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Voriconazole

Product description Pharmacological interactions Uses
Voriconazole
Voriconazole structure
CAS No.
137234-62-9
Chemical Name:
Voriconazole
Synonyms
UK-10949;UK-109496;Voricozole;Vorionazole;Voriconzole;VORICONAZOLE;Voriconsrole;Voriconazole RS;Voriconazole tab;Voriconazole USP
CBNumber:
CB1160110
Molecular Formula:
C16H14F3N5O
Formula Weight:
349.31
MOL File:
137234-62-9.mol

Voriconazole Properties

Melting point:
127-130°C
alpha 
D25 -62° (c = 1 in methanol)
Boiling point:
508.6±60.0 °C(Predicted)
Density 
1.42±0.1 g/cm3(Predicted)
Flash point:
9℃
storage temp. 
2-8°C
solubility 
DMSO: >20mg/mL
pka
11.54±0.29(Predicted)
form 
white powder
Merck 
14,10033
InChIKey
BCEHBSKCWLPMDN-MGPLVRAMSA-N
CAS DataBase Reference
137234-62-9(CAS DataBase Reference)
FDA UNII
JFU09I87TR
NCI Dictionary of Cancer Terms
voriconazole
NCI Drug Dictionary
voriconazole
ATC code
J02AC03
SAFETY
  • Risk and Safety Statements
Symbol(GHS) 
GHS02,GHS06,GHS08
Signal word  Danger
Hazard statements  H301-H351-H361-H373-H412-H225-H301+H311+H331-H370
Precautionary statements  P273-P281-P301+P310-P260-P280-P210-P311
Hazard Codes  Xn,T,F
Risk 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
RIDADR  UN1230 - class 3 - PG 2 - Methanol, solution
WGK Germany  3
RTECS  UV9145000
HazardClass  6.1
PackingGroup  III
HS Code  29335990

Voriconazole price More Price(14)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Sigma-Aldrich V-032 Voriconazole solution 2.0?mg/mL in methanol, ampule of 1?mL, certified reference material, Cerilliant? 137234-62-9 1 mL $103 2021-03-22 Buy
Sigma-Aldrich 32483 Voriconazole VETRANAL 137234-62-9 25mg $116 2021-03-22 Buy
Sigma-Aldrich Y0001395 Voriconazole European Pharmacopoeia (EP) Reference Standard 137234-62-9 $190 2021-03-22 Buy
Sigma-Aldrich 1718008 Voriconazole United States Pharmacopeia (USP) Reference Standard 137234-62-9 100mg $366 2021-03-22 Buy
TCI Chemical V0116 Voriconazole >98.0%(HPLC) 137234-62-9 100mg $22 2021-03-22 Buy

Voriconazole Chemical Properties,Uses,Production

Product description

Voriconazole is a broad-spectrum triazole antifungal ,it is primarily used for the treatment of progressive, possibly life-threatening infections in immune deficiency patients. Indications include: immunosuppressed patients with severe fungal infections, acute invasive aspergillosis (the most common pathogen is Aspergillus fumigatus, followed by A. flavus, Aspergillus niger and Aspergillus soil), severe invasive infections caused by fluconazole-resistant Candida (including C. krusei) severe infection caused by Foot actinomycetes bacteria genus and Fusarium bacteria genus . Moderate to severe renal insufficiency is administered intravenously paying caution.

Pharmacological interactions

Combination With the CYP3A4 substrates, terfenadine, sirolimus, astemizole, cisapride, pimozide or quinidine , can increase blood concentrations of this drug, leading to QT prolongation, and occasionally torsades de pointes ventricular tachycardia.
Combination With Rifampicin, rifabutin, efavirenz, ritonavir (each 400mg, once every 12 hours), carbamazepine and phenobarbital, can significantly lower blood concentrations of voriconazole.
Combination with ergot alkaloids (ergotamine, dihydroergotamine) plasma concentrations of ergot drugs can cause increased ergot poisoning.
The above information is edited by the chemicalbook of Tian Ye.

Uses

broad-spectrum antifungal

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.

Chemical Properties

Cyrstalline Solid

Originator

Pfizer (UK)

Uses

An antifungal. An Ergosterol Biosynthesis inhibitor

Uses

An antifungal (systemic). An ergosterol biosynthesis inhibitor.

Uses

antibacterial

Uses

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.

Definition

ChEBI: A triazole-based antifungal agent used for the treatment of esophageal candidiasis, invasive pulmonary aspergillosis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. It is an inhibitor of cytochr me P450 2C9 (CYP2C9) and CYP3A4.

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.

Manufacturing Process

A solution of 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H- 1,2,4-triazol-1-yl)butan-2-ol, enantiomeric pair B (0.307 g, 0.8 mmol) in ethanol (20 ml) was hydrogenated at atmospheric pressure and at room temperature in the presence of 10% palladium-on-charcoal (30 mg) and sodium acetate (0.082 g, 1 mmol). After 5 hours a further 10 mg of 10% palladium-on-charcoal was added and hydrogenation was continued for an additional 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. 'Flash' chromatography of the residue on silica using 97:3 ethyl acetate/methanol as the eluent provided, after combination and evaporation of appropriate fractions and trituration with diethyl ether, the 2- (2,4-difluorophenyI)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-I-yl)butan- 2-ol enantiomeric pair B, (0.249 g, 89%), m.p. 127°C.
2-(2,4-DifluorophenyI)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol enantiomeric pair A was prepared by a similar method using 3- (4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1- yl)butan-2-ol, enantiomeric pair A as a starting material. This gave the product with m.p. 137°C.

brand name

Vfend (Pfizer).

Therapeutic Function

Antifungal

Antimicrobial activity

The spectrum includes most fungi that cause human disease: dimorphic fungi (Blast. dermatitidis, Coccidioides spp., Hist. capsulatum, Paracocc. brasiliensis, Pen. marneffei and Spor. schenckii), molds (Aspergillus spp., Fusarium spp. and Scedosporium spp.), dematiaceous fungi and yeasts (Candida spp., Cryptococcus spp. and Trichosporon spp.).

Acquired resistance

Some fluconazole- and itraconazole-resistant strains of Candida and Aspergillus spp. show reduced susceptibility to voriconazole.

Pharmaceutical Applications

A synthetic triazole formulated for oral and parenteral use.

Biological Activity

Triazole antifungal agent. Displays potent activity against Candida , Cryptococcus and Aspergillus species.

Pharmacokinetics

Oral absorption: 96%
Cmax 400 mg oral: c. 2 mg/L after 2 h
Plasma half-life: c. 6 h
Volume of distribution: 4.6 L/kg
Plasma protein binding: 58%
Absorption
Oral absorption is rapid and almost complete, and is unaffected by intragastric pH. In adults, there is a disproportionate increase in blood concentrations with increasing oral and parenteral dosage, due to partial saturation of first-pass metabolism. In children given low dosages of the drug, proportional changes in drug levels are seen.
Distribution
It is widely distributed into body tissues and fluids, including brain and CSF.
Metabolism and excretion
It is extensively metabolized by the liver. More than 80% of a dose appears in the urine, but less than 2% is excreted in unchanged form. It is metabolized by several different hepatic cytochrome P450 enzymes. Some people with point mutations in the genes encoding these enzymes are poor metabolizers while others are extensive metabolizers. Drug levels are as much as four-fold lower in individuals who metabolize the drug more extensively.

Clinical Use

Acute and chronic invasive aspergillosis
Serious invasive Candida infections
Serious infections caused by Scedosporium and Fusarium spp.

Side effects

Unwanted effects include mild to moderate visual disturbance, rashes, and transient abnormalities of liver enzymes. Rare side effects include life-threatening hepatitis.

Chemical Synthesis

The synthesis of voriconazole is an excellent example of process research. As depicted in the scheme, 5-fluorouracil (229) was chlorinated in both the 2- and 4- positions using a mixture of phosphorus oxychloride and N,N-dimethylaniline at 95° C to afford 230 in 95% yield. Dichloro pyrimidine 230 was reacted with ethyl magnesium bromide to give dihydropyrimidine adduct 231. Adduct 231 was oxidized prior to quenching using a mixture of iodine and TEA in THF to give 2,4-dichloro-6-ethyl-5-fluoro pyrimidine (232) in 75% yield. Reaction of 232 with two equiv of aqueous NaOH at reflux gave selective displacement of the chloro functionality at 4-position. Acidification of the reaction and extraction with DCM gave 2-chloro-6-ethyl-5-fluoro-4(3H)- pyrimidine which was conveniently isolated as its ammonia salt 233. Dechlorination of 233 was achieved using catalytic hydrogenation at 50℃ to provide 234 in 80% yield. Alternatively, 4-fluoro-6-ethyl-5-fluoropyrimidine (234) was prepared in a two-pot process in which methyl 3- oxopentanoate (235) was fluorinated with fluorine gas to give methyl 2-fluoro-3-oxopentanoate (236) in 80-90% yield. This ester was then cyclized with formamidine acetate in the presence of NaOMe to give 234 in a moderate yield (50-70%). Reaction of 234 with phosphorus oxychloride and TEA afforded 4-chloro-6-methyl-5- fluoropyrimidine (237) in 90% yield. Reaction of 237 with NBS in the presence of AIBN initiator provided bromide 238 in 95% yield. A Reformatsky protocol was employed in the condensation of 238 with ketone 239 which was an intermediate in the commercial synthesis of Diflucan. A solution of iodine in THF was added to a slurry of zinc and lead at rt and then a mixture of bromide 238 and ketone 239 were added to the above mixture at 5°C for 30 min. This provided the best diastereomeric selectivity and the ratio of 241 and 240 enantiomeric pair reached approximately 10 to 1. Adduct 241 was de-chlorinated using standard hydrogenation condition (5% w/w Pd on carbon /15 psi hydrogen) to give the racemate of voriconazole. The racemic voriconazole was resolved using (1R)-10-camphorsulfonic acid (242) and crystallization of the required diastereomeric salt provided optically pure voriconazole (28) in 80% yield.

Veterinary Drugs and Treatments

Voriconazole may be a useful treatment for a variety of fungal infections in veterinary patients, particularly against Blastomyces, Cryptococcus, and Aspergillus. It has high oral bioavailability in a variety of species and can cross into the CNS. Currently available human dosage forms are extremely expensive, however, and little clinical experience has occurred using voriconazole in veterinary patients. There is considerable interest in using voriconazole for treating aspergillosis in pet birds as their relative small size may allow the drug to be affordable; additional research must be performed before dosing regimens are available.

Precautions

Significant drug interactions include cyclosporins(increased cyclosporine levels), phenytoin, rifampin,and rifabutin (decreased voriconazole levels). Becauseof its low toxicity profile, this drug may gain importancein the chronic treatment of infections with invasive dimorphicfungi and resistant Candida spp.

Voriconazole Preparation Products And Raw materials

Raw materials

Preparation Products


Voriconazole Suppliers

Global( 497)Suppliers
Supplier Tel Fax Email Country ProdList Advantage
HubeiwidelychemicaltechnologyCo.,Ltd
18627774460
faith@widelychemical.com CHINA 743 58
Joyochem Co.,Ltd
+8613290333633 +86-0531-82687558
0531-82687996 sales@joyochem.com;sales@jychem.cc China 28 58
Capot Chemical Co.,Ltd.
+86(0)13336195806 +86-571-85586718
+86-571-85864795 sales@capotchem.com China 20012 60
Beijing Cooperate Pharmaceutical Co.,Ltd
010-60279497
010-60279497 sales01@cooperate-pharm.com CHINA 1817 55
Henan Tianfu Chemical Co.,Ltd.
0371-55170693
0371-55170693 info@tianfuchem.com CHINA 22607 55
Hangzhou FandaChem Co.,Ltd.
008615858145714
+86-571-56059825 fandachem@gmail.com CHINA 8909 55
Nanjing ChemLin Chemical Industry Co., Ltd.
025-83697070
product@chemlin.com.cn CHINA 3013 60
Hubei XinRunde Chemical Co., Ltd.
+8615102730682
02783214688 bruce@xrdchem.cn CHINA 567 55
Shanxi Naipu Import and Export Co.,Ltd
+8613734021967
kaia@neputrading.com CHINA 1009 58
Shanghai Zheyan Biotech Co., Ltd.
18017610038
zheyansh@163.com CHINA 3623 58

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View Lastest Price from Voriconazole manufacturers

Image Release date Product Price Min. Order Purity Supply Ability Manufacturer
2021-11-26 Voriconazole
137234-62-9
US $3016.00 / KG 100g/Bag 99% 1000KG Baoji Guokang Bio-Technology Co., Ltd.
2021-11-08 Voriconazole
137234-62-9
US $20.00 / KG 100g 99 20tons Wuhan wingroup Pharmaceutical Co., Ltd
2021-11-02 Voriconazole
137234-62-9
US $234.00 / g 50g 99% 1000KG Baoji Guokang Healthchem co.,ltd

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