Studies on the dynamic resolution of Crizotinib intermediate

Alexandre da S de França; Marcus V M Silva; Rebeca V Neves; Stefania P de Souza; Raquel A C Leão; Carlos M Monteiro; Ângelo Rocha; Carlos A M Afonso; Rodrigo O M A de Souza

doi:10.1016/j.bmc.2017.07.024

Studies on the dynamic resolution of Crizotinib intermediate

Bioorg Med Chem. 2018 Apr 1;26(7):1333-1337. doi: 10.1016/j.bmc.2017.07.024. Epub 2017 Jul 21.

Authors

Alexandre da S de França¹, Marcus V M Silva¹, Rebeca V Neves¹, Stefania P de Souza¹, Raquel A C Leão², Carlos M Monteiro³, Ângelo Rocha⁴, Carlos A M Afonso³, Rodrigo O M A de Souza⁵

Affiliations

¹ Biocatalysis and Organic Synthesis Group, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
² Biocatalysis and Organic Synthesis Group, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Pharmacy School, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
³ Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
⁴ Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, University of Lisbon, Portugal.
⁵ Biocatalysis and Organic Synthesis Group, Chemistry Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Pharmacy School, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: souzarod21@gmail.com.

PMID: 28802669
DOI: 10.1016/j.bmc.2017.07.024

Abstract

Crizotinib is an anti-cancer agent approved for treatment of non-small cell lung carcinoma. Retrosynthetic analysis revels 1-(2,6-dichloro-3-fluorophenyl)ethanol as an important intermediate, which can be made available by different biocatalytic approaches. Herein we report our results on the kinetic and dynamic resolution towards the desired chiral intermediate for Crizotinib synthesis. The results obtained show that very good conversions and high selectivity could be obtained for the kinetic resolution (45% conv. and E>200) while dynamic kinetic resolution under continuous-flow conditions afforded the desired product in 57% conversion and 98% e.e.

Keywords: Continuous-flow; Crizotinib; Dynamic resolution; Kinetic resolution; Lipases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Crizotinib
Kinetics
Molecular Dynamics Simulation*
Molecular Structure
Pyrazoles / chemistry*
Pyridines / chemistry*

Substances

Pyrazoles
Pyridines
Crizotinib