Flow Process for Production of Crisaborole Using Organolithium Chemistry with Control over Impurity Formation.

Area of Science:

• Organic Chemistry
• Process Chemistry
• Pharmaceutical Development

Background:

• Crisaborole is a boron-containing phosphodiesterase inhibitor used for atopic dermatitis and eczema.
• Traditional batch synthesis involves organolithiation at low temperatures, posing scalability challenges.

Purpose of the Study:

• To develop a continuous flow chemistry process for crisaborole synthesis.
• To improve efficiency, yield, and impurity control compared to batch methods.
• To enable kilogram-scale production of crisaborole.

Main Methods:

• Organolithiation via Br/Li exchange using continuous flow reactors.
• One-pot THP deprotection and cyclization of the boronate intermediate.
• Application of a Quality by Design (QbD) approach to optimize process parameters.

Main Results:

• Reduced residence time from 1800 s to 1.5 s.
• Increased temperature from -78 °C to -60 °C while maintaining impurity control.
• Achieved significant improvement in overall yield and successful kilogram-scale production.
• Systematic control and minimization of three critical impurities.

Conclusions:

• Continuous flow chemistry offers a superior method for crisaborole synthesis compared to batch processing.
• The QbD approach ensures process robustness, scalability, and effective impurity management.
• This optimized flow synthesis facilitates efficient and large-scale production of crisaborole for therapeutic use.