Scalable Asymmetric Synthesis of MK-8998, a T-Type Calcium Channel Antagonist

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Pharmacology

Background:

• T-type calcium channels are implicated in various neurological disorders.
• MK-8998 is a potent antagonist of T-type calcium channels.
• Efficient synthesis of drug candidates is crucial for development.

Purpose of the Study:

• To develop scalable and efficient synthetic routes for MK-8998.
• To establish robust methods for controlling stereochemistry in MK-8998 synthesis.

Main Methods:

• Synthesis initiated from a simple pyridine building block.
• Key stereochemistry established via chiral rhodium catalyst-mediated asymmetric hydrogenation of an enamide.
• Alternative stereochemistry control achieved through transamination of an arylketone.

Main Results:

• Two distinct, scalable, and efficient synthetic routes were successfully developed.
• Both methods yielded the target product with high enantioselectivity.
• High overall yields were achieved for the synthetic processes.

Conclusions:

• The developed routes provide efficient access to MK-8998.
• The stereochemical control methods are robust and high-yielding.
• These synthetic strategies facilitate further investigation and development of MK-8998 as a therapeutic agent.