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

tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (CAS 2212021-59-3), also known as (4S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester, is a complex heterocyclic intermediate in the synthesis of orally bioavailable small molecule drugs. The compound has a molecular formula of C₂₀H₂₇FN₄O₂ and a molecular weight of 374.45 g/mol, typically supplied at purities of 98–99% as an off-white to yellow solid.

In medicinal chemistry, tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate is recognized as a key intermediate in the synthesis of Orforglipron (formerly LY3502970), a first-in-class, once-daily oral, non‑peptide GLP‑1 receptor agonist developed for the treatment of Type‑II diabetes and obesity. The compound’s stereochemically defined pyrazolo[4,3-c]pyridine core, combined with the 4‑fluoro-3,5‑dimethylphenyl substituent, is designed to engage the GLP‑1 receptor with high affinity and selectivity while avoiding the metabolic liabilities associated with peptide‑based agonists. Since the GLP‑1 pathway is a cornerstone in treating metabolic diseases, intermediates that can mimic its activation without injection are in high demand.

In pharmaceutical research, tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate is also supplied as Orforglipron Impurity 27, a recognized impurity reference standard used in the quality control and regulatory filing of Orforglipron. The BOC (tert‑butyloxycarbonyl) protecting group enables this molecule to be directly incorporated into multi‑step syntheses, avoiding premature side reactions. The fluorine atom at the 4‑position of the phenyl ring is not merely a substituent; it is a strategic element of modern drug design that enhances bioavailability by modulating pKa and lipophilicity.

In process chemistry, tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate is a workhorse building block. The BOC group allows chemists to install the core early in the synthesis, while the free amine (upon deprotection) serves as a handle for late‑stage diversification, enabling rapid iteration of drug candidates. The compound’s well‑defined three‑dimensional architecture also provides a versatile platform for the development of novel heterocyclic scaffolds for other therapeutic indications, including anti‑inflammatory and anticancer drug discovery.

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Frequently Asked Questions (FAQ)

Q1: What are the primary applications of tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate?

A: It is primarily used as a key synthetic intermediate for the oral non‑peptide GLP‑1 receptor agonist Orforglipron (LY3502970) for Type‑II diabetes and obesity, as Orforglipron Impurity 27 reference standard for analytical method development and quality control, and as a chiral building block for other pyrazolopyridine‑based drug discovery programs.

Q2: How should this compound be stored?

A: Store at 2–8°C in a sealed, airtight container under inert atmosphere (nitrogen or argon), protected from light and moisture. For long‑term storage (>12 months), maintain at –20°C. Avoid repeated freeze‑thaw cycles; aliquot into single‑use portions when possible.

Application Scenarios

1. Orforglipron API Manufacturing

A pharmaceutical manufacturing facility is scaling up GMP production of Orforglipron (LY3502970) for clinical supply. tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate is a key synthetic intermediate in the multi‑step synthesis. The Boc‑protected intermediate is carried forward through deprotection (TFA/DCM), followed by amide coupling with a carboxylic acid partner, and finally purified by preparative HPLC to achieve API purity specifications. The process is documented and validated as part of the drug master file (DMF) submission to regulatory authorities.

2. Orforglipron Impurity 27 Reference Standard for Quality Control

A pharmaceutical QC laboratory is developing an HPLC‑MS method for the quality control of Orforglipron API batches. tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate is supplied as Orforglipron Impurity 27 with full characterization data (NMR, HPLC, GC, MS) compliant with regulatory guidelines. The reference standard is used to prepare calibration curves, establish system suitability parameters, and validate the analytical method for detecting and quantifying this process‑related impurity. The validated method is implemented for batch‑release testing and stability studies, ensuring compliance with ICH guidelines and regulatory requirements for market approval.

3. Generic Drug Development for ANDA Submission

A generic pharmaceutical company is developing an Abbreviated New Drug Application (ANDA) for an Orforglipron‑containing drug product. The regulatory submission requires comprehensive impurity profiling, including identification and control of process‑related impurities such as Orforglipron Impurity 27. The team purchases tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate as a reference standard with full COA, stability data, and characterization spectra. The reference standard is used to develop and validate stability‑indicating methods, to identify and quantify impurities in stability samples, and to establish impurity acceptance criteria, ensuring equivalence to the brand‑name reference listed drug (RLD).

4. Novel GLP‑1 Receptor Agonist Lead Optimization

A medicinal chemistry team is developing a library of novel non‑peptide GLP‑1 receptor agonists with improved pharmacokinetic profiles. tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate serves as the core scaffold. The team systematically modifies the amine substituents after Boc deprotection to explore the structure‑activity relationship (SAR) at the 5‑position, while also derivatizing the 3‑amino group. The resulting compounds are screened for GLP‑1 receptor binding affinity (IC₅₀), cAMP accumulation potency (EC₅₀), and functional selectivity (β‑arrestin recruitment). Lead compounds with improved potency and oral bioavailability are identified for preclinical development.

5. Process Development and Route Scouting for Pyrazolopyridine Intermediates

A process chemistry group is developing a scalable synthetic route for a novel pyrazolopyridine‑based drug candidate. Using tert-butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate as a reference intermediate, the team screens various coupling conditions and protecting group strategies to optimize yield, purity, and scalability. Kinetic studies are performed to understand reaction mechanisms and identify optimal temperature, time, and reagent stoichiometry. The final optimized process is successfully scaled to pilot‑plant and commercial‑scale manufacturing, enabling cost‑effective production of the novel drug candidate for clinical trials.

6. Stability‑Indicating Method Validation for Orforglipron Formulations

A drug product development team is conducting forced degradation studies on an Orforglipron‑containing oral formulation to identify potential degradation products and establish shelf‑life specifications. tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Orforglipron Impurity 27) is used as a marker to monitor degradation pathways that may generate this impurity under stressed conditions (acid, base, thermal, oxidative). The stability‑indicating method is validated using the impurity reference standard, and the results are used to establish shelf‑life specifications and storage conditions for the commercial drug product, supporting regulatory filing.

7. Chiral Method Development for Stereochemical Purity Control

A pharmaceutical analytical laboratory is developing a chiral HPLC method for the simultaneous determination of (4S)-tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (target isomer) and its (4R)-diastereomeric impurity in intermediate batches. The target isomer reference standard and the relevant diastereomer (if available) are used to optimize chiral separation conditions (column type, mobile phase composition, flow rate, column temperature). The validated chiral method is used to monitor the stereochemical purity of the intermediate in production and to ensure that diastereomer content meets specifications for downstream API manufacturing, supporting regulatory submissions and quality assurance.

8. Cross‑Validation Between QC Laboratories for Method Transfer

A pharmaceutical company with multiple manufacturing sites requires cross‑validation of analytical methods between QC laboratories. tert-Butyl (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate reference standard is distributed to each QC site for method transfer studies. The reference standard is used to qualify new HPLC columns, calibrate instrumentation, and ensure consistent impurity quantitation across all manufacturing locations. The cross‑validation results are documented in the method transfer report and submitted as part of the regulatory post‑approval change (PAC) documentation, ensuring regulatory compliance and supply chain continuity.

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