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CC BY 4.0 · Sustainability & Circularity NOW
DOI: 10.1055/a-2571-7048
Original Article

N- and O-Trideuteromethylation of Drugs and Intermediates with Trimethyloxosulphonium Iodide-d9 Enabled by a Mechanochemical Synthesis

Pranal M Dharmik
1   Pharmaceutical Sciences and Technology, Institute of Chemical Technology Department of Pharmaceutical Sciences and Technology, Mumbai, India (Ringgold ID: RIN683322)
,
Sandip J Detke
1   Pharmaceutical Sciences and Technology, Institute of Chemical Technology Department of Pharmaceutical Sciences and Technology, Mumbai, India (Ringgold ID: RIN683322)
,
Omkar C Harasure
1   Pharmaceutical Sciences and Technology, Institute of Chemical Technology Department of Pharmaceutical Sciences and Technology, Mumbai, India (Ringgold ID: RIN683322)
,
Prashant Kharkar 
1   Pharmaceutical Sciences and Technology, Institute of Chemical Technology Department of Pharmaceutical Sciences and Technology, Mumbai, India (Ringgold ID: RIN683322)
› Author AffiliationsSupported by: Department of Science and Technology, Ministry of Science and Technology, India
Supported by: All India Council for Technical Education
Supported by: University Grants Commission
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Solvent-free, sustainable organic synthetic approaches based on the use of microwaves, ultrasound or mechanochemistry are needed from Green Chemistry perspective. Mechanochemical synthesis involves 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-d3, a carcinogenic and relatively expensive reagent, is used for introducing a trideuteromethyl (-OCD¬3) group in drugs/intermediates. Here, the utility of trimethyloxosulphonium iodide-d9 (TDMSOI) was investigated as -OCD¬3 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.



Publication History

Received: 29 October 2024

Accepted after revision: 31 March 2025

Accepted Manuscript online:
01 April 2025

© . The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).

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Bibliographical Record
Pranal M Dharmik, Sandip J Detke, Omkar C Harasure, Prashant Kharkar. N- and O-Trideuteromethylation of Drugs and Intermediates with Trimethyloxosulphonium Iodide-d9 Enabled by a Mechanochemical Synthesis. Sustainability & Circularity NOW ; 0: a25717048.
DOI: 10.1055/a-2571-7048