andersen, J.B.; Nilsson, C.M.; Jansen, C.U.; Rybtke, M.; Jakobsen, T.H.; Nielsen, T.E.; Qvortrup, K.; Moser, C.; Graz, M.; et al. High efficacy treatment of murine Pseudomonas aeruginosa catheter-associated urinary tract infections using the c-di-GMP modulating anti-biofilm compound Disperazol in combination with ciprofloxacin. Antimicrob. Agents Chemother. 2024, 68, e01481-23. [Google Scholar] [CrossRef]
- Jansen, C.U.; Uhd, J.; Andersen, J.B.; Hultqvist, L.D.; Jakobsen, T.H.; Nilsson, M.; Nielsen, T.E.; Givskov, M.; Tolker-Nielsen, T.; Qvortrup, K.M. SAR study of 4-arylazo-3,5-diamino-1 H-pyrazoles: Identification of small molecules that induce dispersal of Pseudomonas aeruginosa biofilms. RSC Med. Chem. 2021, 12, 1868–1878. [Google Scholar] [CrossRef]
- Manner, C.; Dias Teixeira, R.; Saha, D.; Kaczmarczyk, A.; Zemp, R.; Wyss, F.; Jaeger, T.; Laventie, B.-J.; Boyer, S.; Malone, J.G.; et al. A genetic switch controls Pseudomonas aeruginosa surface colonization. Nat. Microbiol. 2023, 8, 1520–1533. [Google Scholar] [CrossRef]
- Tarselli, M.A. Life and death with nitrogen. Nat. Chem. 2012, 4, 686. [Google Scholar] [CrossRef]
- Warawdekar, M.G. Challenges in Scale-Up of Specialty Chemicals—A Development Chemist’s Perspective. In Industrial Catalytic Processes for Fine and Specialty Chemicals; Elsevier: Amsterdam, The Netherlands, 2016; pp. 721–736. [Google Scholar] [CrossRef]
- Partington, S.; Waldram, S.P. Runaway Reaction during Production of an Azo Dye Intermediate. Process Saf. Environ. Prot. 2002, 80, 33–39. [Google Scholar] [CrossRef]
- Sheng, M.; Frurip, D.; Gorman, D. Reactive chemical hazards of diazonium salts. J. Loss Prev. Process Ind. 2015, 38, 114–118. [Google Scholar] [CrossRef]
- Filimonov, V.D.; Krasnokutskaya, E.A.; Bondarev, A.A. Structures, Stability, and Safety of Diazonium Salts. In Aryl Diazonium Salts and Related Compounds; Chehimi, M.M., Pinson, J., Mousli, F., Eds.; Springer International Publishing: Cham, Switzerland, 2022; pp. 35–57. [Google Scholar] [CrossRef]
- Bretherick, L. Bretherick’s Handbook of Reactive Chemical Hazards: An Indexed Guide to Published Data, 8th ed.; Urben, P.G., Ed.; Elsevier: Amsterdam, The Netherlands; Oxford, UK; Cambridge, MA, USA, 2017. [Google Scholar]
- Ullrich, R.; Grewer, T. Decomposition of aromatic diazonium compounds. Thermochim. Acta 1993, 225, 201–211. [Google Scholar] [CrossRef]
- Kittsley, S. Need for minimum standards in evaluating doctoral programs. J. Chem. Educ. 1971, 48, 419. [Google Scholar] [CrossRef]
- Firth, J.D.; Fairlamb, I.J.S. A Need for Caution in the Preparation and Application of Synthetically Versatile Aryl Diazonium Tetrafluoroborate Salts. Org. Lett. 2020, 22, 7057–7059. [Google Scholar] [CrossRef]
- Bondarev, A.A.; Naumov, E.V.; Kassanova, A.Z.; Krasnokutskaya, E.A.; Stankevich, K.S.; Filimonov, V.D. First Study of the Thermal and Storage Stability of Arenediazonium Triflates Comparing to 4-Nitrobenzenediazonium Tosylate and Tetrafluoroborate by Calorimetric Methods. Org. Process Res. Dev. 2019, 23, 2405–2415. [Google Scholar] [CrossRef]
- Deadman, B.J.; Collins, S.G.; Maguire, A.R. Taming Hazardous Chemistry in Flow: The Continuous Processing of Diazo and Diazonium Compounds. Chem.-Eur. J. 2015, 21, 2298–2308. [Google Scholar] [CrossRef]
- Jacq, J.; Pasau, P. Multistep Flow Synthesis of 5-Amino-2-aryl-2 H-[1,2,3]-triazole-4-carbonitriles. Chem.-Eur. J. 2014, 20, 12223–12233. [Google Scholar] [CrossRef]
- Crisóstomo, F.P.; Martín, T.; Carrillo, R. Ascorbic Acid as an Initiator for the Direct C-H Arylation of (Hetero)arenes with Anilines Nitrosated In Situ. Angew. Chem. Int. Ed. 2014, 53, 2181–2185. [Google Scholar] [CrossRef]
- Qiu, D.; Meng, H.; Jin, L.; Wang, S.; Tang, S.; Wang, X.; Mo, F.; Zhang, Y.; Wang, J. Synthesis of Aryl Trimethylstannanes from Aryl Amines: A Sandmeyer-Type Stannylation Reaction. Angew. Chem. Int. Ed. 2013, 52, 11581–11584. [Google Scholar] [CrossRef]
- Chakraborty, A.; Jana, S.; Kibriya, G.; Dey, A.; Hajra, A. tert-Butyl nitrite mediated azo coupling between anilines and imidazoheterocycles. RSC Adv. 2016, 6, 34146–34152. [Google Scholar] [CrossRef]
- He, L.; Qiu, G.; Gao, Y.; Wu, J. Removal of amino groups from anilines through diazonium salt-based reactions. Org. Biomol. Chem. 2014, 12, 6965. [Google Scholar] [CrossRef]
- Hu, T.; Baxendale, I.; Baumann, M. Exploring Flow Procedures for Diazonium Formation. Molecules 2016, 21, 918. [Google Scholar] [CrossRef]
- Mihelač, M.; Siljanovska, A.; Košmrlj, J. A convenient approach to arenediazonium tosylates. Dyes Pigment. 2021, 184, 108726. [Google Scholar] [CrossRef]
- Oger, N.; d’Halluin, M.; Le Grognec, E.; Felpin, F.-X. Using Aryl Diazonium Salts in Palladium-Catalyzed Reactions under Safer Conditions. Org. Process Res. Dev. 2014, 18, 1786–1801. [Google Scholar] [CrossRef]
- Mo, F.; Jiang, Y.; Qiu, D.; Zhang, Y.; Wang, J. Direct Conversion of Arylamines to Pinacol Boronates: A Metal-Free Borylation Process. Angew. Chem. Int. Ed. 2010, 49, 1846–1849. [Google Scholar] [CrossRef]
- Oger, N.; Le Grognec, E.; Felpin, F.-X. Handling diazonium salts in flow for organic and material chemistry. Org. Chem. Front. 2015, 2, 590–614. [Google Scholar] [CrossRef]
- Callonnec, F.L.; Fouquet, E.; Felpin, F.-X. Unprecedented Substoichiometric Use of Hazardous Aryl Diazonium Salts in the Heck-Matsuda Reaction via a Double Catalytic Cycle. Org. Lett. 2011, 13, 2646–2649. [Google Scholar] [CrossRef]
- Susperregui, N.; Miqueu, K.; Sotiropoulos, J.-M.; Le Callonnec, F.; Fouquet, E.; Felpin, F.-X. Sustainable Heck-Matsuda Reaction with Catalytic Amounts of Diazonium Salts: An Experimental and Theoretical Study. Chem.-Eur. J. 2012, 18, 7210–7218. [Google Scholar] [CrossRef]
- Ahmed-Omer, B.; Barrow, D.A.; Wirth, T. Heck reactions using segmented flow conditions. Tetrahedron Lett. 2009, 50, 3352–3355. [Google Scholar] [CrossRef]
- Movsisyan, M.; Delbeke, E.I.P.; Berton, J.K.E.T.; Battilocchio, C.; Ley, S.V.; Stevens, C.V. Taming hazardous chemistry by continuous flow technology. Chem. Soc. Rev. 2016, 45, 4892–4928. [Google Scholar] [CrossRef]
- Smith, C.J.; Smith, C.D.; Nikbin, N.; Ley, S.V.; Baxendale, I.R. Flow synthesis of organic azides and the multistep synthesis of imines and amines using a new monolithic triphenylphosphine reagent. Org. Biomol. Chem. 2011, 9, 1927. [Google Scholar] [CrossRef]
- Nielsen, M.A.; Nielsen, M.K.; Pittelkow, T. Scale-Up and Safety Evaluation of a Sandmeyer Reaction. Org. Process Res. Dev. 2004, 8, 1059–1064. [Google Scholar] [CrossRef]
- Li, B.; Widlicka, D.; Boucher, S.; Hayward, C.; Lucas, J.; Murray, J.C.; O’Neil, B.T.; Pfisterer, D.; Samp, L.; VanAlsten, J.; et al. Telescoped Flow Process for the Syntheses of N-Aryl Pyrazoles. Org. Process Res. Dev. 2012, 16, 2031–2035. [Google Scholar] [CrossRef]
TEST | Compound E |
---|---|
Drop-weight impact/Fallhammer (bulk sample) | >100 J |
Friction sensitivity (bulk sample) | >360 N |
Explosion severity, ES; Ignition sensitivity, IS (dust cloud) | Pmax = 9.6 bar (dP/dt)max = 1128 bar/s Kmax = 306 bar·m/s ES = 2.9 IS = 13.1 |
Minimum explosible concentration, MEC (dust cloud) | 50–60 g/m3 Estimate: 56 g/m3 |
Minimum ignition energy, MIE (dust cloud) | 3–10 mJ Estimate: 8 mJ |
Minimum autoignition temperature, MIT (dust cloud) | >600 °C |
Total combustible content (bulk sample) | 100 wt% > 700 °C |
Parameters | Range Tested |
---|---|
Concentration of A | 0.3 M, 0.4 M, 0.6 M, 0.8 M, 1.0 M, 2.0 M |
Temperature | Room temperature (ranging from 23–26 °C), 28 °C, 30 °C |
Coil resident time | 2.5 min, 3 min, 4 min, 5 min, 6.5 min, 7.5 min, 8 min, 10 min, 12 min, 15 min |
Reagents ratio (A:B:TBN) | 1:1:1, 1:1:1.3, 1:1:1.7, 1:1:2, 1:1:2.3, 1:1.1:1, 1:1.2:1, 1:1.3:2, 1:1.3:1.3, 1:1.5:1.3, 1:2:1.3 |
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Jansen, C.U.; Grier, K.E.; Andersen, J.B.; Hultqvist, L.D.; Nilsson, M.; Moser, C.; Graz, M.; Tolker-Nielsen, T.; Givskov, M.; Qvortrup, K. Upscaling and Risk Evaluation of the Synthesis of the 3,5-Diamino-1H-Pyrazole, Disperazol. Int. J. Mol. Sci. 2024, 25, 6737. https://doi.org/10.3390/ijms25126737
Jansen CU, Grier KE, Andersen JB, Hultqvist LD, Nilsson M, Moser C, Graz M, Tolker-Nielsen T, Givskov M, Qvortrup K. Upscaling and Risk Evaluation of the Synthesis of the 3,5-Diamino-1H-Pyrazole, Disperazol. International Journal of Molecular Sciences. 2024; 25(12):6737. https://doi.org/10.3390/ijms25126737
Chicago/Turabian StyleJansen, Charlotte Uldahl, Katja Egeskov Grier, Jens Bo Andersen, Louise Dahl Hultqvist, Martin Nilsson, Claus Moser, Michael Graz, Tim Tolker-Nielsen, Michael Givskov, and Katrine Qvortrup. 2024. "Upscaling and Risk Evaluation of the Synthesis of the 3,5-Diamino-1H-Pyrazole, Disperazol" International Journal of Molecular Sciences 25, no. 12: 6737. https://doi.org/10.3390/ijms25126737
APA StyleJansen, C. U., Grier, K. E., Andersen, J. B., Hultqvist, L. D., Nilsson, M., Moser, C., Graz, M., Tolker-Nielsen, T., Givskov, M., & Qvortrup, K. (2024). Upscaling and Risk Evaluation of the Synthesis of the 3,5-Diamino-1H-Pyrazole, Disperazol. International Journal of Molecular Sciences, 25(12), 6737. https://doi.org/10.3390/ijms25126737