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

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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.

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Abbreviations

ADM :

Axial dispersion model

Bo [−] :

dimensionless Bodenstein number

c [mmol mL −1 ] :

concentration, subscripts: R – reactant, P – product

D ax [m 2 s −1 ] :

axial dispersion coefficient

d i [mm] :

inner diameter

E [s −1 ] :

differential residence time distribution

E A [J mol −1 ] :

activation energy

F [−] :

cumulative residence time distribution

k [s −1 ] :

reaction rate constant

k 0 [s −1 ] :

reaction rate frequency factor

L [m] :

length of the coil-reactor

R [J K −1 mol −1 ] :

universal gas constant

ρ s [g cm −3 ] :

solvent density

STY [g h −1 mL −1 ] :

Space time yield

T [°C], [K] :

temperature

τ [s] :

residence or reaction time

⊖ [−] :

dimensionless residence time

u [m s −1 ] :

flow velocity

V R [mL] :

reactor volume

\( \dot{V} \) [mL min −1 ] :

volumetric flow rate

X R [−] :

reactant conversion

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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.

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Authors and Affiliations

  1. Institute for Chemical and Thermal Process Engineering, TU Braunschweig, Langer Kamp 7, 38106, Braunschweig, Germany

    M. C. Rehbein, J. Wolters & S. Scholl

  2. Center of Pharmaceutical Engineering, TU Braunschweig, Franz-Liszt-Straße 35a, 38106, Braunschweig, Germany

    M. C. Rehbein, C. Kunick & S. Scholl

  3. Institute for Medicinal and Pharmaceutical Chemistry, TU Braunschweig, Beethovenstraße 55, 38106, Braunschweig, Germany

    C. Kunick

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  1. M. C. Rehbein
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Correspondence to S. Scholl.

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Rehbein, M.C., Wolters, J., Kunick, C. et al. Continuous high-pressure operation of a pharmaceutically relevant Krapcho dealkoxycarbonylation reaction. J Flow Chem 9, 123–131 (2019). https://doi.org/10.1007/s41981-019-00031-2

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