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CC BY 4.0 · Sustainability & Circularity NOW 2025; 02: a25717048
DOI: 10.1055/a-2571-7048
Original Article

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

Pranal M. Dharmik
1   Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga (East), Mumbai, India.
,
Sandip J. Detke
1   Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga (East), Mumbai, India.
,
Omkar C. Harasure
1   Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga (East), Mumbai, India.
,
Prashant S. Kharkar 
1   Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga (East), Mumbai, India.
› Institutsangaben
Gefördert durch: Department of Science and Technology, Ministry of Science and Technology, India
Gefördert durch: All India Council for Technical Education
Funding Information PMD received a post-graduate fellowship from the All India Council for Technical Education (AICTE), New Delhi, India. SJD received a fellowship from the Department of Science and Technology (DST), Government of India. OCH received a post-graduate fellowship from the University Grants Commission (UGC), New Delhi, India.
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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

Supplementary Material

    Supporting information for this article is available online at https://doi.org/10.1055/a-2571-7048.
  • Ergänzendes Material


Publikationsverlauf

Eingereicht: 29. Oktober 2024

Angenommen nach Revision: 31. März 2025

Accepted Manuscript online:
01. April 2025

Artikel online veröffentlicht:
21. Mai 2025

© 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/).

Georg Thieme Verlag KG
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Bibliographical Record
Pranal M. Dharmik, Sandip J. Detke, Omkar C. Harasure, Prashant S. Kharkar. N- and O-Trideuteromethylation of Drugs and Intermediates with Trimethyloxosulphonium Iodide-d 9 Enabled by a Mechanochemical Synthesis. Sustainability & Circularity NOW 2025; 02: a25717048.
DOI: 10.1055/a-2571-7048
 

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