Method Development and Syntheses Examples of Isotopically Labeled Compounds to Foster Operational Excellence in Pharma Industry

The manuscript is dedicated to Prof. Laschat at the occasion of her 60th birthday – thanks Sabine.

Abstract

The different topics and synthetic approaches in an isotope chemistry laboratory of a pharma company are described. Besides the challenges in the synthesis of long-lived isotopes such as ³H or ¹⁴C, short-lived isotopes such as ⁶⁸Ga and stable isotopes such as ¹⁵N, ¹³C or ²H approaches for the isotopic labeling are also demonstrated. Furthermore, method development with emphasis on collaborations with academic groups to tackle the future challenges are discussed.

1 Introduction

2 Isotopic Labeling with Hydrogen Isotopes Deuterium (²H, D) and Tritium (³H, T)

2.1 Deuterium Labeling for MS Standards

2.1.1 Labeled Nitrosamines – The Hunt to Quantify Hazardous Impurities

2.1.2 Deuterated Drugs, an Approach To Improve Existing Drugs or To Find Opportunities in Drug Discovery

2.2 Tritium-Labeling Methods – The Fast Approach to Radioactively Labeled Compounds

2.2.1 Hydrogen Isotope Exchange by Iridium Catalysis

2.2.2 Ruthenium-Catalyzed HIE

2.2.3 Nanoparticles as Catalysts in HIE

2.2.4 Photoredox-Catalyzed HIE

2.2.5 HIE via Classical Radical Mechanism

2.2.6 Beyond HIE – Halogen–Tritium Exchange

3 Challenges in ¹⁴C-Synthesis Projects

4 Short-Lived Isotopes – The Need for Speed

5 Beyond Isotope Science – Late-Stage Functionalization

5.1 Examples of Late-Stage Functionalization for Peptides

5.2 Examples of Catalyst-Controlled Late-Stage Functionalization

6 Conclusion

Key words

isotope science - drug discovery - isotope exchange - CH functionalization - catalysis

Publication History

Received: 31 October 2023

Accepted after revision: 04 December 2023

Accepted Manuscript online:
04 December 2023

Article published online:
17 January 2024

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