Orforglipron Intermediate N-4 3047556-95-3

Orforglipron Intermediate (CAS 3047556-95-3)

Systematic Name:

5-((S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-1-((Z)-N'-hydroxycarbamimidoyl)-2-methylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

Common Aliases:

Orforglipron Intermediate M-3

Orforglipron Intermediate N-4

Orforglipron ACI Amide Precursor

LY3502970 Advanced Building Block

Molecular Formula: C₂₈H₃₄N₄O₃

Molecular Weight: 474.60 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) absolute stereochemistry. This precise control is critical for the biological activity of the final drug substance.

(2) Unique (Z)-N'-Hydroxycarbamimidoyl Moiety: Unlike related intermediates (such as CAS 2212021-82-2), this molecule features a (Z)-N'-hydroxycarbamimidoyl group on the cyclopropane terminus. This structure increases molecular polarity and hydrogen-bonding capacity, conferring unique reactivity profiles in downstream transformations.

(3) Steric Bulk and Rigid Skeleton: The presence of the N-phenyl substituted amide and geminal dimethyl groups creates significant steric bulk, while the incorporated cyclopropane ring provides structural rigidity.

2. Role in Orforglipron Synthesis

Orforglipron (LY3502970), developed by Eli Lilly, is a leading oral, non-peptide GLP-1 receptor agonist in advanced clinical trials for Type 2 Diabetes and Obesity.

In the multi-step convergent synthesis of Orforglipron, CAS 3047556-95-3 serves as the advanced intermediate (M-3) of the left-hand ACI (Indole) fragment. Its primary roles are:

(1) Transformation Precursor: The (Z)-N'-hydroxycarbamimidoyl group can be converted via cyclodehydration in subsequent steps into more reactive leaving groups, such as the oxadiazolone moiety (e.g., converting to CAS 2212021-82-2) prior to final fragment coupling.

(2) Coupling Building Block: In specific process routes, it can also act directly as an electrophilic substrate. It undergoes nucleophilic substitution with the right-hand ZCI fragment (e.g., the amine-containing pyrazolopyridine, CAS 2212022-56-3) to facilitate the ligation of the two complex fragments and construct the signature central imidazol-2-one core of the Orforglipron molecule.