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Mechanistic Investigation of a Ru-Catalyzed Direct Asymmetric Reductive Amination Reaction for a Batch or Continuous Process Scale-Up: An Industrial Perspective

Abstract

A comprehensive assessment of a Ru-catalyzed direct asymmetric reductive amination (DARA) for producing an intermediate for a pharmaceutical active pharmaceutical ingredient (API) was carried out. Experiments were conducted to trend the impact of the process parameters (such as reaction temperature, time, concentration, pressure, Ru-catalyst concentration, acid catalyst, and reagent stoichiometry) on reaction selectivity, enantio-selectivity, and yield. An analysis of experimental data led to the development of a mechanistic mathematical model that was mathematically consistent with data from laboratory development and manufacturing campaigns. A combinatory approach outlined herein, could be used to provide the optimum conditions for the DARA process. Furthermore, the feasible operating region was mapped out, which highlighted the complexity of the investigated chemistry and aided in developing the control strategy and regulatory submission package pertinent to this reaction. The efforts allowed the process to be successfully validated and scaled using a plug flow reactor (PFR), to manufacture 3.2 MT of (S)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-amine under commercial Good Manufacturing Practice (cGMP).

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Publication details

The article was received on 04 May 2017, accepted on 08 Aug 2017 and first published on 08 Aug 2017


Article type: Paper
DOI: 10.1039/C7RE00055C
Citation: React. Chem. Eng., 2017, Accepted Manuscript
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    Mechanistic Investigation of a Ru-Catalyzed Direct Asymmetric Reductive Amination Reaction for a Batch or Continuous Process Scale-Up: An Industrial Perspective

    S. M. Changi, T. Yokozawa, T. Yamamoto, H. Nakajima, M. Embry, R. K. Vaid, C. Luciani, S. Wong, M. D. Johnson and E. Moher, React. Chem. Eng., 2017, Accepted Manuscript , DOI: 10.1039/C7RE00055C

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