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Continuous high-pressure operation of a pharmaceutically relevant Krapcho dealkoxycarbonylation reaction

  • M. C. Rehbein
  • J. Wolters
  • C. Kunick
  • S. SchollEmail author
Full paper
  • 26 Downloads

Abstract

The synthesis of the pharmaceutically relevant scaffold 3,4-dihydro-1H-1-benzazepine-2,5-dione via Krapcho dealkoxycarbonylation in a continuous high temperature high pressure coil reactor is investigated and compared to results from batch experiments. In a first step, the continuous reactors residence time distribution (RTD) is characterized, followed by an initial comparison of batch and continuous reactant conversion profiles indicating a very good agreement between both reactors by means of conversion time. Reaction temperature is increased above the solvents atmospheric boiling point in the continuous reactor system to intensify the reaction and increase throughput. Optimal reaction parameters for complete conversion of the starting material in ≤ 3 min reaction time were estimated based on batch kinetics and confirmed by a continuous experiment. The system is able to generate around 12.2 g product per day.

Keywords

Krapcho dealkoxycarbonylation Synthesis Kinetics Flow chemistry Batch to conti 

Nomenclature

ADM

Axial dispersion model

Bo [−]

dimensionless Bodenstein number

c [mmol mL−1]

concentration, subscripts: R – reactant, P – product

Dax[m2s−1]

axial dispersion coefficient

di[mm]

inner diameter

E [s−1]

differential residence time distribution

EA[J mol−1]

activation energy

F [−]

cumulative residence time distribution

k [s−1]

reaction rate constant

k0[s−1]

reaction rate frequency factor

L [m]

length of the coil-reactor

R [J K−1mol−1]

universal gas constant

ρs[g cm−3]

solvent density

STY [g h−1mL−1]

Space time yield

T [°C], [K]

temperature

τ [s]

residence or reaction time

⊖ [−]

dimensionless residence time

u [m s−1]

flow velocity

VR[mL]

reactor volume

\( \dot{V} \)[mL min−1]

volumetric flow rate

XR[−]

reactant conversion

Notes

Acknowledgments

This study was partially funded by the Niedersächsisches Ministerium für Wissenschaft und Kultur (MWK) in the joint research project μ-Props of the Center of Pharmaceutical Engineering (PVZ) of the Technische Universität Braunschweig – Processing of poorly soluble drugs at small scale.

References

  1. 1.
    Roberge DM, Ducry L, Bieler N, Cretton P, Zimmermann B (2005) Microreactor technology: a revolution for the fine chemical and pharmaceutical industries? Chem Eng Technol 28:318–323.  https://doi.org/10.1002/ceat.200407128 CrossRefGoogle Scholar
  2. 2.
    Roberge DM, Zimmermann B, Rainone F, Gottsponer M, Eyholzer M, Kockmann N (2008) Microreactor technology and continuous processes in the fine chemical and pharmaceutical industry: is the revolution underway? Org Process Res Dev 12:905–910.  https://doi.org/10.1021/op8001273 CrossRefGoogle Scholar
  3. 3.
    Gutmann B (2017) The development of high-temperature/high-pressure flow chemistry — a tribute to the pioneering studies of Jürgen O. Metzger. J Flow Chem 7:1–3.  https://doi.org/10.1556/1846.2016.00038 CrossRefGoogle Scholar
  4. 4.
    Plutschack MB, Pieber B, Gilmore K, Seeberger PH (2017) The Hitchhiker's guide to flow chemistry. Chem Rev.  https://doi.org/10.1021/acs.chemrev.7b00183
  5. 5.
    Zhang C, Zhang J, Luo G (2016) Kinetic study and intensification of acetyl guaiacol nitration with nitric acid—acetic acid system in a microreactor. J. Flow Chem 6:309–314.  https://doi.org/10.1556/1846.2016.00011 CrossRefGoogle Scholar
  6. 6.
    Krapcho AP, Glynn GA, Grenon BJ (1967) The decarbethoxylation of geminal dicarbethoxy compounds. Tetrahedron Lett 8:215–217.  https://doi.org/10.1016/S0040-4039(00)90519-7 CrossRefGoogle Scholar
  7. 7.
    Krapcho AP, Weimaster JF, Eldridge JM, Jahngen EGE, Lovey AJ, Stephens WP (1978) Synthetic applications and mechanism studies of the decarbalkoxylations of geminal diesters and related systems effected in dimethyl sulfoxide by water and/or by water with added salts. J Org Chem 43:138–147.  https://doi.org/10.1021/jo00395a032 CrossRefGoogle Scholar
  8. 8.
    Krapcho AP, Jahngen EGE, Lovey AJ, Short FW (1974) Decarbalkoxylations of geminal diesters and β-keto esters in wet dimethyl sulfoxide. Effect of added sodium chloride on the decarbalkoxylation rates of mono- and di-substituted malonate esters. Tetrahedron Lett 15:1091–1094.  https://doi.org/10.1016/S0040-4039(01)82414-X CrossRefGoogle Scholar
  9. 9.
    Krapcho AP (2007) Recent synthetic applications of the dealkoxycarbonylation reaction. Part 2. Dealkoxycarbonylations of β-keto esters, α-cyanoesters and related analogues. Arkivoc 2007:54–120.  https://doi.org/10.3998/ark.5550190.0008.202 CrossRefGoogle Scholar
  10. 10.
    Krapcho AP (2007) Recent synthetic applications of the dealkoxycarbonylation reaction. Part 1. Dealkoxycarbonylations of malonate esters. Arkivoc 2007:1–53.  https://doi.org/10.3998/ark.5550190.0008.201 Google Scholar
  11. 11.
    Kunick C (1991) Synthese [b]-kondensierter azepindione durch Dealkoxycarbonylierung, arch. Pharm. Pharm. Med Chem 324:579–581.  https://doi.org/10.1002/ardp.2503240910 Google Scholar
  12. 12.
    Seko T, Katsumata S, Kato M, Manako J-I, Ohmoto K WO 2003068753Google Scholar
  13. 13.
    Kling A, Backfisch G, Delzer J, Geneste H, Graef C, Hornberger W, Lange UEW, Lauterbach A, Seitz W, Subkowski T (2003) Design and synthesis of 1,5- and 2,5-substituted tetrahydrobenzazepinones as novel potent and selective integrin α V β 3 antagonists. Bioorg Med Chem 11:1319–1341.  https://doi.org/10.1016/S0968-0896(02)00616-8 CrossRefGoogle Scholar
  14. 14.
    Lubisch W, Haupt A, Braje W, Geneste H WO 2005056546Google Scholar
  15. 15.
    Bastiaans HMM, Donn G, Knittel N, Martelletti A, Rees R, Schwall M, Whitford R WO 2005107471Google Scholar
  16. 16.
    Kunick C (1999) Fused azepinones with antitumor activity. Curr Pharm Des 5:181–194Google Scholar
  17. 17.
    Kunick C, Bleeker C, Prühs C, Totzke F, Schächtele C, Kubbutat MHG, Link A (2006) Matrix compare analysis discriminates subtle structural differences in a family of novel antiproliferative agents, diaryl-3-hydroxy-2,3,3a,10a-tetrahydrobenzobcycylopentaeazepine-4,10(1H,5H)-diones. Bioorg Med Chem Lett 16:2148–2153.  https://doi.org/10.1016/j.bmcl.2006.01.071 CrossRefGoogle Scholar
  18. 18.
    Kohfeld S, Jones PG, Totzke F, Schächtele C, Kubbutat MHG, Kunick C (2007) 1-Aryl-4,6-dihydropyrazolo4,3-d1benzazepin-5(1H)-ones: a new class of antiproliferative agents with selectivity for human leukemia and breast cancer cell lines. Eur J Med Chem 42:1317–1324.  https://doi.org/10.1016/j.ejmech.2007.02.007 CrossRefGoogle Scholar
  19. 19.
    Egert-Schmidt A-M, Dreher J, Dunkel U, Kohfeld S, Preu L, Weber H, Ehlert JE, Mutschler B, Totzke F, Schächtele C, Kubbutat MHG, Baumann K, Kunick C (2010) Identification of 2-anilino-9-methoxy-5,7-dihydro-6H-pyrimido5,4-d1benzazepin-6-ones as dual PLK1/VEGF-R2 kinase inhibitor chemotypes by structure-based lead generation. J Med Chem 53:2433–2442.  https://doi.org/10.1021/jm901388c CrossRefGoogle Scholar
  20. 20.
    Achermann G, Ballard TM, Blasco F, Broutin P-E, Büttelmann B, Fischer H, Graf M, Hernandez M-C, Hilty P, Knoflach F, Koblet A, Knust H, Kurt A, Martin JR, Masciadri R, Porter RHP, Stadler H, Thomas AW, Trube G, Wichmann J (2009) Discovery of the imidazo1,5-a1,2,4-triazolo1,5-d1,4benzodiazepine scaffold as a novel, potent and selective GABA(A) alpha5 inverse agonist series. Bioorg Med Chem Lett 19:5746–5752.  https://doi.org/10.1016/j.bmcl.2009.07.153 CrossRefGoogle Scholar
  21. 21.
    Severson B, Chung DH, Jonsson CB, White EL, Rasmussen L, Maddox CB, Ananthan S, Pathak AK, Maddry JA WO 2011097607Google Scholar
  22. 22.
    Schmees N, Kuhnke J, Haendler B, Neuhaus R, Lejeune P, Siegel S, Krueger M, Fernandez-Montalvan AE, Kuenzer H, Gallenkamp D WO 2014048945Google Scholar
  23. 23.
    Falke H, Chaikuad A, Becker A, Loaëc N, Lozach O, Abu Jhaisha S, Becker W, Jones PG, Preu L, Baumann K, Knapp S, Meijer L, Kunick C (2015) 10-iodo-11H-indolo3,2-cquinoline-6-carboxylic acids are selective inhibitors of DYRK1A. J Med Chem 58:3131–3143.  https://doi.org/10.1021/jm501994d CrossRefGoogle Scholar
  24. 24.
    Schultz C, Link A, Leost M, Zaharevitz DW, Gussio R, Sausville EA, Meijer L, Kunick C (1999) Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/cyclin B inhibition, and in vitro antitumor activity. J Med Chem 42:2909–2919.  https://doi.org/10.1021/jm9900570 CrossRefGoogle Scholar
  25. 25.
    Tolle N, Kunick C (2011) Paullones as inhibitors of protein kinases. Curr Top Med Chem 11:1320–1332.  https://doi.org/10.2174/156802611795589601 CrossRefGoogle Scholar
  26. 26.
    Stukenbrock H, Mussmann R, Geese M, Ferandin Y, Lozach O, Lemcke T, Kegel S, Lomow A, Burk U, Dohrmann C, Meijer L, Austen M, Kunick C (2008) 9-cyano-1-azapaullone (cazpaullone), a glycogen synthase kinase-3 (GSK-3) inhibitor activating pancreatic beta cell protection and replication. J Org Chem 51:2196–2207.  https://doi.org/10.1021/jm701582f Google Scholar
  27. 27.
    Lyssiotis CA, Foreman RK, Staerk J, Garcia M, Mathur D, Markoulaki S, Hanna J, Lairson LL, Charette BD, Bouchez LC, Bollong M, Kunick C, Brinker A, Cho CY, Schultz PG, Jaenisch R (2009) Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4. Proc Natl Acad Sci U S A 106:8912–8917.  https://doi.org/10.1073/pnas.0903860106 CrossRefGoogle Scholar
  28. 28.
    Becker A, Kohfeld S, Lader A, Preu L, Pies T, Wieking K, Ferandin Y, Knockaert M, Meijer L, Kunick C (2010) Development of 5-benzylpaullones and paullone-9-carboxylic acid alkyl esters as selective inhibitors of mitochondrial malate dehydrogenase (mMDH). Eur J Med Chem 45:335–342.  https://doi.org/10.1016/j.ejmech.2009.10.018 CrossRefGoogle Scholar
  29. 29.
    Orban OCF, Korn RS, Benítez D, Medeiros A, Preu L, Loaëc N, Meijer L, Koch O, Comini MA, Kunick C (2016) 5-substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms. Bioorg Med Chem 24:3790–3800.  https://doi.org/10.1016/j.bmc.2016.06.023 CrossRefGoogle Scholar
  30. 30.
    Teitz T, Fang J, Goktug AN, Bonga JD, Diao S, Hazlitt RA, Iconaru L, Morfouace M, Currier D, Zhou Y, Umans RA, Taylor MR, Cheng C, Min J, Freeman B, Peng J, Roussel MF, Kriwacki R, Guy RK, Chen T, Zuo J (2018) CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. J Exp Med 215:1187–1203.  https://doi.org/10.1084/jem.20172246 CrossRefGoogle Scholar
  31. 31.
    Kumaniaev I, Subbotina E, Sävmarker J, Larhed M, Galkin MV, Samec JSM (2017) Lignin depolymerization to monophenolic compounds in a flow-through system. Green Chem 19:5767–5771.  https://doi.org/10.1039/C7GC02731A CrossRefGoogle Scholar
  32. 32.
    Kirschning A, Kupracz L, Hartwig J (2012) New synthetic opportunities in miniaturized flow reactors with inductive heating. Chem Lett 41:562–570.  https://doi.org/10.1246/cl.2012.562 CrossRefGoogle Scholar
  33. 33.
    Ceylan S, Coutable L, Wegner J, Kirschning A (2011) Inductive heating with magnetic materials inside flow reactors. Chem Eur J 17:1884–1893.  https://doi.org/10.1002/chem.201002291 CrossRefGoogle Scholar
  34. 34.
    Bagley MC, Jenkins RL, Lubinu MC, Mason C, Wood R (2005) A simple continuous flow microwave reactor. J Org Chem 70:7003–7006.  https://doi.org/10.1021/jo0510235 CrossRefGoogle Scholar
  35. 35.
    Glasnov TN, Kappe CO (2011) The microwave-to-flow paradigm: translating high-temperature batch microwave chemistry to scalable continuous-flow processes. Chem Eur J 17:11956–11968.  https://doi.org/10.1002/chem.201102065 CrossRefGoogle Scholar
  36. 36.
    Levenspiel O (1999) Chemical reaction engineering3rd edn. Wiley, New YorkGoogle Scholar
  37. 37.
    Levenspiel O, Smith WK (1957) Notes on the diffusion-type model for the longitudinal mixing of fluids in flow. Chem Eng Sci 6:227–233.  https://doi.org/10.1016/0009-2509(96)81816-1
  38. 38.
    Müller-Erlwein E, Chemische Reaktionstechnik (2015) 3rd ed., Springer Spektrum, Wiesbaden, GermanyGoogle Scholar
  39. 39.
    Gmehling J et al., Pure compound data from DDB, 1983–2016Google Scholar
  40. 40.
    Rehbein MC, Husmann S, Lechner C, Kunick C, Scholl S (2018) Fast and calibration free determination of first order reaction kinetics in API-synthesis using in-situ ATR-FTIR. Eur J Pharm Biopharm 126:95–100.  https://doi.org/10.1016/j.ejpb.2017.09.013
  41. 41.
    Rossi D, Gargiulo L, Valitov G, Gavriilidis A, Mazzei L (2017) Experimental characterization of axial dispersion in coiled flow inverters. Chem Eng Res Des 120:159–170.  https://doi.org/10.1016/j.cherd.2017.02.011 CrossRefGoogle Scholar
  42. 42.
    Rojahn P, Hessel V, Nigam KDP, Schael F (2018) Applicability of the axial dispersion model to coiled flow inverters containing single liquid phase and segmented liquid-liquid flows. Chem Eng Sci 182:77–92.  https://doi.org/10.1016/j.ces.2018.02.031 CrossRefGoogle Scholar

Copyright information

© Akadémiai Kiadó 2019

Authors and Affiliations

  • M. C. Rehbein
    • 1
    • 2
  • J. Wolters
    • 1
  • C. Kunick
    • 2
    • 3
  • S. Scholl
    • 1
    • 2
    Email author
  1. 1.Institute for Chemical and Thermal Process EngineeringTU BraunschweigBraunschweigGermany
  2. 2.Center of Pharmaceutical EngineeringTU BraunschweigBraunschweigGermany
  3. 3.Institute for Medicinal and Pharmaceutical ChemistryTU BraunschweigBraunschweigGermany

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