Process Understanding of transamination reaction in chiral pharmaceutical intermediate production catalyzed by an engineered amine transaminase

Chiral amines are key building blocks for the synthesis of many active pharmaceutical ingredients (APIs). Biocatalytic routes offer significant advantages to provide sustainable access to such motifs on commercial scale, with sacubitril valsartan sodium hydrate as a recent example. In this study a deeper mechanistic and kinetic understanding of the central biocatalytic step in the synthesis of sacubitril valsartan sodium hydrate, applying the evolved transaminase CDX-043, was gained. The equilibrium of the transamination reaction was investigated in detail, and two kinetic models (ping-pong two-substrate kinetics and Michaelis–Menten double substrate kinetics) were established, considering substrate and product inhibition. The determined equilibrium constant indicates that the equilibrium lies strongly on the product side. The results of the kinetic studies demonstrate that the transaminase reaction is in conformity with the Michaelis–Menten double substrate kinetic model. Product inhibition was found to be more severe than substrate inhibition. The application of a plug flow reactor (PFR) was shown to be the preferred reactor setup to reduce the occurring inhibition.

Subjects

Biotransformation | Kinetic models | Optimization | Reactor selection | ω-Transaminase

DDC Class

540: Chemistry

620: Engineering

Funding(s)

Projekt DEAL

Publication version

publishedVersion

Lizenz

https://creativecommons.org/licenses/by/4.0/

Name

ChemCatChem - 2024 - Perçin - Process Understanding of Transamination Reaction in Chiral Pharmaceutical Intermediate.pdf

Type

Main Article

Size

1.08 MB

Format

Adobe PDF

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Process Understanding of transamination reaction in chiral pharmaceutical intermediate production catalyzed by an engineered amine transaminase