1140909-48-3 Cabozantinib Malate

✅ Pharmaceutical API

1. Medullary Thyroid Carcinoma (MTC): First-line treatment for progressive/metastatic unresectable MTC, relieves tumor-related symptoms and prolongs progression-free survival (PFS).

2. Renal Cell Carcinoma (RCC): Monotherapy for advanced RCC; first-line combination therapy with Nivolumab for advanced clear cell RCC; second-line treatment for RCC patients with disease progression after anti-VEGF therapy.

3. Hepatocellular Carcinoma (HCC): Indicated for advanced HCC patients who failed Sorafenib treatment, significantly improves overall survival (OS) and PFS.

4. Differentiated Thyroid Cancer (DTC): For locally advanced/metastatic radioactive iodine-refractory DTC (adults & adolescents ≥12 years) with disease progression after VEGFR-targeted therapy.

5. Neuroendocrine Tumors (NETs): Approved for unresectable locally advanced/metastatic well-differentiated pancreatic/extra-pancreatic NETs (≥12 years) with prior treatment failure.

6. Off-label Uses: Treatment of prostate cancer, breast cancer, non-small cell lung cancer (NSCLC) with MET/RET gene mutation; control of bone metastases in solid tumors.

✅ Biomedical Research

1. Preclinical research on MET/VEGFR signaling pathway, tumor angiogenesis mechanism, and bone metastasis regulation.

2. Clinical trials on combination therapy with PD-1/PD-L1 inhibitors for solid tumors; research on targeted therapy for RET fusion-positive NSCLC.

▶ API Raw Material Packaging

▸ Lab/Research Grade: Sealed amber glass vials with Teflon-lined screw caps, specs: 1g, 5g, 10g, 25g, 50g, 100g; purity ≥99.8%, vacuum-sealed to prevent light/heat/moisture-induced degradation.

▸ Industrial/Pharmaceutical Grade: HDPE plastic drums/fiber drums with double PE inner liners (moisture-proof/oxygen-barrier), specs: 1kg, 5kg, 25kg, 50kg; drum labels include CAS No., batch No., purity, net weight, storage conditions, GMP certificate, hazard warnings (avoid skin/eye contact, no oral intake).

▸ Customized Export Packaging: 10g/50g/100g aluminum foil vacuum bags for small-batch shipment; labeled with ICH Q7 standards, UN transport marks (non-hazardous chemical for export).

▶ Storage & Shelf Life Requirements

2-8°C cold storage, protected from light, dry & well-ventilated environment; avoid contact with strong acids/oxidants/heavy metals; shelf life 36 months under sealed conditions.

Transportation: Cold chain transportation for API (insulated containers with temperature monitors, 2-8°C); normal temperature transportation for finished products with heat-insulating packaging in summer.

Raw Materials: Methyl 2-amino-4,5-dimethoxybenzoate, 4-nitrophenol, 1,1-cyclopropanedicarboxylic acid, 4-fluoroaniline, (S)-malic acid

Steps (7-step industrial scalable synthesis, mild conditions, low impurity)

1. Cyclization & Chlorination: Cyclize methyl 2-amino-4,5-dimethoxybenzoate in concentrated sulfuric acid to form 6,7-dimethoxy-4-hydroxyquinoline; chlorinate with phosphorus oxychloride (POCl₃) in toluene at 80-90°C to obtain 4-chloro-6,7-dimethoxyquinoline (intermediate 1).

2. Nucleophilic Substitution: React intermediate 1 with 4-nitrophenol under K₂CO₃ catalysis in DMF at 90-100°C to get 6,7-dimethoxy-4-(4-nitrophenoxy)quinoline (intermediate 2).

3. Reduction: Reduce intermediate 2 with Pd/C (10%) and hydrogen gas (1atm) in ethanol at 30-40°C to produce 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (intermediate 3, purity ≥99.5%).

4. First Amidation: Acylate 1,1-cyclopropanedicarboxylic acid with thionyl chloride (SOCl₂) in DCM at 20-30°C; condense with intermediate 3 under triethylamine catalysis to form 1-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenylcarbamoyl)cyclopropanecarboxylic acid (intermediate 4).

5. Second Amidation: Couple intermediate 4 with 4-fluoroaniline using HBTU/HOBt (1:1.5 molar ratio) as coupling reagent and DIPEA as base in DMF at 25-35°C to obtain cabozantinib free base.

6. Purification: Recrystallize cabozantinib free base from ethanol/ethyl acetate mixture to remove impurities, purity ≥99.8%.

7. Salt Formation: React purified free base with (S)-malic acid (1:1 molar ratio) in isopropanol/water (3:1) at 50-60°C; cool to 0-5°C for crystallization, filter and vacuum-dry at 45-55°C to get cabozantinib malate white crystalline powder.

Advantages: Mild reaction conditions, no ultra-high temperature required, low corrosive reagent usage, easy industrial scale-up, minimal by-products, compliant with environmental protection requirements.