Intensification of Free-Radical Racemization for a Non-activated Amine in a Continuous Flow Reactor

Published as part of the Special Topic Synthesis in Industry

Abstract

The free-radical racemization of non-activated amines is a powerful tool for process design in the pharmaceutical industry, allowing the recycling of undesired enantiomers after chiral separation. This paper describes the development of the free-radical racemization of a key API intermediate in a continuous flow reactor. Upon development, a significant reduction of the solvent usage and radical initiator was made possible thanks to the conversion into a continuous flow mode. This intensification positively impacted both the environmental footprint and the safety of the reaction as well as maintaining satisfactory productivity.

Key words

racemization - radical reaction - hydrogen atom transfer - flow chemistry - intensification - drugs

• References

• 1a Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
• 1b Lovering F. Med Chem Comm 2013; 4: 515
• 2 Gruttadauria M, Giacalone F, Noto R. Chem. Soc. Rev. 2008; 37: 1666
• 3 Sheldon RA, Brady D. ChemSusChem 2019; 12: 2859
• 4 Margalef J, Pàmies O, Diéguez M. Tetrahedron Lett. 2016; 57: 1301
• 5 Escoubet S, Gastaldi S, Vanthuyne N, Gil G, Siri D, Bertrand MP. J. Org. Chem. 2006; 71: 7288
• 6 Roberts BP. Chem. Soc. Rev. 1999; 28: 25
• 7 Barrett KE. J, Waters WA. Discuss. Faraday Soc. 1953; 14: 221
• 8 Dénès F, Pichowicz M, Povie G, Renaud P. Chem. Rev. 2014; 114: 2587
• 9 Dang H.-S, Roberts BP. J. Chem. Soc., Perkin Trans. 1 2002; 1161
• 10 Roberts BP, Smits TM. Tetrahedron Lett. 2001; 42: 137
• 11 Roberts BP, Dang H.-S. Tetrahedron Lett. 2000; 41: 8595
• 12 Allen RP, Roberts BP, Willis CR. J. Chem. Soc., Chem. Commun. 1989; 1387
• 13a Enquist JA. Jr, Stoltz BM. Nature 2008; 453: 1228
• 13b Brill ZG, Grover HK, Maimone TJ. Science 2016; 352: 1078
• 14 Loh YY, Nagao K, Hoover AJ, Hesk D, Rivera NR, Colletti SL, Davies IW, MacMillan DW. C. Science 2017; 358: 1182
• 15 Dong J, Wang X, Wang Z, Song H, Liu Y, Wang Q. Chem. Sci. 2020; 11: 1026
• 16 Soulard V, Vila G, Vollmar DP, Renaud P. J. Am. Chem. Soc. 2018; 140: 155
• 17a Routaboul L, Vanthuyne N, Gastaldi S, Gil G, Bertrand M. J. Org. Chem. 2008; 73: 364
• 17b Yerande SG, Yerande RS, Thakare PP, Shendage DM, Galave S, Gangopadhyay AK. Org. Process Res. Dev. 2014; 18: 652
• 18a Gastaldi S, Escoubet S, Vanthuyne N, Gil G, Bertrand MP. Org. Lett. 2007; 9: 837
• 18b El Blidi L, Vanthuyne N, Siri D, Gastaldi S, Bertrand MP, Gil G. Org. Biomol. Chem. 2010; 8: 4165
• 19a Brocks JJ, Beckhaus H.-D, Beckwith AL. J, Rüchardt C. J. Org. Chem. 1998; 63: 1935
• 19b Blanksby SJ, Ellison GB. Acc. Chem. Res. 2003; 36: 255
• 20 Hao H, Chang T, Cui L, Sun R, Gao R. Catalysts 2018; 8: 648