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Mathematical modelling and optimization of (R)-2- azido-1-(4-trifluoromethyl-phenyl)-ethanol synthesis catalysed by halohydrin dehalogenase

(R)-2-Azido-2-[4-(trifluoromethyl)phenyl]ethanol is a valuable and diverse building block as its structural analogues are used for the synthesis of molecules displaying antiplasmodial, antibacterial, antitubercular and beta-blocker activities1-3. Trifluoromethyl moiety is predominantly employed structural motif in design of pharmaceuticals4, but direct fluorination of the target molecule is expensive, conducted under harsh conditions with toxic reagents and represents significant synthetic challenge5. Halohydrin dehalogenase (HHDH) can be employed in modification of existing fluorinated synthons in enantiopure fashion6. We developed a kinetic mathematical model of HHDH-catalysed and azide- mediated rac-2-[4-(trifluoromethyl)phenyl]oxirane kinetic resolution to obtain (R)-2-Azido-2-[4- (trifluoromethyl)phenyl]ethanol. Mathematical modelling enables obtaining the maximal productivity over a minimal reaction time through identification of reaction bottlenecks and selection of optimal operating conditions and enzyme microenvironment7. Since mathematical modelling is the foundation for scale-up of the biocatalytic process, through process simulations we have presented different synthesis outcomes dependent on the selected reactor type and reaction conditions. Funding: Croatian Science Foundation, IP-2018-01-4493 1 Eur. J. Med. Chem. 2017, 138, 1089-1105 2 J. Nat. Prod. 2020, 83 (1), 26-35 3 J. Org. Chem. 2008, 73 (16), 6433-6436 4 Organofluorine Chemistry, Elsevier Inc., 2020 5 Drug Discover Today 2018, 23 (8), 1458-1462 6 Catal. Commun 2021, 152, 106285 7 Adv. Synth. Catal. 2021, 363 (2), 388-410

halohydrin dehalogenase ; fluorinated building blocks ; kinetic mathematical modelling ; process simulations

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