Orforglipron Intermediate N-5 2212021-81-1

Orforglipron Intermediate (CAS 2212021-81-1)

Systematic Name:

1-((1S,2S)-1-cyano-2-methylcyclopropyl)-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide

Common Aliases:

Orforglipron Intermediate M-4

Orforglipron Intermediate N-5

Orforglipron Key Building Block

LY3502970 Advanced Intermediate

Molecular Formula: C₂₈H₃₁N₃O₂

Molecular Weight: 441.57 g/mol

1. Structural Complexity & Characteristics

This compound is a highly sophisticated advanced chiral intermediate featuring a complex polycyclic architecture. Its molecular scaffold integrates:

(1) An Indole Core: Serving as the central pharmacophore backbone.

(2) A Chiral Cyclopropane Moiety: Specifically configured as (1S,2S), bearing both a cyano group and a methyl substituent. The stereoselective installation of this fragment presents significant synthetic challenges.

(3) A Tetrahydropyran (THP) Ring: Incorporating a (4S) stereocenter with geminal dimethyl groups.

(4) An N-Methyl-N-phenyl Carboxamide: Attached at the 2-position of the indole nucleus.

The convergence of multiple stereocenters and heterocyclic systems makes this intermediate a high-value target for process chemistry optimization and scale-up.

2. Role in Orforglipron Synthesis

Orforglipron (LY3502970), developed by Eli Lilly, is a leading oral, non-peptide GLP-1 receptor agonist. Unlike injectable peptide therapies (e.g., Semaglutide), Orforglipron offers the distinct advantages of oral bioavailability and independence from food/water restrictions, positioning it as a pivotal candidate for Type 2 Diabetes and Obesity.

In Lilly’s convergent synthesis strategy, CAS 2212021-81-1 represents the final form of the left-hand Indole-2-carboxylic acid fragment (ACI). This intermediate undergoes an amide coupling reaction—typically via activation of its carboxylic acid functionality—with the right-hand Imidazolin-2-one fragment (ZCI). This step completes the macrocyclic closure to directly yield the Orforglipron Active Pharmaceutical Ingredient (API).