Chemical Methods for Azine, Piperidine and Piperazine Stable Radioisotopes Interconversion

At a Glance

A novel method for the interconversion of pyridine and Nitrogen-14 to Nitrogen-15 isotopes through ring-opened NTf-Zincke imines. The process allows for the incorporation of Nitrogen-15 via recyclization with Nitrogen-15 ammonium salts or Nitrogen-15 based ammonia. This method also enables deuterium isotopes to be incorporated into the pyridine structure by subjecting the NTf-Zincke imine intermediates to acidic solutions of deuterium-containing solvents.

Background

This invention converts chemicals such pyridines, diazines, and related azines, into stable radioisotopes. The chemical process can install nitrogen 15 atoms within these rings and transform their C–H bonds into C–D bonds. The method involves ring-opening of the azines’ corresponding NTf-salts with amine nucleophiles. This method is further extendable into piperidine derivatives.

This invention enables rapid and broad access to stable isotopes of azines and related saturated heterocycles. Stable isotopes of these heterocycles have a multitude of uses in the pharmaceutical, agrochemical, and academic sciences, but there is currently no broadly applicable method to obtain them.

These labeled compounds are particularly valuable for toxicology studies in drug and agrochemical development, where heavier mass isotopologs are frequently used in these studies. They are also valuable as NMR active probes, as well as enabling mechanistic studies of chemical reactions and biochemical processes.

Overview

A two-step protocol to transform pyridine-containing drugs into ¹⁵N-isotopologs. First, the pyridine-containing drug into the NTf-Zincke imine is converted using Tf₂O, dibenzylamines, collidine, or other weak bases and isolate via precipitation or chromatography to remove any unlabeled drug. Second, we cyclize the NTf-Zincke imines with ¹⁵NH4X salts (where X = OAc, Cl, etc.) or ¹⁵NH3 in alcohol solutions to reform the pyridines with ¹⁵N incorporated into the ring structure (Scheme 1). This reaction applies to related heterocycles such as quinolines and isoquinolines and fused systems such as azaindoles.

Benefits

Rapid and broad access to stable isotopes of azines and related saturated heterocycles.
Enables Nitrogen-15 isotopic incorporation that matches the isotopic purity of the Nitrogen-15 source.
Allows for the incorporation of deuterium isotopes into the pyridine structure.
Provides a new and efficient method of isotope interconversion.
Has a broad substrate scope of substituted pyridines and other azines.

Applications

Potential application in the field of isotopic labeling in drug development and safety studies.
Useful in research in the field of chemistry and biochemistry for structure determination and mechanistic studies.
Agrichemical and medicinal discovery programs and scale up
Cost effective versus commercially available pyridine isotopologs

Publications

Boyle, et al. (2022) Halogenation of the 3-position of pyridines through Zincke imine intermediates Science.

Last Updated: August 2023

Opportunity

Available for Licensing
TRL: 4

Inventors

Andrew McNally
Benjamin Boyle
Jeffrey Levy

Reference Number

2023-043

Licensing Manager

Steve Foster
Steve.Foster@colostate.edu
970-491-7100