201530-41-8

Basic information

• Product Name: Deferasirox
• Synonyms: Deferasirox(CGP-72670);4-[3,5-bis(6-oxocyclohexa-2,4-dien-1-ylidene)-1,2,4-triazolidin-1-yl]benzoic acid;Deferasirox(Exjade);4-[3,5-bis(2-hydroxyphenyl);20kg;Deferasirox, >=99%;Deferasirox D8;4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid
• CAS NO: 201530-41-8
• Molecular Formula: C₂₁H₁₅N₃O₄
• Molecular Weight: 373.3615
• EINECS: 1806241-263-5
• Product Categories: Aromatics;Chelating Agents & Ligands;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Pharmaceutical intermediate;Exjade, ICL-670, ICL-670A, CGP-72670;Chelating agent (iron);Aromatics Compounds
• Mol File: 201530-41-8.mol
• Article Data: 36

Chemical Properties

• Melting Point: 260-2620C
• Boiling Point: 672.123 °C at 760 mmHg
• Flash Point: 360.287 °C
• Appearance: /
• Density: 1.405 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.699
• Storage Temp.: -20°C Freezer
• Solubility: Soluble in DMSO (10 mg/ml)
• PKA: pKa1 4.57, pKa2 8.71, pKa3 10.56 (Nick); Also reported in H2O/DM
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.
• CAS DataBase Reference: Deferasirox(CAS DataBase Reference)
• NIST Chemistry Reference: Deferasirox(201530-41-8)
• EPA Substance Registry System: Deferasirox(201530-41-8)

Safety Data

• Hazardous Substances Data: 201530-41-8(Hazardous Substances Data)

Usage

Description

Deferasirox, also known as Exjade, is an orally active tridentate iron chelator developed by Novartis. It is a white to off-white solid with the chemical name 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid. Deferasirox is the first routinely used oral iron chelator approved by the US FDA for the treatment of iron overloading caused by blood transfusions in patients older than 2 years with chronic anemia. It is also recommended as a first-line treatment for patients older than 6 years suffering from blood iron overload in Europe. In addition to its primary use, Deferasirox exhibits pharmacological properties such as antifungal, anti-cell proliferation, anti-malaria, antioxidant stress injury, and anti-cytotoxicity induced apoptosis.

Uses

1. Used in Pharmaceutical Industry:
Deferasirox is used as an orally active tridentate iron chelator for the treatment of chronic iron overload in patients receiving long-term blood transfusions.
2. Used in Treatment of Fanconi Syndrome:
Deferasirox is used as a treatment for reversible renal insufficiency caused by Fanconi syndrome.
3. Used in Treatment of Secondary Hemochromatosis:
Deferasirox is used as a treatment for secondary hemochromatosis.
4. Used in Treatment of Delayed Skin Porphyria:
Deferasirox is used as a treatment for delayed skin porphyria.
5. Used in Treatment of Myelodysplastic Syndromes:
Deferasirox is used as a treatment for myelodysplastic syndromes.
6. Used in Treatment of Iron Overloading in Chronic Anemia Patients:
Deferasirox is used for the treatment of iron overloading caused by blood transfusions in patients (older than 2 years old) with chronic anemia.
7. Used as an Internal Standard in Mass Spectrometry:
Deferasirox, labeled as an internal standard, is used for the quantification of Deferasirox by GCor LC-mass spectrometry in the field of chemical analysis and research.

Preparation

Take salicylic acid as raw material; it undergoes chlorination through thionyl chloride to obtain salicylic acid chloride. Salicylic acid chloride and salicylic acid amide are placed under the condition of high temperature and vacuum distillation instead of ordinary reflux method to obtain intermediates, further evaporating into large amount of low-boiling and by-products through high temperature vacuum distillation, making the mass fraction of the intermediate be increased from 88.7% to 97.5%. Finally, after the removal of hydrochloric acid, the carboxyl-phenylhydrazine hydrochloride is subject to cyclization with the intermediate to prepare the product of deferasirox, reducing the steps of desalting and solvents steaming-off in the post-reaction treatment while reducing the amount of anhydrous ethanol as well so that the operation becomes simpler. 1. Preparation of salicylic acid chloride (Compound 1) Salicylic acid (13.8 g, 0.1 mol), 10 drops of anhydrous pyridine and 10 mL of thionyl chloride were added to the reaction flask. The mixture was subject to stirred reaction at room temperature for 30 min and slowly heated to 70 °C with stirring until almost no hydrogen chloride gas was released. Further heat to 80 °C and stir for 3 h. Residual thionyl chloride was distilled off under reduced pressure to give a pale yellow liquid which was cooled to precipitate crystals and used directly in the next reaction. 2. Preparation of the 2-(2-hydroxyphenyl)-[1, 3] benzoxazinone (Compound 2) Salicylic acid (13.7 g, 0.1 mol) and the compound 1 obtained from the last step of reaction are added to the reaction flask equipped with a distillation apparatus and heated to 180 ° C. The reaction mixture was reacted with distillation under reduced pressure at the same time for 3 h to remove water from the reaction. 50 mL of absolute ethanol was added under melting to precipitate the solid yellow product. After filtration and recrystallization from anhydrous ethanol, we can obtain 16.8 g of a yellow product with a yield 70.3% and mp 210-213 °C. 3. Preparation of p-carboxyphenylhydrazine hydrochloride (Compound 3) 4-aminobenzoic acid (6.85 g, 0.05 mol) and 10 mL of distilled water were added into a 250 mL three-necked flask. The mixture was stirred to become a paste and added of drop wise of 12.5 mL of concentrated hydrochloric acid at 5 ° C. The solution was cooled to 5 ° C in an ice-salt bath. Upon stirring, slowly add drop wise of a sodium nitrite saturated solution (3.5 g, 0.05 mol of sodium nitrite is dissolved in a small amount of water (8 g)) for diazotization reaction. The reaction temperature is kept below 5 ℃ and further stirred for 30 mins after the completion of dropping. The diazonium salt solution was then poured into a solution with sodium sulfite (25.2 g, 0.2 mol) dissolved in water (100 mL) pre-cooled to 5 °C. Stir at this temperature for 30 min, and heat to 80 ° C for 1.5 h. The orange-red solution will be changed to yellowish. Cool it to room temperature; slowly add hydrochloric acid for acidification to pH 3 to obtain the p-carboxyphenylhydrazine hydrochloride precipitate. Further apply filtration and drying to get 8.3 g white product with a yield of 88.3%. 4. Preparation of Deferasirox The compound 3 (3.8 g, 0.02 mol) was adjusted to pH 6 with 30% NaOH, stirred, and stand for layering so that the water layers were separated. The oil layer was p-carboxyphenylhydrazine. The oil layer was placed in a flask; add compound II (5.0 g; 0.02 mol) and reflux for 2 h in anhydrous ethanol (75 mL). Cool, precipitate the crystals; filtrate and rinse with 10 mL of ice ethanol, dry and perform ethanol-water recrystallization, to obtain 6.3 g micro-yellow product with a yield of 84.45%. Figure 1 synthetic route of Deferasirox

Pharmacological effects

DFS has antifungal activity (such as Mucor growing in the iron-rich environment), anti-cell proliferation, anti-malaria, anti-oxidative stress injury, anti-cytotoxicity induced apoptosis and other pharmacological effects. 1.? DFS and fungal infection Iron is a substance that fungi rely on, and plays a very important role in the growth and toxicity of fungi. The antifungal effect of iron chelator may be due to their effect of removal of the iron necessary for fungal growth, so as to achieve the purpose of treatment of fungal infection. 2. DFS and cell proliferation Iron plays a very important role in the process of cell proliferation. Iron chelators may have anti-proliferative properties, suggesting that iron chelators may be a novel anticancer agent for the treatment of tumors.

Pharmacokinetics

DFS is a tridentate iron chelator that binds ferric ions in a 2: 1 ratio to form complexes that are excreted from the feces, reducing the storage of iron in the body. As DFS persists in plasma, the plasma non-transferring binding iron can be continuously reduced, thus directly eliminating the iron toxicity formed in vivo. The main metabolic pathway of DFS is via glucuronidation for producing metabolites M3 (acylglucuronide) and M6 (2-O-glucuronide). Administration of large-dose DFS may present some acute adverse reactions, such as gastrointestinal symptoms (15%) and rash (11%). However, patients who finally discontinue the drug treatment due to these symptoms are rare.

Side effects

For patients with renal insufficiency, DFS can lead to increased creatinine levels with 38% of patients getting creatinine levels increased by 33% or more. But DFS-induced creatinine increase will generally not exceed the normal upper limit and there has not yet been progress in renal disease reported. After a reduction in DFS, creatinine levels returned to normal or remained stable in 13% of patients. <1% of patients can get hearing impairment (hearing loss, hearing reduction) and ocular diseases (lens opacities, cataracts, elevated intraocular pressure and retinopathy), and therefore it is recommended to participate into hearing and visual capability examination (including slit lamp examination and fundus examination)annually before and during the period of iron therapy, once found, it should be considered to disable DFS. Common side effects of deferasirox in Chinese patients with thalassemia include: rash, abdominal pain, diarrhea, and elevated transaminase level and serum creatinine level; mostly mild with no serious adverse reactions. Deferasirox can cause renal damage and gastrointestinal bleeding, and therefore it is recommended to detect 2 times of creatine clearance rates before the treatment; detect once per week during the initial stage of treatment, followed by once per month. Gastrointestinal bleeding is a common adverse reaction of this drug that can be fatal in older patients with advanced malignancies or thrombocytopenia, and these patients are unlikely to benefit from the treatment with this drug. Deferasirox may lead to serious adverse effects of liver failure. The patient must subject to regular monitoring of liver function during the medication process. If there is difficult to explain, persistent or progressive increase on the serum aminotransferase levels, we should adjust the usage or withdraw the drug.

Precautions

Patients with allergy to deferasirox are disabled.

Originator

Novartis (Switzerland)

Clinical Use

Treatment of iron overload

Synthesis

Synthesis of deferasirox started with cyclization of salicylamide (26) with salicyloyl chloride (27) by heating at 170 C without any solvents to give 2-(2-hydroxyphenyl)-benz[e]oxazin-4-one (28) in 55% yield. Compound 28 was reacted with 4-hydrazinobenzoic acid (29) in refluxing ethanol for 2 hours to give deferasirox V as colorless crystals.

Drug interactions

Potentially hazardous interactions with other drugsAluminium-containing antacids: avoid concomitant use.Aminophylline and theophylline: concentration of aminophylline and theophylline increased, consider reducing aminophylline and theophylline dose.Other nephrotoxic agents: avoid concomitant therapy

Metabolism

Metabolism of deferasirox is mainly glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) enzymes. Cytochrome P450 isoenzyme-mediated metabolism appears to be minor. Deconjugation of the glucuronidates in the intestine and subsequent enterohepatic recycling are likely to occur. It is excreted mainly in the faeces via bile, as metabolites and as unchanged drug. About 8% of a dose is excreted in the urine.

References

Heinz et al. (1999), 4-[3,5-Bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid: A Novel Efficient and Selective Iron(III) Complexing Agent; Ang. Chem. Int. Ed., 38 2568 Palumbo et al. (2021), From Biology to Clinical Practice: Iron Chelation Therapy With Deferasirox; Front. Oncol., 11 752192 Roatsch et al. (2019), The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases; ACS Chem. Biol., 14 1737 Lui et al. (2015), Targeting cancer by binding iron: Dissecting cellular signaling pathways; Oncotarget, 6 18748 Ibrahim and O’Sullivan (2020), Iron chelators in cancer therapy; Biometals, 33 201 Szymonik et al. (2021), The Impact of Iron Chelators on the Biology of Cancer Stem Cells; Int. J. Mol. Sci., 23 89

InChI:InChI=1/C21H15N3O4/c25-17-7-3-1-5-15(17)19-22-20(16-6-2-4-8-18(16)26)24(23-19)14-11-9-13(10-12-14)21(27)28/h1-12,25-26H,(H,27,28)

Upstream product

• 619-67-0 4-Hydrazinobenzoic acid 
• 65-45-2 salicylamide 
• 69-72-7 salicylic acid 
• 13316-79-5 O-Benzoylsalicylamide 
• 3084-52-4 2-phenyl-4H-1,3-benzoxazin-4-one 
• 98-88-4 benzoyl chloride 
• 21958-32-7 2-(2-hydroxyphenyl)-4H-benzo[d][1,3]oxazin-4-one 
• 1642597-22-5 1-benzyl-3,5-bis(2-methoxyphenyl)-1H-1,2,4-triazole 
• 106724-85-0 1-benzyl-3,5-dibromo-1H-[1,2,4]triazole 
• 1642597-21-4 methyl 4-(3,5-bis(2-methoxyphenyl)-1H-1,2,4-triazol-1-yl)benzoate 
• 1642597-20-3 methyl 4-(3,5-dibromo-1H-1,2,4-triazol-1-yl)-benzoate 
• 1642597-27-0 3,5-bis(2-methoxyphenyl)-1H-1,2,4-triazole 
• 99768-12-4 4-methoxycarbonylphenylboronic acid 
• 36850-04-1 o-trimethylsiloxybenzonitrile 

Downstream Products

• 1266741-01-8 deferasirox methylamine salt 
• 1266741-03-0 deferasirox n-butylamine salt 
• 1266741-02-9 deferasirox isopropylamine salt 
• 1266741-04-1 deferasirox dicyclohexylamine salt 
• 1266741-05-2 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid methyl ester 
• 1149568-62-6 DFOB-LDX 
• 201530-44-1 (4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)phenyl)(4-methylpiperazin-1-yl)methanone 
• 872005-50-0 4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoyl chloride 

Relevant articles and documents

Fabrication of deferasirox-decorated aptamer-targeted superparamagnetic iron oxide nanoparticles (SPION) as a therapeutic and magnetic resonance imaging agent in cancer therapy

In the current study, the synthesis of a theranostic platform composed of superparamagnetic iron oxide nanoparticles (SPION)-deferasirox conjugates targeted with AS1411 DNA aptamer was reported. In this regard, SPION was amine-functionalized by (3-aminopropyl)trimethoxysilane (ATPMS), and then deferasirox was covalently conjugated onto its surface. Finally, to provide guided drug delivery to cancerous tissue, AS1411 aptamer was conjugated to the complex of SPION-deferasirox. The cellular toxicity assay on CHO, C-26 and AGS cell lines verified higher cellular toxicity of targeted complex in comparison with non-targeted one. The evaluation of in vivo tumor growth inhibitory effect in C26 tumor-bearing mice illustrated that the aptamer-targeted complex significantly enhanced the therapeutic outcome in comparison with both non-targeted complex and free drug. The diagnostic capability of the prepared platform was also evaluated implementing C26-tumor-bearing mice. Obtained data confirmed higher tumor accumulation and higher tumor residence time for targeted complex through MRI imaging due to the existence of SPION as a contrast agent in the core of the prepared complex. The prepared multimodal theranostic system provides a safe and effective platform for fighting against cancer.

Deferasirox loaded on fumed silica nanoparticles used in cancer treatment

The present study has demonstrated a paradigm of successful in vitro drug delivery systems using Fumed Silica Nanoparticles (FSNPs) as a scaffold. The surface of FSNPs was first coated with (3-aminopropyl)trimethoxysilane (APTMS) by a silanization reaction and then was linked with deferasirox via the reaction between -NH2 and -COOH to form well-dispersed surface functionalized biocompatible FSNPs. The obtained nanoparticles were thoroughly characterized by various spectroscopic and microscopic methods such as Fourier Transform Infrared Spectroscopy (FT-IR), Thermo Gravimetric Analysis (TGA) and Brunauer, Emmett and Teller (BET) surface area analysis. The morphology of these structures was investigated by Scanning Electron Microscopy (SEM). The cytotoxicity of these compounds were screened for antitumor activity against MCF-7, MDA-MB-231, HeLa, HT-29, Neuro-2a, L929 cell lines and cisplatin was used as a comparative standard by a MTT assay. Our results presented herein provide experimental evidence that fumed silica nanoparticles loaded with deferasirox induce apoptosis in cancer cell lines. Our flow cytometry results confirm that the investigated compound showed a high population of apoptotic cells (55.20%) and 1.2-fold higher than cisplatin (45.15%) at the same concentration and could induce apoptosis of human breast cancer cell lines (MDA-MB-231).

4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid: A novel efficient and selective iron(III) complexing agent

An exceptionally stable 1:2 complex [FeL2]3- is formed from the ligand H3L and Fe(III). In contrast, the affinity of this ligand for other biometals is relatively small. These properties make H3L a highly promising candidate for medical applications (e.g. for the treatment of iron overload).

Deferasirox (ExJade): An FDA-Approved AIEgen Platform with Unique Photophysical Properties

Deferasirox, ExJade, is an FDA-approved iron chelator used for the treatment of iron overload. In this work, we report several fluorescent deferasirox derivatives that display unique photophysical properties, i.e., aggregation-induced emission (AIE), excited state intramolecular proton transfer, charge transfer, and through-bond and through-space conjugation characteristics in aqueous media. Functionalization of the phenol units on the deferasirox scaffold afforded the fluorescent responsive pro-chelator ExPhos, which enabled the detection of the disease-based biomarker alkaline phosphatase (ALP). The diagnostic potential of these deferasirox derivatives was supported by bacterial biofilm studies.

Industrialized production method of deferasirox

The invention discloses an industrialized production method of deferasirox. The industrialized production method includes the following steps that (1) 2-Cyanophenol reacts with acyl chloride or acid anhydride, and after the reaction is completed, an alcohol solution of hydrogen chloride is added to a reaction solution to obtain a compound IV; (2) the compound IV reacts with salicylic acid chlorideto obtain a compound VI; and (3) the compound VI reacts with p-hydrazinobenzoic acid or hydrochloride thereof to obtain deferasirox. According to the synthesis method, the problems of complicated operation, large pollution and potential safety hazards in existing methods are solved, the synthesis method adjusts starting materials for synthesis, so that the reaction conditions of an entire processroute are mild, hydrogen chloride gas is not need to be introduced in the reaction process, using of diethyl ether to wash intermediate products is not needed, using of palladium-carbon catalytic hydrogenation to remove corresponding substituents is not needed, the process is greatly simplified, the production cost and potential safety hazards are reduced, and large scale industrial production can be carried out.