Ir-Catalyzed Borylation as an Efficient Route to a Nicotine Hapten

JaniceE. Sieser, Mark T. Maloney, Esmort Chisowa, Steven J. Brenek, Sebastien Monfette, John J. Salisbury, Nga M. Do, Robert A. Singer

Index: 10.1021/acs.oprd.8b00053

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Abstract

The process development of a nicotine analog or hapten (1) for conjugation to a protein as an antigen is described. The original process in early development used an Ir-catalyzed borylation reaction to enable rapid derivatization of nicotine with the desired regiocontrol. While the process was very efficient, it required chromatography to meet purity targets. A related process was later developed that possessed crystalline intermediates to better control levels of process-related impurities and heavy metals in 1. This control strategy for 1 was essential due to the strict purity requirements for conjugation of 1 when forming an antigen. In addition, the Ir-catalyzed borylation was studied to enable robust manufacture via this methodology which led to an efficient process for the preparation of 1.