Orforglipron Intermediate N-3 2212021-83-3

Orforglipron Intermediate (CAS 2212021-83-3)

Systematic Name:

5-[(S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl]-1-[(1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl]-1H-indole-2-carboxylic acid

Common Aliases:

Orforglipron intermediate N-2

Orforglipron ACI Acid Intermediate

Orforglipron Activated Ester Precursor

LY3502970 Carboxylic Acid Fragment

Molecular Formula: C₂₂H₂₅N₃O₅

Molecular Weight: 411.46 g/mol

1. Structural Complexity & Characteristics

This compound is a highly functionalized and complex chiral molecule. Its key structural features include:

(1) Multiple Stereocenters: The molecule contains three defined stereogenic centers (two on the cyclopropane ring and one on the tetrahydropyran ring), all configured with specific (S) or (R) absolute stereochemistry. This precise control is critical for the biological activity of the final drug substance.

(2) Activated Carboxylic Acid: The structure incorporates a 1,2,4-oxadiazol-5-one moiety. This group functions as a highly activated carboxylic acid derivative, serving as an excellent leaving group for subsequent amide bond formation.

(3) Steric Hindrance: The presence of the tetrahydropyran ring and geminal dimethyl groups creates significant steric bulk around the reactive center.

2. Role in Orforglipron Synthesis

Orforglipron (LY3502970), developed by Eli Lilly, is a leading oral, non-peptide GLP-1 receptor agonist. Recent positive outcomes from its Phase 3 ACHIEVE-1 trial highlight its significant potential in glucose lowering and weight management.

In the multi-step convergent synthesis of Orforglipron, CAS 2212021-83-3 serves as the advanced carboxylic acid intermediate of the left-hand ACI (Indole) fragment. Its primary roles are:

(1) Coupling Precursor: The carboxyl group is pre-activated as the oxadiazolone. This electrophile is designed to undergo a nucleophilic addition-elimination reaction with the right-hand ZCI fragment (e.g., the amine-containing pyrazolopyridine, CAS 2212022-56-3), facilitating the crucial ligation of the two complex fragments.

(2) Cyclization Precursor: Under specific conditions, this intermediate can directly participate in an intramolecular cyclization to construct the signature central imidazol-2-one core of the Orforglipron molecule.