N- and O-Trideuteromethylation of Drugs and Intermediates with Trimethyloxosulphonium Iodide-d ₉ Enabled by a Mechanochemical Synthesis

Abstract

Solvent-free, sustainable organic synthetic approaches based on the use of microwaves, ultrasound, or mechanochemistry are needed from a green chemistry perspective. Mechanochemical synthesis involves the coupling of mechanical and chemical processes at the molecular level. In the present study, we have applied mechanochemistry for the deuteration of drugs and intermediates, particularly N- and O-trideuteromethylation. Conventionally, MeI-d ₃, a carcinogenic and relatively expensive reagent, is used for introducing a trideuteromethyl (–OCD₃) group in drugs/intermediates. Here, the utility of trimethyloxosulphonium iodide-d ₉ (TDMSOI) was investigated as the –OCD₃ source, for developing and optimizing a novel, one-pot, solvent-free, mechanochemical method for N- and O-trideuteromethylation of several drugs/intermediates with appreciable degree of deuteration (~90% D), particularly those containing phenol, acid, and amine functional groups. The investigated method is scalable and is of potential interest to the Medicinal Chemistry and Drug Discovery community, given the perceived importance of deuteration as a viable strategy for affecting the in vivo half-life of drugs.

Keywords

Deuterated drugs - Solvent-free synthesis - Mechanochemistry - Green synthesis - Trideuteromethylation

Publication History

Received: 29 October 2024

Accepted after revision: 31 March 2025

Accepted Manuscript online:
01 April 2025

Article published online:
21 May 2025

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