Practical syntheses of a CXCR3 antagonist

Area of Science:

• Medicinal Chemistry
• Organic Synthesis

Background:

• The CXCR3 receptor plays a role in inflammatory diseases.
• Developing targeted inhibitors is crucial for therapeutic intervention.

Purpose of the Study:

• To establish novel and reliable synthetic routes for a pyrido[2,3-d]-pyrimidine CXCR3 receptor inhibitor.
• To achieve scalable and efficient production of the enantioenriched active pharmaceutical ingredient (API).

Main Methods:

• A nine-step synthesis from 2-aminonicotinic acid was scaled to multikilogram production, including a classical resolution step.
• A second, gram-scale synthesis utilizing Goldberg coupling was developed, starting from (+)-(D)-Boc alanine and 2-chloronicotinic acid.

Main Results:

• Both synthetic routes successfully produced the enantioenriched API.
• The second route intersected the first at a common intermediate, achieving a formal synthesis with higher overall yield.
• The second route eliminated the need for a separate resolution step.

Conclusions:

• Two viable synthetic strategies for the CXCR3 inhibitor have been demonstrated.
• The second synthetic approach offers an improved, more efficient route to the enantioenriched API.