Regorafenib

Base Information

• Chemical Name: Regorafenib
• CAS No.: 755037-03-7
• Molecular Formula: C21H15ClF4N4O3
• Molecular Weight: 482.822
• Hs Code.: 29242990
• European Community (EC) Number: 815-051-1
• UNII: 24T2A1DOYB
• DSSTox Substance ID: DTXSID60226441
• Nikkaji Number: J2.963.976K
• Wikipedia: Regorafenib
• Wikidata: Q3891664
• NCI Thesaurus Code: C78204
• RXCUI: 1312397
• Pharos Ligand ID: 3HJ7GSS5ADN3
• Metabolomics Workbench ID: 65150
• ChEMBL ID: CHEMBL1946170
• Mol file: 755037-03-7.mol

Synonyms:4-(4-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)amino)-3-fluorophenoxy)-n-methylpyridine-2-carboxamide;BAY 73-4506;BAY-73-4506;BAY73-4506;regorafenib;Stivarga

Chemical Property of Regorafenib

Chemical Property:

• Melting Point: 206.0 to 210.0 °C
• Boiling Point: 513.4 °C at 760 mmHg
• PKA: 12.04±0.70(Predicted)
• Flash Point: 264.3 °C
• PSA: 92.35000
• Density: 1.491 g/cm³
• LogP: 6.22570
• Storage Temp.: Refrigerator
• Solubility.: DMSO (Slightly), Methanol (Slightly)
• XLogP3: 4.2
• Hydrogen Bond Donor Count: 3
• Hydrogen Bond Acceptor Count: 8
• Rotatable Bond Count: 5
• Exact Mass: 482.0768807
• Heavy Atom Count: 33
• Complexity: 686

Purity/Quality:

99%MIN ^*data from raw suppliers

Regorafenib ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: CNC(=O)C1=NC=CC(=C1)OC2=CC(=C(C=C2)NC(=O)NC3=CC(=C(C=C3)Cl)C(F)(F)F)F
• Recent ClinicalTrials: A Trial to Learn Whether Regorafenib in Combination With Nivolumab Can Improve Tumor Responses and How Safe it is for Participants With Solid Tumors
• Recent EU Clinical Trials: A Randomized Open-Label Phase 3 Study of XL092 + Atezolizumab vs Regorafenib in Subjects with Metastatic Colorectal Cancer
• Recent NIPH Clinical Trials: A Phase 3 Study of Lenvatinib Plus Pembrolizumab in Previously Treated Participants with Metastatic Colorectal Cancer (LEAP-017)
• Description: In September 2012, theUSFDAapproved regorafenib for the treatment of patients with metastatic colorectal cancer (CRC), especially those for whom standard therapies have failed, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, ananti-EGFRtherapy. Regorafenib is a multikinase inhibitor with potent inhibitory activity versus VEGFRs and PDFRs. Both of these classes of receptors are expressed on tumor cells and affect proliferation and angiogenesis. Regorafenib inhibited growth in murine xenograft models for colon, breast, renal, lung, melanoma, pancreatic, and ovarian tumors when dosed at 10–30 mg/kg. Regorafenib is a fluorinated analog of sorafenib, a multikinase inhibitor co-marketed by Bayer and Onyx for the treatment of kidney and liver cancer. The synthesis of regorafenib is accomplished in two steps from commercially available starting materials. 4-Aminophenol is coupled to 4-chloro-N-methyl- 2-pyridinecarboxamide to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. Subsequent treatment with 4-chloro-3-(trifluoromethyl)phenyl isocycanate affords the urea, regorafenib. Regorafenib is an orally bioavailable multi-kinase inhibitor with anticancer activity. It inhibits RET, C-RAF, VEGFR2, c-Kit, VEGFR1, and PDGFRβ with IC50 values of 1.5, 2.5, 4.2, 7, 13, and 22 nM, respectively. Regorafenib also inhibits B-RAF, VEGFR3, FGFR, and Tie2 (IC50s = 28, 46, 202, and 311 nM, respectivey) as well as other kinases. In vivo, regorafenib (10 mg/kg) reduces tumor size in the MDA-MB-231 breast and 786-O renal cancer mouse xenograft models. It also reduces tumor microvessel area and inhibits tumor growth in a panel of mouse xenograft models. Formulations containing regorafenib have been used in the treatment of advanced gastrointestinal stromal tumors and metastatic colorectal cancer.
• Uses: It inhibits PDGFR tyrosine kinase with IC50=83nM. It is useful for the treatment of inflammation and as an anti-proliferative agent. BAY 73-4506 (Regorafenib) is a multikinase inhibitor with IC50 of 17, 40 and 69 nM c-KIT, VEGFR2, B-Raf. Regorafenib (BAY 73-4506) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively
• Clinical Use: Treatment of colorectal cancer and gastrointestinal stromal tumours Treatment of hepatocellular carcinoma
• Drug interactions: Potentially hazardous interactions with other drugs Analgesics: avoid with mefenamic acid. Antibacterials: concentration reduced by rifampicin - avoid. Anticoagulants: increased risk of bleeding with warfarin. Antifungals: concentration increased by ketoconazole - avoid. Antipsychotics: avoid with clozapine (increased risk of agranulocytosis).

Technology Process of Regorafenib

There total 31 articles about Regorafenib 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: 96.8%

4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methyl amide (757251-39-1) + Methyl 4-methyl-3-oxopentanoate (42558-54-3) + 4-chloro-3-trifluoromethyl-aniline (320-51-4) → regorafenib (755037-03-7)

Guidance literature:

With dmap; In N,N-dimethyl-formamide; at 140 ℃; for 4h; Temperature; Green chemistry;

Reference yield: 96.2%

4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methyl amide (757251-39-1) + S,S-dimethyl dithiocarbonate (868-84-8) + 4-chloro-3-trifluoromethyl-aniline (320-51-4) → regorafenib (755037-03-7)

Guidance literature:

With tetra(n-butyl)ammonium hydroxide; In tetrahydrofuran; at 35 ℃; for 1.33333h; Green chemistry;

Reference yield: 94.5%

4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methyl amide (757251-39-1) + 4-chloro-3-(trifluoromethyl)phenyl isocyanate (327-78-6) → regorafenib (755037-03-7)

Guidance literature:

In ethyl acetate; at 20 ℃; for 1.5h;

DOI:10.1007/s11164-015-2206-z

upstream raw materials:

4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methyl amide

4-chloro-3-(trifluoromethyl)phenyl isocyanate

4-amino-3-fluorophenol

C₁₂H₁₆FNO

Downstream raw materials:

4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methyl amide

4-chloro-3-trifluoromethyl-aniline

1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-hydroxyphenyl)urea

Refernces

• 1、 -. "Preparation method of regorafenib". Paragraph 0025-0040. . Retrieved 2021/05/29.
• 2、 Wilde, Myron,Arzur, Danielle,Baratte, Blandine,Lefebvre, Dorian,Robert, Thomas,Roisnel, Thierry,Le Jossic-Corcos, Catherine,Bach, Stéphane,Corcos, Laurent,Erb, William. "Regorafenib analogues and their ferrocenic counterparts: Synthesis and biological evaluation". supporting information. p. 19723 - 19733. Retrieved 2020/12/04.