Enhancing the Retrosynthetic Strategy for Orforglipron (LY3502970) Using ChemAIRS: Developing a More Streamlined and Efficient Synthetic Route Suggestion
Orforglipron: A Needle-Free Breakthrough for Diabetes & Obesity
Obesity is a major global health risk, and GLP-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and weight management. However, current GLP-1RAs are peptide-based, requiring injections or complex oral formulations. To improve convenience, efforts are focused on developing non-peptide oral alternatives.
Orforglipron, a next-generation, orally bioavailable non-peptide GLP-1RA, eliminates the need for absorption enhancers. Initially discovered by Chugai Pharmaceuticals (OWL833) and later licensed by Eli Lilly (LY3502970), it is in Phase III trials, with potential U.S. approval expected in 2026, according to Lilly’s CEO, Dave Ricks.
If approved, Orforglipron could revolutionize diabetes and obesity treatment, making it more accessible and convenient than ever. Could this be the future of metabolic health?
ChemAIRS Optimizes Retrosynthesis of Orforglipron with a More Concise Pathway
ChemAIRS generated a more concise retrosynthetic plan for Orforglipron (LY3502970), identifying a key disconnection approach centered on two pivotal building blocks: indole-2-carboxylic acid (3a) and imidazol-2-one (3b). These intermediates underwent an amide bond formation to furnish the final target (Scheme 1). This strategy closely parallels Eli Lilly’s reported synthetic route. However, given the extensive 28-step synthesis disclosed in US20250042899, ChemAIRS proposed an alternative, more concise synthetic pathway.
Scheme 1: ChemAIRS' proposed approach for the synthesis of Orforglipron
Reducing the Synthesis of Imidazol-2-one Intermediate from 15 to 8 Steps
ChemAIRS suggested an 8-step route to imidazol-2-one (Scheme 2), significantly reducing the synthetic burden compared to the reported 15-step sequence. The key transformations involved the coupling of precursors 2a and 2b, followed by cyclization to furnish 3b. Deprotection and reductive amination of 3b led to intermediate 4c.
A key deviation from the reported route was the imidazole formation: ChemAIRS proposed treating 4c with formic acid and glyoxal to afford imidazole 6b, whereas Eli Lilly’s approach employed intramolecular cyclization with methanesulfonic acid. The final imidazol-2-one was obtained by coupling 6b with 6a, followed by deprotection of the resulting 7a.
Scheme 2: ChemAIRS' proposed synthetic route for the imidazol-2-one intermediate
Additionally, ChemAIRS provided optimized reaction conditions for the large-scale coupling of 6a and 6b (Figure 1).
Figure 1: ChemAIRS' Proposed Optimized Scale-Up Conditions for the compound 7a
Optimizing Synthesis of Indole-2-carboxylic Acid Intermediate: Step Reduction from 11 to 7
Although indole-2-carboxylic acid is commercially available, its high cost prompted the development of a 7-step synthetic route (Scheme 3), streamlining the original 11-step process. The sequence involved cyclopropanation of indole carboxylate 4b using (R)-(-)-4-methyl-2,2-dioxo-1,3,2-dioxathiolane 4a, followed by hydroxylamine addition to afford amidoxime 6b. Intramolecular cyclization with phenyl chloroformate (6a) yielded 7a, which was subsequently hydrolyzed to furnish the target carboxylic acid.
Scheme 3: ChemAIRS' proposed synthetic route for the indole-2-carboxylic acid intermediate
ChemAIRS proposed an alternative 16-step synthetic route to Orforglipron, offering a significantly shorter pathway compared to Eli Lilly’s patented approach. While retrosynthetic planning is crucial for identifying efficient disconnections, real-world validation remains essential to optimize reaction conditions and establish the most practical and scalable route.