137234-62-9 Usage
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 lookchem of Tian Ye.
Originator
Pfizer (UK)
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.
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.
Biochem/physiol Actions
Voriconazole is an antifungal used to treat serious fungal infections. Voriconazole inhibits ergosterol synthesis by inhibiting CYP450-dependent 14-α sterol demethylase resulting in a depletion of ergosterol in fungal cell membranes.
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.
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.
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%.
Metabolism
Voriconazole is metabolised by hepatic cytochrome P450
isoenzyme CYP2C19; the major metabolite is the inactive
N-oxide. Metabolism via isoenzymes CYP2C9 and
CYP3A4 has also been shown in vitro.
Voriconazole is eliminated via hepatic metabolism with
less than 2% of the dose excreted unchanged in the urine.
After administration of a radiolabelled dose of
voriconazole, approximately 80% of the radioactivity
is recovered in the urine as metabolites. The majority
(>94%) of the total radioactivity is excreted in the first 96
hours after both oral and intravenous dosing
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.
references
[1] sabo ja, abdel-rahman sm. voriconazole: a new triazole antifungal. ann pharmacother. 2000 sep;34(9):1032-43.[2] johnson lb, kauffman ca. voriconazole: a new triazole antifungal agent. clin infect dis. 2003 mar 1;36(5):630-7.
Check Digit Verification of cas no
The CAS Registry Mumber 137234-62-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,7,2,3 and 4 respectively; the second part has 2 digits, 6 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 137234-62:
(8*1)+(7*3)+(6*7)+(5*2)+(4*3)+(3*4)+(2*6)+(1*2)=119
119 % 10 = 9
So 137234-62-9 is a valid CAS Registry Number.
InChI:InChI=1/C16H14F3N5O/c1-10(15-14(19)5-20-7-22-15)16(25,6-24-9-21-8-23-24)12-3-2-11(17)4-13(12)18/h2-5,7-10,25H,6H2,1H3
137234-62-9Relevant articles and documents
Process development of voriconazole: A novel broad-spectrum triazole antifungal agent
Butters, Mike,Ebbs, Julie,Green, Stuart P.,MacRae, Julie,Morland, Matthew C.,Murtiashaw, Charles W.,Pettman, Alan J.
, p. 28 - 36 (2001)
In the synthesis of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1- yl)-2-butanol (voriconazole), the relative stereochemistry is set in the addition of a 4-(1-metalloethyl)-5-fluoropyrimidine derivative to 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-1-ethanone. The diastereo-control of this reaction has been examined by variation of pyrimidine substitution pattern and by changes in the metalation and reaction conditions. Excellent diastereoselection (12: 1) is obtained using an organozinc derivative of 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine. After removal of the chlorine from the pyrimidine ring, the absolute stereochemistry of voriconazole is established via a diastereomeric salt resolution process using (1R)-10-camphorsulfonic acid. Synthetic routes to the pyrimidine partner have also been evaluated. The initial six-step development route from 5-fluorouracil has been superseded by a four-step synthesis involving fluorination of methyl 3-oxopentanoate and cyclisation with formamidine acetate.
Voriconazole synthesis process
-
Paragraph 0078-0080, (2021/09/08)
The invention discloses a synthesis process of voriconazole bulk drug, which comprises the following steps: preparing halogenated ethyl fluorouracil and carrying out Grignard reaction. 2 - (2, 4 - Difluorophenyl) -3 - (1, 2, 4 - triazol -1 -yl) -1, 2 - propylene glycol was oxidized to give a propylene oxide compound. The Grignard reagent and the propylene oxide compound are mixed and reacted to obtain voriconazole. To the synthesis process, the reaction steps can be simplified, the dehydrochlorination and hydrogenolysis of palladium carbon are not needed, the reaction period is shortened, and furthermore, the energy consumption is reduced, the cost is reduced, and voriconazole and the racemate thereof are obtained with higher yield.
Voriconazole synthesis method
-
Paragraph 0011; 0048; 0076-0091, (2020/08/02)
The invention relates to a voriconazole synthesis method, which comprises: 1, carrying out catalytic hydrogenation on an SM, anhydrous methanol and anhydrous sodium acetate reaction system by using palladium carbon; after treatment, crystallization is performed to obtain a voriconazole racemate; 2, the voriconazole racemate, an acetone solvent and an L(-)-camphor-10-sulfonic acid system are subjected to a reflux reaction, crystallization and filtration are performed after the reaction is completed, voriconazole camphorsulfonate is obtained, and the molar ratio of L-camphorsulfonic acid to thevoriconazole racemate is 0.5:1; and 3, adjusting the pH value of the voriconazole camphor sulfonate, dichloromethane and water system to 10-11 by using a sodium hydroxide aqueous solution, layering, and temporarily storing an organic phase; extracting the water phase with dichloromethane; and merging the organic phases, carrying out reduced pressure distillation to remove the solvent, and carryingout post-treatment to obtain voriconazole.
Improved voriconazole racemate preparation method
-
, (2020/12/31)
The invention relates to an improved voriconazole racemate preparation method. The method comprises the following steps: (1) reacting 2 '4'-difluoro-2-[1- (1H-1, 2, 4-triazolyl)] acetophenone with 4-(1-bromoethyl)-5-fluoro-6-chloropyrimidine in the presence of zinc powder, lead powder and iodine to prepare R, S/S and R-1; (2) in the presence of a palladium-carbon catalyst and under a heating condition, taking R, S/S, R-1 or a salt thereof as a reaction substrate to react with ammonium formate in a reaction solvent to prepare a voriconazole racemate reaction solution; and filtering the reactionsolution, collecting a filtrate, carrying out concentrating, adding water, adjusting the pH value of the solution to 7-9, stirring, filtering, collecting a filter cake, and drying to obtain the product; and (3) splitting the voriconazole racemate by using 1R-(-)- camphorsulfonic acid to prepare the voriconazole. According to the preparation method, alkali degradation is avoided, and impurities are reduced; meanwhile, the preparation method does not need to treat R, S/S and R-1 hydrochloride, direct reaction can be carried out, meanwhile, post-treatment does not need operations such as extraction, and the preparation method has the advantages of being simple and convenient to operate, safe, controllable, high in reproducibility, high in product yield, high in purity, low in cost, suitablefor industrial production and the like.
Synthesis method of voriconazole and intermediate of voriconazole
-
Paragraph 0049; 0053-0058, (2020/02/14)
The invention relates to a synthesis method of voriconazole and an intermediate of voriconazole. The synthesis method comprises the following step: in a protective gas atmosphere, reacting a compoundshown in formula I and a compound shown in formula II in an organic solvent under the action of a metal catalyst, N-heterocyclic carbene, samarium diiodide and elemental iodine to obtain the voriconazole intermediate shown in formula III. According to the synthesis method of the voriconazole intermediate, under the action of the metal catalyst and SmI2, N-heterocyclic carbene is simultaneously added as a ligand, and elemental iodine is used as an initiator to initiate a reformask coupling reaction between the compound shown in formula I and the compound shown in formula II, so that the defectsof low yield, more byproducts and the like of the traditional reaction are overcome, and the yield and the purity are further improved.
A process for the preparation of key intermediates of Voriconazole
-
Paragraph 0046-0048, (2017/11/16)
The invention discloses a novel method for preparing a voriconazole key intermediate. The method comprises the following steps: catalyzing 1-(4-chloro-5-fluoropyridine-6-yl) halogenated ethane and 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl) ethanone by adopting a high-stereoselectivity chiral amino alcohol catalyst and a zinc-copper coupling agent, producing an asymmetric addition reaction to obtain (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyridine-4-yl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol, performing hydrogenation and dehalogenation to prepare a voriconazole key intermediate (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyridine-4-yl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol, and resolving to obtain the voriconazole. According to the method, the relatively economic and environment-friendly natural chiral amino alcohol catalyst is used; halogenated hydrocarbons and ketone are adopted to be subjected to the high-stereoselectivity asymmetric addition reaction, the process of preparing the halogenated hydrocarbons and active zinc into an organic zinc metal compound at first and then producing the asymmetric addition reaction between the compound and the ketone is removed, the operation is simplified, the production cost is reduced, and the industrialization is facilitated.
Method for synthesizing voriconazole
-
Paragraph 0043; 0044; 0045; 0046; 0047-0061; 0063-0083, (2017/08/29)
The invention provides a method for synthesizing voriconazole, belonging to the field of medicine synthesis. The method comprises the following steps: by taking an intermediate A as a raw material, performing catalytic reaction with potassium formate and palladium-charcoal in the presence of inert gas so as to obtain a crude product of voriconazole, and recrystallizing the crude product of voriconazole, thereby obtaining voriconazole. According to the method, potassium formate is adopted as a hydrogen source and palladium-charcoal is adopted as a catalyst, helium atoms on pyrimidine rings of the intermediate A are removed, and thus raceme of voriconazole can be obtained. According to the method, the quantity of byproducts is few, the product quality is high, the reaction condition is gentle, the process security is high and the method is applicable to industrial large-scale production.
A preparation method of Voriconazole
-
, (2017/08/25)
The invention relates to a preparation method for voriconazole. The preparation method comprises the following steps: 1) a compound A is reacted with D-camphor-10-sulfonyl chloride as shown in the description to obtain a compound B; 2) the compound B is brominated to obtain a compound C; 3) the compound C and a compound 5 are subjected to condensation to obtain a compound 6; 4) the compound is subjected to palladium-carbon catalytic hydrogenation to obtain the voriconazole. According to the prepared method, the synthesis method is simple, the three-dimensional selectivity is high, raw materials are easy to obtain, and the cost is low.
Preparation method of voriconazole
-
Paragraph 0024; 0025; 0028; 0029, (2017/08/28)
The invention discloses a preparation method of voriconazole, which includes the steps of: dissolving a compound B in a solvent, controlling the temperature of the reaction liquid to be -70 - 0 DEG C, stirring the reaction liquid, adding alkali with stirring and controlling the temperature of the reaction liquid to be -70 - 0 DEG C, stirring the reaction liquid, dropwise adding a mixed liquid of A and a solvent, and after the mixed liquid is added completely, controlling the temperature of the reaction liquid to be -70 - 0 DEG C to perform a reaction for 2-48 h to obtain the compound (1). In the process, a required chiral configuration is introduced from the raw material A, so that the method has high stereoselectivity and is free of chiral resolution in the subsequent steps. Qualified product can be produced only through a simple re-crystallization step, so that the method is suitable for industrial production.
Synthetic method of voriconazole intermediate
-
Paragraph 0061; 0062, (2016/10/20)
The invention provides a synthetic method of a novel voriconazole intermediate condensation compound shown as a formula II or an acid addition salt thereof. The voriconazole intermediate is prepared by compounds shown as a formula III and a formula IV, the feeding way is adjusted, the reaction condition is moderate and controllable, the generation of an impurity A is reduced, the impurity A is controlled within 0.74 percent, the use of toxic metal lead is avoided, and the danger caused by the residue of toxic metal in a drug is eliminated; and the product purity is higher, and the industrial application value is high.
