tert-Butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

tert-Butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (CAS 2212021-61-7), also known as Orforglipron Impurity 16, (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester, or simply as a key Orforglipron intermediate, is a chiral heterocyclic compound belonging to the pyrazolo[4,3-c]pyridine class of fused bicyclic systems. The molecular formula is C₂₃H₂₈FN₅O₃ with a molecular weight of 441.5 g/mol, typically supplied as a white to off‑white solid at purities of 98–99%.

In medicinal chemistry, tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate is a recognized pharmaceutical intermediate in the synthesis of Orforglipron (LY3502970), a first‑in‑class, once‑daily oral, non‑peptide GLP‑1 receptor agonist developed for the treatment of Type‑II diabetes and obesity. By activating the GLP‑1 pathway via a non‑peptide scaffold, tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate enables the construction of the core structure that mimics the bioactive conformation of endogenous GLP‑1 peptide agonists. The compound contains a key 2-oxo-2,3-dihydro-1H-imidazol-1-yl group, which is crucial for binding to the GLP‑1 receptor with high affinity and selectivity, while the Boc protecting group allows for controlled functionalization during multi‑step synthesis.

In pharmaceutical quality control, tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate is supplied as Orforglipron Impurity 16 with detailed characterization data compliant with regulatory guidelines (ICH, FDA, EMA). The reference standard is used for analytical method development, method validation (AMV), quality control (QC) applications, and abbreviated new drug application (ANDA) submissions during the commercial production of Orforglipron.

In process chemistry, tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate serves as a key building block for assembling the Orforglipron core via late‑stage coupling, and as a starting material for generating impurity reference standards for regulatory filings.

Product Parameters

Quality Assurance at Cosperpharm

Each batch undergoes:

● Gas chromatography (GC) – purity ≥97.0%

● Non‑aqueous titration – purity ≥97.0%

● Refractive index – confirmatory analysis

● ¹H NMR – structural verification

● Appearance – colorless to light yellow to light orange clear liquid

A comprehensive COA, MSDS (with full GHS information), and certificate of origin accompany every shipment.

Synthetic Route

The synthesis of tert-butyl (S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3-(2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate involves the construction of the pyrazolo[4,3-c]pyridine bicyclic core and the installation of the 2-oxo-imidazole moiety at the 3‑position.

General Synthetic Approach:

● Pyrazole ring formation – A suitable hydrazine derivative (starting from 4-fluoro-3,5-dimethylaniline) is condensed with a β‑ketoester or α,β‑unsaturated carbonyl precursor to construct the pyrazole ring.

● Pyridine ring annulation – The fused pyridine ring is formed through cyclization reactions involving the pyrazole core, often using a piperidine or tetrahydropyridine intermediate.

● Introduction of (4S)-stereochemistry – Asymmetric synthesis or chiral resolution is employed to establish the (4S)-absolute configuration at the methyl-bearing carbon.

● Introduction of the imidazole moiety – This step involves the reaction of the pyrazolopyridine intermediate with an imidazole derivative, often under reflux conditions in the presence of a suitable catalyst. Boc protection – The secondary amine at the 5‑position of the pyrazolo[4,3-c]pyridine core is protected as its tert‑butyloxycarbonyl derivative using Boc anhydride ((Boc)₂O) under basic conditions (e.g., triethylamine or DMAP).

● Introduction of the 2-oxo-imidazole – The imidazole ring is then converted to the 2-oxo-2,3-dihydro-1H-imidazol-1-yl group via controlled oxidation or cyclization with a suitable carbonyl source.

Industrial Production Scale‑Up

Industrial manufacturing typically follows optimized synthetic routes using continuous flow reactors and automated systems to enhance efficiency, yield, and safety. The process involves careful control of reaction parameters, including temperature, pressure, and inert atmosphere, to achieve consistent quality. The final product is purified by recrystallization or preparative HPLC to achieve ≥98% purity.

Frequently Asked Questions (FAQ)

Q1: What is the role of the 2-oxo-imidazole group in this compound?

A: The 2-oxo-2,3-dihydro-1H-imidazol-1-yl group at the 3‑position of the pyrazolopyridine core is crucial for binding to the GLP‑1 receptor. It contributes essential hydrogen‑bonding interactions and π‑stacking within the orthosteric binding pocket, enabling the non‑peptide agonist to mimic the bioactive conformation of endogenous GLP‑1 peptides and achieve high receptor affinity and functional activity.

Q2: What are the key spectroscopic identifiers for this compound?

A: CAS number 2212021-61-7, InChI Key QQFGCLFJMCFLDIO-HNNXBMFYSA-N, MDL number not determined, SMILES C[C@H]1C2=C(N(N=C2CCN1C(=O)OC(C)(C)C)C3=CC(=C(C(=C3)C)F)C)N4C=CNC4=O. These identifiers facilitate easy verification of product identity.

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