Vandetanib

Base Information

• Chemical Name: Vandetanib
• CAS No.: 443913-73-3
• Deprecated CAS: 338992-00-0
• Molecular Formula: C22H24BrFN4O2
• Molecular Weight: 475.361
• Hs Code.: 29333220
• European Community (EC) Number: 669-841-4
• NSC Number: 760766,744325
• UNII: YO460OQ37K
• DSSTox Substance ID: DTXSID1046681
• Nikkaji Number: J1.720.281B
• Wikipedia: Vandetanib
• Wikidata: Q7914515
• NCI Thesaurus Code: C2737
• RXCUI: 1098413
• Pharos Ligand ID: F9H7UFM8UY6Z
• Metabolomics Workbench ID: 52532
• ChEMBL ID: CHEMBL24828
• Mol file: 443913-73-3.mol

Synonyms:caprelsa;N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine;vandetanib;Zactima;ZD 6474;ZD-64;ZD-6474;ZD6474

Chemical Property of Vandetanib

Chemical Property:

• Appearance/Colour: Yellow solid
• Vapor Pressure: 0mmHg at 25°C
• Melting Point: 240-243 °C
• Refractive Index: 1.629
• Boiling Point: 538.22 °C at 760 mmHg
• PKA: 8.92±0.10(Predicted)
• Flash Point: 279.306 °C
• PSA: 59.51000
• Density: 1.406 g/cm³
• LogP: 5.01510
• Storage Temp.: -20?C Freezer
• Solubility.: Soluble in DMSO (30 mg/ml); Ethanol (10 mg/ml with warming)
• XLogP3: 4.9
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 7
• Rotatable Bond Count: 6
• Exact Mass: 474.10667
• Heavy Atom Count: 30
• Complexity: 539

Purity/Quality:

98%, ^*data from raw suppliers

Vandetanib ^*data from reagent suppliers

Safty Information:

• Safety Statements: 24/25

MSDS Files:

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: CN1CCC(CC1)COC2=C(C=C3C(=C2)N=CN=C3NC4=C(C=C(C=C4)Br)F)OC
• Recent ClinicalTrials: A Study of Pralsetinib Versus Standard of Care (SOC) for Treatment of RET-Mutated Medullary Thyroid Cancer (MTC).
• Recent EU Clinical Trials: A PHASE III, RANDOMIZED, OPEN-LABEL STUDY OF PRALSETINIB VERSUS STANDARD OF CARE FOR TREATMENT OF RET-MUTATED MEDULLARY THYROID CANCER
• Recent NIPH Clinical Trials: VERIFY
• Description: In April 2011, the U.S. FDA approved vandetanib (ZD6474) for the treatment of symptomatic or progressive medullary thyroid cancer (MTC) in adult patients with inoperable advanced ormetastatic disease. Vandetanib inhibits KDR/VEGFR2, VEGFR3, EGFR, and RET kinases with IC50's of 40, 110, 500, and <100 nM, respectively. In athymic mice bearing MTC tumors, a 14.5-fold reduction of tumor volume was observed after 45 days of treatment with vandetanib at 50 mg/kg/day. The decrease in tumor volume was accompanied by decreases in mitotic index (Ki67) and tumor angiogenesis in treated xenografts. Key steps in the synthesis of vandetanib include the displacement of the chlorine atom from 7-benzyloxy-4-chloro-6-methoxyquinazoline with 4-bromo-2- fluoroaniline under acidic conditions in a protic solvent and a Mitsunobu reaction of a N-protected piperidine alcohol with a phenol.
• Uses: Vandetanib (Zactima, ZD6474) is a potent inhibitor of VEGFR2 with IC50 of 40 nM. Vandetanib (ZD6474) is a potent inhibitor of VEGFR2 with IC50 of 40 nM Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity. The activity of Vandetanib plus Docetaxel was assessed in patients with previously treated non-small-cell lung cancer (NSCLC). Vandetanib is a broad spectrum, orally available kinase inhibitor that targets primarily tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR), with IC50 values in the nanomolar range. It also potently blocks non-receptor tyrosine kinases, including ABL, RET, and SRC, as well as several serine/threonine kinases. Primarily because of its effects on receptor tyrosine kinases like VEGFR and EGFR, vandetanib inhibits angiogenesis, cell growth, and metastasis and is effective against certain forms of cancer.[Cayman Chemical]
• Clinical Use: Vandetanib, an oral VEGF, EGF, and RET receptor tyrosine kinase inhibitor, was developed by AstraZeneca for the treatment of symptomatic or aggressive medullary thyroid cancer (MTC) in patients with advanced or metastatic disease. This is the first drug approved for the treatment of MTC. Trials for other cancer indications such as small-cell lung cancer (SCLC), breast cancer, head and neck cancer, colorectal cancer, hormone-resistant prostate cancer, and papillary thyroid cancer are currently being explored. While AstraZeneca had previously developed ZD-4190 which displays similar efficacy and pharmacokinetic profile to vandetanib, vandetanib exhibited significantly improved solubility.
• Drug interactions: Potentially hazardous interactions with other drugs Analgesics: possibly increased risk of ventricular arrhythmias with methadone - avoid. Anti-arrhythmics: possibly increased risk of ventricular arrhythmias with amiodarone or disopyramide - avoid. Antibacterials: possibly increased risk of ventricular arrhythmias with parenteral erythromycin and moxifloxacin - avoid; concentration reduced by rifampicin - avoid. Antihistamines: possibly increased risk of ventricular arrhythmias with mizolastine - avoid. Antimalarials: possibly increased risk of ventricular arrhythmias with artemether with lumefantrine - avoid. Antipsychotics: possibly increased risk of ventricular arrhythmias with amisulpiride, chlorpromazine, haloperidol, pimozide, sulpiride and zuclopenthixol - avoid; avoid concomitant use with clozapine, risk of agranulocytosis. Beta-blockers: possibly increased risk of ventricular arrhythmias with sotalol - avoid. Cytotoxics: possibly increased risk of ventricular arrhythmias with arsenic trioxide - avoid. Hormone antagonist: possibly increased risk of ventricular arrhythmias with toremifene - avoid. 5HT3 -receptor antagonists: possibly increased risk of ventricular arrhythmias with ondansetron - avoid. Pentamidine: possibly increased risk of ventricular arrhythmias - avoid.

Technology Process of Vandetanib

There total 21 articles about Vandetanib which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 94.0%

formaldehyd (50-00-0,30525-89-4,61233-19-0) + 4-(((4-((4-bromo-2-fluorophenyl)amino)-6-methoxyquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (338992-20-4) → vandetanib (443913-73-3)

Guidance literature:

formaldehyd; 4-(((4-((4-bromo-2-fluorophenyl)amino)-6-methoxyquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester; With formic acid; In water; at 80 ℃; for 6.5 - 8.5h;

With potassium hydroxide; In methanol; water; at 60 ℃; for 2h; Product distribution / selectivity;

Reference yield: 89.0%

4-bromo-2-fluoroaniline (367-24-8) + 4-chloro-6-methoxy-7-[(1'-methylpiperidin-4'-yl)methoxy]-quinazoline (264208-72-2) → vandetanib (443913-73-3)

Guidance literature:

In isopropyl alcohol; at 80 ℃; for 0.533333h; Microwave irradiation;

DOI:10.1016/j.tet.2009.11.091

Reference yield: 85.0%

formaldehyd (50-00-0,30525-89-4,61233-19-0) + N-Desmethylvandetanib (338992-12-4) → vandetanib (443913-73-3)

Guidance literature:

With sodium triacetoxyborohydride; acetic acid; In methanol; dichloromethane; water; at 20 ℃; for 2h;

DOI:10.1016/j.bmcl.2011.04.049

upstream raw materials:

formaldehyd

N-Desmethylvandetanib

4-(((4-((4-bromo-2-fluorophenyl)amino)-6-methoxyquinazolin-7-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester

4-bromo-2-fluoroaniline

Downstream raw materials:

4-((4-bromo-2-fluorophenyl)amino)-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-6-ol

Refernces

• 1、 Brocklesby, Kayleigh L.,Waby, Jennifer S.,Cawthorne, Chris,Smith, Graham. "An alternative synthesis of Vandetanib (Caprelsa) via a microwave accelerated Dimroth rearrangement". . p. 1467 - 1469. Retrieved 2017/03/23.
• 2、 -. "SUBSTITUTED QUINAZOLINE INHIBITORS OF GROWTH FACTOR RECEPTOR TYROSINE KINASES". Page/Page column 23. . Retrieved 2010/04/23.