Solution- and solid-phase parallel synthesis of 4-alkoxy-substituted pyrimidines with high molecular diversity

Area of Science:

• Organic Chemistry
• Medicinal Chemistry

Background:

• Pyrimidine derivatives are crucial scaffolds in medicinal chemistry.
• Developing efficient and selective synthesis routes is essential for drug discovery.

Purpose of the Study:

• To develop a novel and versatile methodology for synthesizing 2,6-disubstituted-4-alkoxypyrimidine derivatives.
• To adapt the methodology for both solution-phase and solid-phase synthesis, enabling automated parallel synthesis.

Main Methods:

• Development of a straightforward synthetic route.
• Adaptation of the methodology to solid-phase synthesis using automated parallel systems.
• Utilizing a thioether linkage at the 2-position for selectivity and as a safety-catch linker.

Main Results:

• Successful synthesis of novel 2,6-disubstituted-4-alkoxypyrimidine derivatives (types 16 and 19).
• High selectivity for O-alkylation products attributed to the steric effect of the thioether linkage.
• Demonstrated utility of the thioether as a robust attachment point and a safety-catch linker for introducing diversity via N-nucleophiles.

Conclusions:

• The developed methodology is simple, straightforward, and highly efficient.
• The thioether linkage plays a dual role, ensuring selectivity and enabling facile diversification.
• The approach is amenable to automated parallel synthesis, facilitating rapid library generation for drug discovery.