Installation of d3-methyl group to drugs by continuous-flow solid-phase synthesis

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Materials Science

Background:

• The d3-methyl group is valuable in medicinal chemistry, combining the
• magic methyl effect
• and deuterium effect.
• Existing d3-methyl reagents lack universal applicability, cost-effectiveness, and ease of handling.

Purpose of the Study:

• To design a novel, universally applicable, cost-effective, and recyclable d3-methyl reagent.
• To develop a heterogeneous d3-methylation system for broad substrate scope.
• To establish a scalable and sustainable platform for d3-methylation in drug synthesis.

Main Methods:

• Design and synthesis of a thianthrene-based organic polymer (TT-OP) as a d3-methyl reagent carrier.
• Utilizing the developed heterogeneous reagent (TT-OP-CD3) for selective d3-methylation.
• Integration of solid-phase synthesis with continuous-flow technology for automated, high-throughput d3-methylation.

Main Results:

• The TT-OP polymer exhibits excellent loading capacity, scalability, and stability for d3-methyl reagent capture and release.
• Selective d3-methylation of over 35 biologically active molecules at oxygen, nitrogen, sulfur, and carbon sites was achieved.
• An automated platform demonstrated high-throughput and scalable d3-methylation, proving sustainability and practicality.

Conclusions:

• A novel, stable, and recyclable heterogeneous d3-methyl reagent (TT-OP-CD3) has been successfully developed.
• This reagent facilitates challenging d3-methylation reactions on diverse biologically relevant molecules.
• The integrated automated platform offers a sustainable and practical approach for d3-methylation in pharmaceutical development.