Orforglipron (CAS 2212020-52-3)

Orforglipron (CAS No. 2212020-52-3, development code LY3502970) is the world’s first oral non-peptide small-molecule GLP-1 receptor agonist developed by Eli Lilly, approved in 2026 for type 2 diabetes mellitus (T2DM) and chronic obesity management. Unlike injectable peptide GLP-1 therapies (semaglutide, tirzepatide), Orforglipron delivers once-daily oral administration without strict food/water intake restrictions, achieving superior glycemic control and weight loss in Phase 3 clinical trials published in The Lancet and NEJM. Its multi-step total synthesis relies on three proprietary fluorinated indazole & aniline intermediates: 4-Bromo-3-fluoro-2-methylaniline (127408-03-1), 5-Bromo-4-fluoro-1H-indazole (1082041-85-7), and 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole (2490501-34-1). These three building blocks form the heterocyclic core skeleton of Orforglipron API, and our company supplies cGMP-grade bulk intermediates for global pharmaceutical R&D and commercial API manufacturing.

H2: What Are the Primary Clinical Applications of Orforglipron (CAS 2212020-52-3)?

H3: 1. Treatment of Adult Type 2 Diabetes Mellitus (T2DM)

Orforglipron is indicated for adults with inadequately controlled type 2 diabetes via diet and exercise alone. As a biased GLP-1R allosteric agonist, it triggers glucose-dependent insulin secretion and suppresses hepatic glucagon release, lowering HbA1c without severe hypoglycemia risk.

Phase 3 ACHIEVE-3 trial data: 36mg daily Orforglipron reduced HbA1c by 2.2%, vs 1.4% for oral semaglutide 14mg; 75% of participants reached HbA1c ≤6.5% target.

Early efficacy onset: Significant blood glucose improvements observed within 4 weeks of daily oral dosing.

H3: 2. Chronic Weight Management for Obesity & Overweight Patients

Orforglipron’s central nervous system penetration suppresses hypothalamic appetite signaling, delivering sustained, clinically meaningful weight reduction without injection requirements.

ATTAIN-1 72-week obesity trial maximum dose result: Average body weight loss of 12.4% (27.3 lbs) at 36mg daily.

Head-to-head comparison vs oral semaglutide: Orforglipron delivered 73.6% greater relative weight loss (9.2% vs 5.3%).

Additional metabolic benefits: Reduces triglycerides, LDL cholesterol, systolic blood pressure to lower cardiovascular disease risk in obese patients.

H3: 3. Exploratory Pipeline Indications

Pharmaceutical developers are advancing Orforglipron research for secondary metabolic disorders:

Non-alcoholic steatohepatitis (NASH)

Metabolic syndrome with combined dyslipidemia and hypertension

Weight maintenance post-obesity treatment to mitigate weight rebound

H2: What Mechanisms Drive Orforglipron’s Therapeutic Efficacy?

Non-peptide allosteric GLP-1R binding: Unlike peptide GLP-1s that bind the orthosteric pocket, Orforglipron targets a unique transmembrane allosteric site, eliminating degradation by DPP-4 proteases and enabling oral bioavailability.

G-protein biased agonism: Prioritizes cAMP signaling over β-arrestin recruitment, reducing GLP-1 receptor desensitization for long-lasting efficacy and milder gastrointestinal side effects.

Dual peripheral + central activity: Acts on pancreatic β-cells for glycemic control and brain feeding centers to curb overeating simultaneously.

H2: What Are the 3 Key Synthetic Intermediates for Orforglipron API Production?

The full synthetic route of Orforglipron (molecular formula C₄₈H₄₈F₂N₁₀O₅, MW 882.97) centers on fluorinated indazole core construction, sequentially built from three tiered intermediates. Below is standardized technical specification table for each intermediate, including CAS, chemical identity, exact synthetic role in Orforglipron manufacturing, and industrial grade standards.

Table 1: Full Parameter Comparison of 3 Core Orforglipron Intermediates

H3: 1. 4-Bromo-3-fluoro-2-methylaniline (CAS 127408-03-1): Tier 1 Starting Material

This fluorinated bromoaniline is the foundational feedstock for the entire indazole ring assembly of Orforglipron. In patent-disclosed scalable synthetic workflows, it undergoes multi-step diazotization and intramolecular cyclization to construct the 4-fluoro-5-bromo indazole aromatic skeleton. Without this high-purity aniline precursor, manufacturers cannot avoid toxic isomer byproducts that complicate downstream API purification and fail ICH impurity limits for pharmaceutical-grade Orforglipron.

Exclusive Application: Only used as the primary starting intermediate for synthesizing Orforglipron’s indazole core fragment; no mainstream alternative GLP-1 API relies on this compound.

H3: 2. 5-Bromo-4-fluoro-1H-indazole (CAS 1082041-85-7): Tier 2 Indazole Parent Intermediate

Produced via ring closure of 4-Bromo-3-fluoro-2-methylaniline, this unalkylated indazole is the critical mid-stage fragment before N-substitution. The free N-H position on the indazole ring enables selective cyclopropylation to generate the late-stage Orforglipron building block.

Key Production Advantage: Our plant’s recrystallization process eliminates 4-fluoro-6-bromo indazole isomers, a common manufacturing bottleneck that lowers Orforglipron API yield and purity.

Exclusive Application: Specialized intermediate for oral small-molecule GLP-1 Orforglipron API commercial and lab-scale synthesis.

H3: 3. 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole (CAS 2490501-34-1): Tier 3 Late-Stage API Fragment

After N1 cyclopropylation of 5-Bromo-4-fluoro-1H-indazole, this fully substituted fluorinated indazole becomes the final heterocyclic fragment coupled with the pyrazolo[4,3-c]pyridine core to form crude Orforglipron API. Its bromine leaving group enables palladium-catalyzed cross-coupling reactions required to complete the full target molecule structure.

Supply Chain Value: Global Orforglipron commercialization has created tight supply for this intermediate; our company offers kg to ton-scale cGMP batches with complete COA, SDS, and impurity profiling documentation for FDA/EMA filing.

H2: Why Do API Manufacturers Need High-Purity Grades of These 3 Orforglipron Intermediates?

ICH Impurity Compliance: Fluorinated bromo-heterocycle impurities from low-grade intermediates cannot be removed in late-stage API recrystallization and will fail regulatory toxicology testing for Orforglipron oral solid dosage forms.

Synthetic Yield Stability: Regioisomer contamination in the three intermediates reduces cross-coupling reaction yields by 30–50%, raising total API production costs significantly.

GMP Commercial Batch Scaling: Our intermediate production lines are validated for ton-scale manufacturing, supporting pharmaceutical companies scaling Orforglipron from lab R&D to commercial oral tablet production post-FDA approval in 2026.

H2: Frequently Asked Questions

Q1: What is Orforglipron CAS number?

A1: Orforglipron official CAS registry number is 2212020-52-3, also referenced by development code LY3502970.

Q2: What makes Orforglipron different from injectable GLP-1 weight loss drugs?

A2: Orforglipron is a fully synthetic non-peptide small molecule with oral bioavailability, requiring no subcutaneous injection, no strict fasting rules before dosing, and delivers comparable or superior weight loss and glycemic control vs oral semaglutide per Phase 3 clinical data from The Lancet 2026 trials.

Q3: What are the three mandatory core intermediates to synthesize Orforglipron API?

A3: The three non-substitutable synthetic building blocks are:

4-Bromo-3-fluoro-2-methylaniline (CAS 127408-03-1) – Tier 1 starting aniline

5-Bromo-4-fluoro-1H-indazole (CAS 1082041-85-7) – Tier 2 indazole parent ring

5-bromo-1-cyclopropyl-4-fluoro-1H-indazole (CAS 2490501-34-1) – Tier 3 late-stage coupling fragment

Q4: Can I substitute other indazole intermediates to produce Orforglipron?

A4: No. The specific 4-fluoro, 5-bromo substitution pattern plus N1 cyclopropyl group is structurally required to match Orforglipron’s GLP-1 receptor binding pocket; alternative indazole analogs produce inactive off-target compounds with zero therapeutic efficacy.

Q5: What purity grade of these Orforglipron intermediates meets pharmaceutical commercial standards?

A5: For cGMP commercial API manufacturing:

4-Bromo-3-fluoro-2-methylaniline ≥98% HPLC

5-Bromo-4-fluoro-1H-indazole ≥98% HPLC

5-bromo-1-cyclopropyl-4-fluoro-1H-indazole ≥98% HPLC

All batches must include full impurity profiling, residual solvent testing, and heavy metal analysis aligned with ICH Q3A/B guidelines.

Q6: What applications outside diabetes/obesity use Orforglipron and its intermediates?

A6: The API is exclusively developed for metabolic disorders (T2DM, obesity, NASH). The three fluorinated indazole/aniline intermediates have no major alternative pharmaceutical applications and are purpose-built for Orforglipron total synthesis.

H2: Our Company Supply Advantages for Orforglipron API & Core Intermediates

Full supply chain coverage: We manufacture all three tiered intermediates in-house, eliminating third-party raw material cost and supply delay risks for pharmaceutical clients.

Regulatory documentation support: COA, SDS, impurity profile charts, synthetic route technical whitepapers, and custom trial batch samples available for pre-clinical and Phase 3 trial filing.

Flexible order volume: R&D gram samples, kilogram pilot batches, and ton-scale commercial cGMP bulk production for global biotech and API manufacturers.

Global logistics compliance: UN-certified chemical packaging, cold-chain shipping for fluorinated heterocycles, and complete customs documentation for EU, US, Southeast Asia pharmaceutical import.

Orforglipron (CAS 2212020-52-3) is a transformative oral small-molecule GLP-1 agonist for type 2 diabetes and obesity treatment, differentiated by needle-free daily oral administration and robust Phase 3 clinical efficacy data. Its scalable total synthesis depends entirely on three proprietary fluorinated heterocyclic intermediates: 4-Bromo-3-fluoro-2-methylaniline (127408-03-1), 5-Bromo-4-fluoro-1H-indazole (1082041-85-7), and 5-bromo-1-cyclopropyl-4-fluoro-1H-indazole (2490501-34-1). As a specialized pharmaceutical intermediate manufacturer, we provide high-purity, cGMP-compliant batches of these three critical building blocks to support global Orforglipron API R&D and post-2026 commercial mass production. For custom quotes, trial samples, or full technical data packs, contact our pharmaceutical chemical sales team directly via our website inquiry form.