CRTH2 antagonist MK-7246: a synthetic evolution from discovery through development.

Area of Science:

• Process Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Development of synthetic routes for novel pharmaceutical compounds is crucial for drug discovery and development.
• Efficient synthesis is required for structure-activity relationship (SAR) studies and preclinical/clinical evaluation.

Purpose of the Study:

• To report the development of diverse synthetic routes for MK-7246.
• To enable rapid SAR exploration and supply of target molecules for evaluation.
• To engineer a scalable and cost-effective manufacturing route for MK-7246.

Main Methods:

• Initial aziridine opening/cyclodehydration strategy.
• Development of a manufacturing route featuring Ir-catalyzed intramolecular N-H insertion.
• Enzymatic conversion of ketone to amine using a transaminase process.

Main Results:

• Successful synthesis of MK-7246 via multiple routes.
• Streamlined transition from milligram to kilogram-scale production.
• Achieved excellent enantioselectivity in key catalytic steps.

Conclusions:

• Innovative chemo- and biocatalysis significantly impact pharmaceutical synthesis efficiency.
• Developed routes facilitate early drug evaluation and large-scale production.
• Optimized manufacturing route enhances scalability and cost-effectiveness.