Voriconazole

Base Information

• Chemical Name: Voriconazole
• CAS No.: 137234-62-9
• Deprecated CAS: 173967-54-9
• Molecular Formula: C16H14F3N5O
• Molecular Weight: 349.315
• Hs Code.: 29335990
• European Community (EC) Number: 629-701-5,941-833-8
• NSC Number: 759888
• UNII: JFU09I87TR,USG4B1CD29
• DSSTox Substance ID: DTXSID5046485,DTXSID201019420
• Nikkaji Number: J709.476K
• Wikipedia: Voriconazole
• Wikidata: Q412236
• NCI Thesaurus Code: C1707
• RXCUI: 121243
• Pharos Ligand ID: RMWVQW96R8LU
• Metabolomics Workbench ID: 42913
• ChEMBL ID: CHEMBL638
• Mol file: 137234-62-9.mol

Synonyms:UK 109,496;UK 109496;UK-109,496;UK-109496;UK109,496;UK109496;Vfend;voriconazole

Chemical Property of Voriconazole

Chemical Property:

• Appearance/Colour: cyrstalline solid
• Vapor Pressure: 3.63E-11mmHg at 25°C
• Melting Point: 127-130 °C
• Refractive Index: 1.616
• Boiling Point: 508.6 °C at 760 mmHg
• PKA: 11.54±0.29(Predicted)
• Flash Point: 261.4 °C
• PSA: 76.72000
• Density: 1.42 g/cm³
• LogP: 2.17690
• Storage Temp.: Store at +4°C
• Solubility.: DMSO: >20mg/mL
• XLogP3: 1.5
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 8
• Rotatable Bond Count: 5
• Exact Mass: 349.11504457
• Heavy Atom Count: 25
• Complexity: 448

Purity/Quality:

99%min ^*data from raw suppliers

Voriconazole ≥99%(HPLC) ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xn
• Hazard Codes: Xn,T,F
• Statements: 22-36/38-52/53-48/22-40-25-61-39/23/24/25-23/24/25-11
• Safety Statements: 26-36-45-36/37-22-53-16

MSDS Files:

SDS file from LookChem

Total 1 MSDS from other Authors

Useful:

• Drug Classes: Antifungal Agents
• Canonical SMILES: CC(C1=NC=NC=C1F)C(CN2C=NC=N2)(C3=C(C=C(C=C3)F)F)O
• Isomeric SMILES: C[C@@H](C1=NC=NC=C1F)[C@](CN2C=NC=N2)(C3=C(C=C(C=C3)F)F)O
• Recent ClinicalTrials: A Pilot of Pediatric/Adult Study of Gene Expression Profiling and Clinical Characterization of Phototoxicity
• Recent EU Clinical Trials: A Phase 3, Multicenter, Prospective, Randomized, Double-blind Study of Two Treatment Regimens for Candidemia and/or Invasive Candidiasis: Intravenous Echinocandin followed by Oral Ibrexafungerp versus Intravenous Echinocandin followed by Oral Fluconazole (MARIO)
• Recent NIPH Clinical Trials: A phase 3, multi-center, open label study to evaluate safety and efficacy of AK1820 for treatment of adult Japanese patients with deep mycosis.
• Uses: broad-spectrum antifungal An antifungal. An Ergosterol Biosynthesis inhibitor An antifungal (systemic). An ergosterol biosynthesis inhibitor. antibacterial Voriconazole is a triazole, antifungal agent that inhibits a broad range of pathogenic yeasts, including Candida (MIC = 0.03-8 μg/ml), and filamentous fungi such as Aspergillus, Scedosporium, and Fusarium. Its inhibitory action results from its ability to inhibit the synthesis of ergosterol, the major sterol of the fungal cell membrane.
• Description: Voriconazole was introduced in the US for the treatment of acute invasive aspergillosis, candidosis and other emerging fungal infections seen in immuno compromised patients. It can be synthesized in 3 steps by reaction of readily available 6-( 1 -bromoethyl)-4-chloro-5 fluoropyrimidine with I-(2,4-difluorophenyl)-2-(1,2,4-triazol-I-yl) ethanone in the presence of zinc metal. The resulting racemic mixture was submitted to a reductive dechlorination step followed by resolution with (R)-camphorsulfonic acid. Voriconazole is structurally related to fluconazole (Pfizer, diflucan?) and acts by inhibiting the cytochrome P450- dependant enzyme 14a-sterol demethylase of ergosterol synthesis (thereby resulting in the formation of a cell membrane with abnormal characteristics and accumulation of toxic sterol intermediates). Voriconazole was more active than itraconazole and fluconazole against Cryptococcus neoformans and a variety of Candidas species such as C. albicans, C. glabrata C. krusei. It also exhibits similar or superior activity compared to amphotericin B and itraconazole against filamentous fungi such as Aspergillus, an important pathogen which is not susceptible to fluconazole. In clinical trials, voriconazole was effective in the treatment of neutropenic patients with acute invasive aspergillosis, non-neutropenic patients with chronic invasive aspergillosis and HIV patients with oropharyngeal candidiasis. Voriconazole is available as oral or intravenous formulations. Following oral administration, absorption is rapid and the bioavailability is greater than 80%. Voriconazole exhibits non linear pharmacokinetics, a large volume of distribution (2 L/Kg) and a relatively short half-life (6 h). It was extensively metabolized via hepatic cytochrome P450 and has a drug interactions potential similar to itraconazole. Voriconazole was generally well tolerated, the most common treatment-related adverse events were transient visual disturbances.
• Indications: Voriconazole (Vfend), a derivative of fluconazole, is a second-generation triazole that has improved antifungal activity against Aspergillus and Fusarium spp., P. boydii, Penicillium marneffei, and fluconazole-resistant Candida spp. Like fluconazole, voriconazole has high oral bioavailability and good cerebrospinal fluid penetration, but unlike fluconazole, it undergoes extensive hepatic metabolism and is highly protein bound. No significant amount of bioactive drug is excreted into the urine. Dosage reduction is necessary with severe hepatic insufficiency but not with renal insufficiency.
• Therapeutic Function: Antifungal
• Clinical Use: Acute and chronic invasive aspergillosis Serious invasive Candida infections Serious infections caused by Scedosporium and Fusarium spp.
• Drug interactions: Potentially hazardous interactions with other drugs Analgesics: concentration of diclofenac, ibuprofen, alfentanil, methadone and oxycodone increased, consider reducing alfentanil and methadone dose; concentration of fentanyl possibly increased. Anti-arrhythmics: avoid with dronedarone. Antibacterials: concentration reduced by rifabutin; increase dose of voriconazole from 200 to 350 mg and from 100 to 200 mg (depends on patient’s weight), and increase IV dose to 5 mg/kg if used in combination - avoid concomitant use if possible; increased rifabutin levels - monitor for toxicity; concentration reduced by rifampicin - avoid. Anticoagulants: avoid with apixiban and rivaroxaban; enhanced effect of coumarins. Antidepressants: avoid concomitant use with reboxetine; concentration reduced by St John’s wort - avoid. Antidiabetics: possibly increased concentration of sulphonylureas. Antiepileptics: concentration possibly reduced by carbamazepine, phenobarbital and primidone - avoid; fosphenytoin and phenytoin reduces voriconazole concentration and voriconazole increases fosphenytoin and phenytoin concentration - double oral voriconazole dose and increase IV to 5 mg/kg dose if using with phenytoin; avoid if possible. Antimalarials: avoid concomitant use with artemether/lumefantrine and piperaquine with artenimol. Antipsychotics: concentration of lurasidone increased - avoid concomitant use; increased risk of ventricular arrhythmias with pimozide - avoid concomitant use; possibly increased quetiapine levels - avoid concomitant use. Antivirals: concentration increased or decreased by atazanavir and concentration of atazanavir reduced; concentration of daclatasvir possibly increased - reduce daclatasvir dose; concentration possibly affected by darunavir; concentration reduced by efavirenz and ritonavir; also concentration of efavirenz increased - avoid with ritonavir; with efavirenz reduce dose by 50% and increase dose of voriconazole to 400 mg twice daily; concentration possibly increased by simeprevir - avoid; concentration possibly affected by telaprevir - increased risk of ventricular arrhythmias; possibly increased saquinavir levels; concentration of simeprevir possibly increased - avoid. Avanafil: possibly increased avanafil concentration - avoid. Benzodiazepines: may inhibit metabolism of diazepam and midazolam. Ciclosporin: AUC increased - reduce ciclosporin dose by 50% and monitor closely. Clopidogrel: possibly reduced antiplatelet effect. Cytotoxics: possibly increases bosutinib concentration - avoid or reduce dose of bosutinib; possibly increases crizotinib and everolimus concentration - avoid; possibly increases ibrutinib, pazopanib and ponatinib concentration - reduce dose of ibrutinib, pazopanib and ponatinib; avoid with ceritinib, lapatinib, nilotinib, cabazitaxel and docetaxel (or reduce dose of cabazitaxel, ceritinib and docetaxel); reduce dose of panobinostat and ruxolitinib. Domperidone: possible increased risk of arrhythmias - avoid. Ergot alkaloids: risk of ergotism - avoid. Ivacaftor and lumacaftor: possibly increase ivacaftor concentration - reduce dose of ivacaftor and ivacaftor with lumacaftor. Lipid-lowering drugs: possibly increased risk of myopathy with atorvastatin or simvastatin; avoid with lomitapide. Ranolazine: possibly increased ranolazine concentration - avoid. Retinoids: possibly increased risk of tretinoin toxicity. Sirolimus: increased sirolimus concentration - avoid. Tacrolimus: AUC increased - reduce tacrolimus dose to a third and monitor closely. Ulcer-healing drugs: esomeprazole and omeprazole concentration increased - reduce omeprazole dose by 50%.

Technology Process of Voriconazole

There total 71 articles about Voriconazole 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: 92.0%

2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol (137234-63-0,173967-54-9,188416-29-7) → voriconazole (137234-62-9,137234-63-0,173967-54-9,188416-29-7)

Guidance literature:

2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol; With (1S)-10-camphorsulfonic acid; In methanol; acetone; for 1h; Reflux;

With sodium hydroxide; In dichloromethane; water; pH=11 - 12;

Reference yield: 92.0%

(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1R)-10-camphorsulfonate (188416-34-4,137234-71-0) → voriconazole (137234-62-9,137234-63-0,173967-54-9,188416-29-7)

Guidance literature:

With sodium hydrogencarbonate; In dichloromethane; for 0.5h;

Reference yield: 92.0%

voriconazole L-camphorsulfate → voriconazole (137234-62-9,137234-63-0,173967-54-9,188416-29-7)

Guidance literature:

With sodium hydrogencarbonate; In dichloromethane; for 0.5h;

upstream raw materials:

2-fluoro-3-oxopentanoic acid ethyl ester

6-Ethyl-5-fluoropyrimidin-4(3H)-one

4-chloro-6-ethyl-5-fluoropyrimidine

(2R,3S)-2-(2,4-diflurophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl)butan-2-ol R-(-)-10-camphor sulphonate salt

Downstream raw materials:

(2R,3S)-2-(2,4-diflurophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1yl)butan-2-ol R-(-)-10-camphor sulphonate salt

C₁₆H₁₄F₃N₅O*C₇H₆O₃

C₁₆H₁₄F₃N₅O*C₇H₇NO₂

C₁₆H₁₄F₃N₅O*C₇H₅NO₄

Refernces

• 1、 -. "Voriconazole synthesis process". Paragraph 0078-0080. . Retrieved 2021/09/08.
• 2、 -. "Synthesis method of voriconazole and intermediate of voriconazole". Paragraph 0049; 0053-0058. . Retrieved 2020/02/14.