Biocatalysis Innovations & Trends in Recent Patent Literature 2018-2022

Biocatalysis is a valuable technology for the industrial production of fine chemicals. In recent years, a slew of chemical firms have embraced biocatalysis for the production of chemicals. In this insight, the examples given agree with the general trend of employing established enzyme classes - such as lipases and aldolases - in immobilized form.

A recent review by David L. Hughes summarizes trends and innovations in biocatalysis in the patent literature starting from 2018. [1] At SpinChem, we like to follow the example but to highlight patent examples using immobilized enzymes a little extra.


  • Case 1: Due to limited solubilities of amino acids in organic solvents, the direct amidation of them with ammonia has previously not been reported. However, in this work, a group around Thermo Fisher Scientific introduced a strategy for direct conversion of acids and esters to amides by lipase catalysis. Their approach used immobilized CalB in MTBE, 1,4-dioxane, diisopropyl ether, and 2-methyl-2-butanol. [2]


  • Case 2: A group from Pfizer described the direct amidation of diester pharmeceutical intermediate. This reaction has a few noteworthy features: (i) The reaction did not work with soluble lipase but worked well with several immobilized formulations— demonstrating the stabilization that is possible by immobilization. This may be especially important for reactions in organic media. (ii) The use of hexamethyldisilazane (HMDS) as a sort of ammonia alternative was reported as a first. (iii) The reaction was carried out up to a scale of 110 kg, demonstrating an example of the increasing use of biocatalysis in pilot and production scale in the pharmaceutical industry. [3]


  • Case 3: Biocatalytic carbon-carbon bond forming reactions are still in early development. While lipases were demonstrated to catalyze aldol reactions in 2003, [4] in 2020 a research group developed the concept to involve three-component chromene-forming reactions. Screening of 13 immobilized lipases and 2 control proteins for activity on the system of 4-chlorobenzaldehyde, 4-hydroxycoumarin, and malonitrile ranked Novozyme TLIM as the most active immobilized lipase, giving the product Chromene at 46% yield. With high enzyme loadings, a range of aldehydes gave products in the three-component reaction in the 97-99% range. The enzyme retained high activity for five re-uses. [5]


  • Case 4: Normally, L-threonine aldolases catalyze the retro-aldol of threonine to glycine and acetaldehyde. Several patents now report on catalysis by engineered L-threonine aldolase (LTA) in the synthesis direction for the production of aryl b-hydroxy-a-amino acids from benzaldehyde and glycine. A remarkable number of uses were demonstrated for the reaction. [6]

Applications of lipases using RBR technology


The rotating bed reactor (RBR) makes the process fast and simple, provides efficient sampling and monitoring of the process without filtration steps and keeps the immobilized catalyst safely confined inside the rotating bed reactor.

Interested in the rotating bed reactor? Let SpinChem help you understand how the RBR technology can simplify or improve your process.

Get in touch with us today to get started towards better, more efficient biocatalysis.


[1] David L. Hughes, Org. Process Res. Dev., 2022, 26(7), pp. 1878−1899.

[2] P. Poechlauer, P. Selig, C. Zinganell, J. Pitzer, A. Glieder, W. Kroutil, K. Steiner, Single Step Biocatalytic Amidation. WO2020126484A1, June 25, 2020.

[3] M. S. Brown, M. A. Caporello, A. E. Goetz, A. M. Johnson, K. N. Jones, K. M. Knopf, S. A. Kulkarni, T. Lee, B. Li, C. V. Lu, J. Magano, A. L. A. Puchlopek-Dermenci, G. P. Reyes, S. G. Ruggeri, L. Wei, G. A. Weisenburger, R. A. Wisdom, M. Zhang, Streamlined Synthesis of a Bicyclic Amine Moiety Using an Enzymatic Amidation and Identification of a Novel Solid Form. Org. Process Res. Dev., 2021, 25(6), pp. 1419−1430.

[4] C. Branneby, P. Carlqvist, A. Magnusson, K. Hult, T. Brinck, P. Berglund, Carbon-Carbon Bonds by Hydrolytic Enzymes. J. Am. Chem. Soc., 2003, 125(4), pp. 874-875.

[5] X. Ma, Z. Lu, Y. Hu, Y. Fu, Method for Synthesizing Chromene Compounds by Catalysis of Lipase. CN111471725A, July 31, 2020.

[6] W. Wang, H. Tan, Environment-Friendly Process for Preparing 2-Amino-3-Substituted Phenyl-3-hydracrylic Acid. CN112301067A, February 02, 2021.

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