Comprehensive Risdiplam Synthesis Overview: From Cross-Coupling Reliance to Complete Palladium Independence

Area of Science:

• Medicinal and Organic Chemistry
• Drug Discovery and Development
• Neuroscience

Background:

• Spinal muscular atrophy (SMA) is a severe neuromuscular disorder.
• Risdiplam is the first small-molecule therapy approved for SMA.
• Risdiplam's complex structure presents significant synthetic challenges and opportunities.

Purpose of the Study:

• To systematically review risdiplam assembly strategies and synthetic approaches.
• To analyze developments in risdiplam synthesis from 2013 to the present.
• To highlight the chemical interest in risdiplam's heterocyclic fragments.

Main Methods:

• Literature review of publications and patent applications.
• Analysis of diverse synthetic methodologies for risdiplam.
• Evaluation of scalable manufacturing routes for risdiplam and its intermediates.

Main Results:

• Identification of numerous synthetic strategies for risdiplam.
• Development of efficient and scalable manufacturing routes by the authors' group.
• Characterization of key heterocyclic fragments (imidazo[1,2-b]pyridazine, pyrido[1,2-a]pyrimidin-4-one, 4,7-diazaspiro[2.5]octane) as synthetic building blocks and pharmacophores.

Conclusions:

• Risdiplam's synthesis is an active area of research with diverse approaches.
• Efficient manufacturing routes are crucial for the clinical availability of risdiplam.
• The unique heterocyclic structure of risdiplam holds significance for future drug design.