Automated Optimization of a Multistep, Multiphase Continuous Flow Process for Pharmaceutical Synthesis.

Area of Science:

• Green Chemistry
• Process Chemistry
• Sustainable Synthesis

Background:

• Flow synthesis presents a safer and more sustainable alternative to traditional batch processes.
• Continuous flow reactions minimize waste and reduce operator exposure to hazardous materials.
• Telescoped reactions streamline processes by reducing the number of unit operations.

Purpose of the Study:

• To explore a two-step synthesis involving hydrogenation and amidation using flow chemistry.
• To optimize individual steps and a telescoped multistep process for improved yield and purity.
• To demonstrate the benefits of automated optimization in pharmaceutical synthesis development.

Main Methods:

• Utilized a two-step flow process: three-phase heterogeneous hydrogenation followed by homogeneous amidation.
• Employed a Bayesian optimization algorithm for remote automated control and optimization.
• Assessed reaction performance using High-Performance Liquid Chromatography (HPLC) analysis.
• Selected 2-methyltetrahydrofuran (2-MeTHF) as a green solvent.

Main Results:

• Achieved optimized yields for both individual steps and the telescoped process.
• Demonstrated good atom economy in the heterogeneous hydrogenation step using pure hydrogen.
• Successfully applied automated optimization to accelerate the investigation of synthetic processes.
• Significantly reduced process mass intensity values through efficient synthesis.

Conclusions:

• Multistage automated optimization in flow chemistry accelerates the development of pharmaceutical syntheses.
• Telescoping and automated optimization minimize experimental runs and reduce waste.
• Flow synthesis, combined with optimization, offers a greener and more efficient approach to chemical production.