137234-62-9

Basic information

• Product Name: Voriconazole
• Synonyms: Voriconazole 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol;Voriconazole solution;(2R,3S)-2-(2,4-Difluorophenyl)-3;2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1,2,4-triazol-1-yl)butan-2-ol;2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1,2,4-triazol-1-yl)butan-2-ol;Voriconazole, >=98.5%;(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-((1H)-1,2,4-triazol-1-yl)-butan-2-;Voriconazole≥ 99.9% (HPLC, Dried basis)
• CAS NO: 137234-62-9
• Molecular Formula: C16H14F3N5O
• Molecular Weight: 349.31
• EINECS: 200-261-5
• Product Categories: Fine Chemical;antifungal;API;Antifungal (Systemic);Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Aromatics;Heterocycles;Pfizer compounds;Inhibitor;ZINACEF
• Mol File: 137234-62-9.mol
• Article Data: 35

Chemical Properties

• Melting Point: 127-130°C
• Boiling Point: 508.6 °C at 760 mmHg
• Flash Point: 9℃
• Appearance: cyrstalline solid
• Density: 1.42 g/cm³
• Vapor Pressure: 3.63E-11mmHg at 25°C
• Refractive Index: 1.616
• Storage Temp.: Store at +4°C
• Solubility: DMSO: >20mg/mL
• PKA: 11.54±0.29(Predicted)
• Merck: 14,10033
• CAS DataBase Reference: Voriconazole(CAS DataBase Reference)
• NIST Chemistry Reference: Voriconazole(137234-62-9)
• EPA Substance Registry System: Voriconazole(137234-62-9)

Safety Data

• 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
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• WGK Germany: 3
• RTECS: UV9145000
• HazardClass: 6.1
• PackingGroup: III
• Hazardous Substances Data: 137234-62-9(Hazardous Substances Data)

Usage

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 lookchem of Tian Ye.

Uses

Different sources of media describe the Uses of 137234-62-9 differently. You can refer to the following data:
1. broad-spectrum antifungal
2. An antifungal. An Ergosterol Biosynthesis inhibitor
3. An antifungal (systemic). An ergosterol biosynthesis inhibitor.
4. antibacterial
5. 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.

Chemical Properties

Cyrstalline Solid

Originator

Pfizer (UK)

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.

General Description

Voriconazole is a synthetically prepared, broad-spectrum triazole derivative of fluconazole, which shows in vitro activity against many yeasts and a broad-spectrum of mold and dermatophyte isolates. Its mode of action involves the inhibition of cytochrome P450 (CYP)-dependent enzyme, 14-α-sterol demethylase, and hence it is involved in disrupting the cell membrane and terminate the fungal growth.

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.

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

Synthetic route

(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)

Conditions	Yield
With sodium hydrogencarbonate In dichloromethane for 0.5h;	92%
With sodium hydrogencarbonate In water; ethyl acetate	90.47%
With sodium hydroxide In water at 45 - 55℃; for 2.5h; Product distribution / selectivity;	87.22%

(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol R-(-)-10-camphorsulfonate → voriconazole (137234-62-9)

Conditions	Yield
With sodium hydroxide In dichloromethane; water pH=11 - 12;	92%

voriconazole L-camphorsulfate → voriconazole (137234-62-9)

Conditions	Yield
With sodium hydrogencarbonate In dichloromethane for 0.5h;	92%
With sodium hydroxide In dichloromethane; water at 15 - 25℃; pH=10 - 11;

voriconazole L-camphor sulfonate → voriconazole (137234-62-9)

Conditions	Yield
With sodium hydrogencarbonate In dichloromethane for 0.5h;	90.8%
With sodium hydroxide In dichloromethane; water pH=12.3; Product distribution / selectivity; Alkaline aqueous solution; Industry scale;	72%
With sodium hydroxide In dichloromethane; water pH=11; Product distribution / selectivity; Alkaline aqueous solution;

C26H28F3N5O5S → voriconazole (137234-62-9)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In ethanol under 760.051 Torr;	86.3%

(2R,3S)-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1 yl)butan-2-ol (188416-38-8) → voriconazole (137234-62-9)

Conditions	Yield
With palladium 10% on activated carbon; potassium formate In ethanol; water at 30℃; for 1h; Temperature; Reagent/catalyst; Inert atmosphere;	84.9%
With palladium 10% on activated carbon; hydrogen; sodium acetate In water; toluene at -21 - 40℃; under 3750.38 Torr; for 22h;

(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 (848469-32-9) → voriconazole (137234-62-9)

Conditions	Yield
With sodium carbonate In dichloromethane; water at 20℃; for 0.333333h; pH=~ 10; Product distribution / selectivity;	76%
With sodium hydroxide In dichloromethane; water pH=11 - 12; Product distribution / selectivity;

(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol ((1R,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1yl)methanesulfonate → voriconazole (137234-62-9)

Conditions	Yield
With water In ethanol at 32.5℃; Concentration; Solvent; Temperature;	76%

2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butane-2-ol → voriconazole (137234-62-9)

Conditions	Yield
With [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid In methanol; acetone for 2h; Reflux;	43%
With (R)-10-camphorsulfonic acid In methanol; acetone at 0 - 5℃; Resolution of racemate;	40.1%
Multi-step reaction with 2 steps 1: acetone; methanol / 15 h / -20 - 25 °C 2: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme
Multi-step reaction with 2 steps 1: methanol; acetone / Reflux 2: sodium hydroxide / water; dichloromethane / pH 11 View Scheme

5-fluoro-4-vinylpyrimidine (1602485-93-7) + 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone (86404-63-9) → voriconazole (137234-62-9)

Conditions	Yield
With CuF(PPh3)3 methanol solvate; (R)-(−)-1-[(R)-2-(2′-diphenylphosphinophenyl)ferrocenyl]ethylbis(di-3,5-trifluoromethylphenyl)phosphine at 0℃; for 21.5h; Reagent/catalyst; Inert atmosphere;	40%

3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (188416-35-5) → voriconazole (137234-62-9)

Conditions	Yield
Stage #1: 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol With 5%-palladium/activated carbon; hydrogen; sodium acetate In methanol at 25℃; under 760.051 Torr; Stage #2: With [(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid In methanol; acetone for 2h; Reflux;	35%
Multi-step reaction with 3 steps 1.1: sodium acetate / ethyl acetate; water / 0.5 h / 25 - 30 °C 1.2: 25 - 30 °C / 3677.86 Torr 1.3: 0.5 h / 20 - 25 °C 2.1: acetone; methanol / 15 h / -20 - 25 °C 3.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme
Multi-step reaction with 4 steps 1.1: hydrogen; sodium acetate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 1.2: 0.5 h / 20 - 25 °C 1.3: 12.5 h / 25 - 30 °C 2.1: sodium hydroxide / dichloromethane; water / 0.5 h / pH 9 - 12 3.1: acetone; methanol / 15 h / -20 - 25 °C 4.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme
Multi-step reaction with 4 steps 1.1: hydrogen; sodium acetate; sodium carbonate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 1.2: 0.5 h / 20 - 25 °C 1.3: 10 - 25 °C 2.1: potassium carbonate / dichloromethane; water / 0.5 h / pH 8 - 10 3.1: acetone; methanol / 15 h / -20 - 25 °C 4.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme

1,2,4-Triazole (288-88-0) + 4-((S)-1-((R)-2-(2,4-difluorophenyl)oxirane-2-yl)ethyl)-5-fluoropyrimidine (1474024-68-4) → (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(4H-1,2,4-triazol-4-yl)butan-2-ol (1028563-65-6) + (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol + voriconazole (137234-62-9)

Conditions	Yield
In ethanol at 80℃; for 18h; Inert atmosphere;	A 27% B n/a C n/a

4-bromo-5-fluoro-pyrimidine (1003706-87-3) + (3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane → voriconazole (137234-62-9)

Conditions	Yield
In tetrahydrofuran at -70 - 30℃; for 25h; Temperature; Inert atmosphere;	26.3%

(3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl]oxirane + 2,4-dichloro-5-fluoropyrimidine (347418-42-2) → voriconazole (137234-62-9)

Conditions	Yield
In tetrahydrofuran at -70 - 30℃; for 25h; Temperature; Inert atmosphere;	20.7%

(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol → (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol + voriconazole (137234-62-9)

Conditions	Yield
With hydrogen; sodium acetate; palladium on activated charcoal In ethanol at 20℃;

2-fluoro-3-oxopentanoic acid ethyl ester (759-67-1) → voriconazole (137234-62-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1) MeONa, MeOH 2: POCl3 / Heating 3: LDA / tetrahydrofuran 4: H2, AcONa / Pd/C / ethanol / 20 °C View Scheme

6-Ethyl-5-fluoropyrimidin-4(3H)-one (137234-87-8) → voriconazole (137234-62-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: POCl3 / Heating 2: LDA / tetrahydrofuran 3: H2, AcONa / Pd/C / ethanol / 20 °C View Scheme

4-chloro-5-fluoro-6-ethylpyrimidine (137234-74-3) → voriconazole (137234-62-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: LDA / tetrahydrofuran 2: H2, AcONa / Pd/C / ethanol / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: sodium acetate / ethyl acetate; water / 0.5 h / 25 - 30 °C 2.2: 25 - 30 °C / 3677.86 Torr 2.3: 0.5 h / 20 - 25 °C 3.1: acetone; methanol / 15 h / -20 - 25 °C 4.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme
Multi-step reaction with 5 steps 1.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 1.2: 2 h / -80 - -55 °C 1.3: -70 - -10 °C 2.1: hydrogen; sodium acetate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 2.2: 0.5 h / 20 - 25 °C 2.3: 12.5 h / 25 - 30 °C 3.1: sodium hydroxide / dichloromethane; water / 0.5 h / pH 9 - 12 4.1: acetone; methanol / 15 h / -20 - 25 °C 5.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme

2-(2,4difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol-R(-)-10-camphor sulphonate (321589-01-9) → voriconazole (137234-62-9)

Conditions	Yield
With sodium hydroxide In dichloromethane; water at 25 - 35℃; pH=11 - 12; Alkaline conditions;

1-(4-chloro-5-fluoropyrimidin-6-yl)bromoethane (188416-28-6) + 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone (86404-63-9) → (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol + voriconazole (137234-62-9)

Conditions	Yield
Stage #1: 1-(4-chloro-5-fluoropyrimidin-6-yl)bromoethane; 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone With zinc(II) chloride; zinc In tetrahydrofuran at -5 - 5℃; for 1h; Stage #2: With ammonium formate; zinc In methanol at 20℃; for 16h; Stage #3: Product distribution / selectivity; Heating / reflux;

3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride → (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol + voriconazole (137234-62-9)

Conditions	Yield
With ammonium formate; zinc In methanol Product distribution / selectivity;

C10H16O4S*C16H14F3N5O → (2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol + voriconazole (137234-62-9)

Conditions	Yield
With sodium hydrogencarbonate In water; ethyl acetate at 20 - 25℃;

2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (182230-43-9) → voriconazole (137234-62-9)

Conditions	Yield
Stage #1: 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol With (R)-10-camphorsulfonic acid In methanol; acetone at 25 - 60℃; for 2h; Stage #2: With sodium hydroxide In dichloromethane; water; isopropyl alcohol at 20 - 30℃; pH=12 - 13; Product distribution / selectivity;
With (1S)-10-camphorsulfonic acid In methanol; acetone at 20 - 30℃; for 3.5h; Reflux;
Multi-step reaction with 2 steps 1: sodium hydroxide / water / 3 h / 45 °C 2: camphor-10-sulfonic acid / methanol; acetone View Scheme

C6H5FN2O (1289559-75-6) → voriconazole (137234-62-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate / ethanol / 5 h 2.1: triethylamine / dmap / dichloromethane / 20 - 30 °C 3.1: zinc; zinc(II) chloride / tetrahydrofuran / 0 - 30 °C 4.1: (R)-10-camphorsulfonic acid / acetone; methanol / 2 h / 25 - 60 °C 4.2: 20 - 30 °C / pH 12 - 13 View Scheme

1-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethanone (1289559-65-4) → voriconazole (137234-62-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogen; sodium acetate / palladium on activated carbon / ethanol / 25 °C 2.1: sodium tetrahydroborate / ethanol / 5 h 3.1: triethylamine / dmap / dichloromethane / 20 - 30 °C 4.1: zinc; zinc(II) chloride / tetrahydrofuran / 0 - 30 °C 5.1: (R)-10-camphorsulfonic acid / acetone; methanol / 2 h / 25 - 60 °C 5.2: 20 - 30 °C / pH 12 - 13 View Scheme

1-(5-fluoropyrimidin-4-yl)ethanol (1289559-66-5) → voriconazole (137234-62-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / dmap / dichloromethane / 20 - 30 °C 2.1: zinc; zinc(II) chloride / tetrahydrofuran / 0 - 30 °C 3.1: (R)-10-camphorsulfonic acid / acetone; methanol / 2 h / 25 - 60 °C 3.2: 20 - 30 °C / pH 12 - 13 View Scheme

2-chloro-1-(2,4-dichlorophenyl)ethanone (51336-94-8) → voriconazole (137234-62-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: potassium carbonate / tetrahydrofuran / 7 h / 20 °C 2: lead; zinc; iodine / tetrahydrofuran / -15 - 20 °C / Inert atmosphere 3: ammonium formate / palladium on carbon / toluene / 3 h / 80 °C 4: acetone; methanol / 1 h / Reflux 5: sodium hydrogencarbonate / dichloromethane / 0.5 h View Scheme
Multi-step reaction with 5 steps 1: potassium carbonate / tetrahydrofuran / 7 h / 20 °C 2: lead; zinc; iodine / tetrahydrofuran / 2 h / -15 - -10 °C / Inert atmosphere 3: ammonium formate / 10% palladium on charcoal / toluene / 3 h / 80 °C 4: acetone; methanol / 1 h / Reflux 5: sodium hydrogencarbonate / dichloromethane / 0.5 h View Scheme

6-ethyl-5-fluoro-4-hydroxypyrimidine (137234-87-8) → voriconazole (137234-62-9)

Conditions	Yield
Multi-step reaction with 6 steps 1: triethylamine / dichloromethane / 5 h / 20 °C 2: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / dichloromethane / 12 h / 45 - 50 °C 3: lead; zinc; iodine / tetrahydrofuran / -15 - 20 °C / Inert atmosphere 4: ammonium formate / palladium on carbon / toluene / 3 h / 80 °C 5: acetone; methanol / 1 h / Reflux 6: sodium hydrogencarbonate / dichloromethane / 0.5 h View Scheme
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane / 5 - 10 °C 1.2: 8 h / 10 - 55 °C / Reflux 1.3: 0.5 h / 15 - 20 °C 2.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 2.2: 2 h / -80 - -55 °C 2.3: -70 - -10 °C 3.1: sodium acetate / ethyl acetate; water / 0.5 h / 25 - 30 °C 3.2: 25 - 30 °C / 3677.86 Torr 3.3: 0.5 h / 20 - 25 °C 4.1: acetone; methanol / 15 h / -20 - 25 °C 5.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme
Multi-step reaction with 6 steps 1.1: triethylamine / dichloromethane / 5 - 10 °C 1.2: 8 h / 10 - 55 °C / Reflux 1.3: 0.5 h / 15 - 20 °C 2.1: diisopropylamine; n-butyllithium / n-heptane; hexane; tetrahydrofuran / 0.25 h / -80 - -70 °C / Inert atmosphere 2.2: 2 h / -80 - -55 °C 2.3: -70 - -10 °C 3.1: hydrogen; sodium acetate / palladium 10% on activated carbon / ethyl acetate; water / 25 - 30 °C / 3677.86 Torr 3.2: 0.5 h / 20 - 25 °C 3.3: 12.5 h / 25 - 30 °C 4.1: sodium hydroxide / dichloromethane; water / 0.5 h / pH 9 - 12 5.1: acetone; methanol / 15 h / -20 - 25 °C 6.1: sodium hydroxide / dichloromethane; water / 0.25 h / pH 11 - 14 View Scheme

6-ethyl-5-fluoropyrimidin-4-yl methanesulfonate (1237496-99-9) → voriconazole (137234-62-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / dichloromethane / 12 h / 45 - 50 °C 2: lead; zinc; iodine / tetrahydrofuran / -15 - 20 °C / Inert atmosphere 3: ammonium formate / palladium on carbon / toluene / 3 h / 80 °C 4: acetone; methanol / 1 h / Reflux 5: sodium hydrogencarbonate / dichloromethane / 0.5 h View Scheme
Multi-step reaction with 5 steps 1: 2,2'-azobis(isobutyronitrile); N-Bromosuccinimide / dichloromethane / 12 h / 45 - 50 °C 2: lead; zinc; iodine / tetrahydrofuran / 2 h / -15 - -10 °C / Inert atmosphere 3: ammonium formate / 10% palladium on charcoal / toluene / 3 h / 80 °C 4: acetone; methanol / 1 h / Reflux 5: sodium hydrogencarbonate / dichloromethane / 0.5 h View Scheme

4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoic acid (150994-82-4) + voriconazole (137234-62-9) → 4-((1,3-bis(octanoyloxy)propan-2-yl)oxy)-4-oxobutanoate 4-((2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)-5-fluoropyrimidin-1-ium

Conditions	Yield
In acetonitrile at 50℃; for 6h;	100%

(2E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoic acid + voriconazole (137234-62-9) → (2E)-4-((1,3-bis(dodecanoyloxy)propan-2-yl)oxy)-4-oxobut-2-enoate 4-((2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butan-2-yl)-5-fluoropyrimidin-1-ium

Conditions	Yield
In acetonitrile at 50℃; for 3h;	100%

voriconazole (137234-62-9) → voriconazole hydrochloride

Conditions	Yield
With hydrogenchloride In water at 20℃; for 1h;	100%

(2-chloro-6-fluorophenyl)methanol (56456-50-9) + voriconazole (137234-62-9) → Bis(2-chloro-6-fluorobenzyl) (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butyl phosphate (194798-93-1)

Conditions	Yield
With 1-methyl-1H-imidazole; anhydrous phosphorus trichloride; dihydrogen peroxide In dichloromethane; tert-butyl methyl ether; water	88%

voriconazole (137234-62-9) → C16H13F3N6O3 (1620283-07-9)

Conditions	Yield
With sulfuric acid; nitric acid at 20℃; for 3h;	88%
With sulfuric acid; nitric acid at 0 - 20℃; for 3h;	77%

C9H16ClNO5 + voriconazole (137234-62-9) → C20H22F3N6O4(1+)*I(1-)

Conditions	Yield
Stage #1: C9H16ClNO5; voriconazole With potassium iodide In acetonitrile for 15h; Reflux; Stage #2: With hydrogenchloride; water In methanol at 50 - 55℃; for 20h; Stage #3: In methanol; tert-butyl methyl ether at 10 - 65℃; for 18h;	87%

voriconazole (137234-62-9) → C16H14F3N5O*HNO3

Conditions	Yield
With nitric acid In methanol; water	86.62%

chloromethyl 2-methoxyethyl carbonate (432037-32-6) + voriconazole (137234-62-9) → C21H23F3N5O5(1+)*Cl(1-)

Conditions	Yield
In acetonitrile for 10h; Reflux;	85%

chloromethyl 2-methoxyethyl carbonate (432037-32-6) + voriconazole (137234-62-9) → C21H23F3N5O5(1+)*Cl(1-)

Conditions	Yield
In acetonitrile for 12h; Reflux;	80%

chloromethyl 2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethyl carbonate (431894-46-1) + voriconazole (137234-62-9) → C38H56F3N5O15(2+)*2Cl(1-)

Conditions	Yield
In acetonitrile for 14h; Reflux;	79%

voriconazole (137234-62-9) → voriconazole hydrochloride

Conditions	Yield
With hydrogenchloride In methanol; water	78.62%

isobutyric Acid (79-31-2) + voriconazole (137234-62-9) → (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-6-isopropylpyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol + (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-2,6-diisopropylpyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Conditions	Yield
With bis-[(trifluoroacetoxy)iodo]benzene; 9-mesityl-10-methylacridinium ion In acetonitrile at 20℃; Irradiation;	A 77% B 11%

trifluoroacetic acid (76-05-1) + voriconazole (137234-62-9) → (2R,3S)-2-(5-bromo-2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol trifluoroacetic acid

Conditions	Yield
With N-Bromosuccinimide for 16h; Inert atmosphere;	73%

potassium trifluoro(isopropenyl)borate(1-) + voriconazole (137234-62-9) → (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-6-isopropylpyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Conditions	Yield
With N,N,N,N-tetraethylammonium tetrafluoroborate; trifluoroacetic acid; 9-(2-mesityl)-10-methylacridinium perchlorate In water; acetonitrile at 20℃; for 10h; Inert atmosphere; Schlenk technique; Irradiation; regioselective reaction;	72%

C9H17ClN2O4 + voriconazole (137234-62-9) → C20H23F3N7O3(1+)*I(1-)

Conditions	Yield
Stage #1: C9H17ClN2O4; voriconazole With potassium iodide In acetonitrile for 15h; Reflux; Stage #2: With hydrogenchloride; water In methanol at 50 - 55℃; for 20h; Stage #3: In methanol; tert-butyl methyl ether at 10 - 65℃; for 15h;	70%

(1S)-10-camphorsulfonic acid (3144-16-9) + voriconazole (137234-62-9) → (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 (848469-32-9)

Conditions	Yield
In methanol; acetone at 30 - 50℃; for 1.33333h; Heating / reflux;	65%

C23H43ClN4O8 + voriconazole (137234-62-9) → C24H33F3N9O3(1+)*I(1-)

Conditions	Yield
Stage #1: C23H43ClN4O8; voriconazole With potassium iodide In acetonitrile for 15h; Reflux; Stage #2: With hydrogenchloride; water In methanol at 50 - 55℃; for 20h; Stage #3: In methanol; tert-butyl methyl ether at 10 - 65℃; for 18h;	65%

chloromethyl (2-methoxyethyl)carbamate (1402915-09-6) + voriconazole (137234-62-9) → C21H24F3N6O4(1+)*I(1-)

Conditions	Yield
Stage #1: chloromethyl (2-methoxyethyl)carbamate; voriconazole With potassium iodide In acetonitrile for 15h; Reflux; Stage #2: In methanol; tert-butyl methyl ether at 10 - 65℃; for 20h;	63%

voriconazole (137234-62-9) + Cyclohexanecarboxylic acid (98-89-5) → (2R,3S)-3-(6-cyclohexyl-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Conditions	Yield
With hydrogenchloride; cerium(III) chloride heptahydrate; tetrabutyl-ammonium chloride In 2,2,2-trifluoroethanol; water for 17h; Schlenk technique; Inert atmosphere; Electrochemical reaction; Irradiation;	60%

potassium trifluoro(isopropenyl)borate(1-) + trifluoroacetic acid (76-05-1) + voriconazole (137234-62-9) → (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-6-isopropylpyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol trifluoroacetic acid

Conditions	Yield
Stage #1: potassium trifluoro(isopropenyl)borate(1-); voriconazole With manganese triacetate; acetic acid In water at 50℃; for 18h; Inert atmosphere; Stage #2: trifluoroacetic acid In water; acetonitrile Inert atmosphere;	58%

silver perchlorate + voriconazole (137234-62-9) → Ag(1+)*ClO4(1-)*2C16H14F3N5O

Conditions	Yield
In ethanol; water	58%

Upstream product

• 188416-28-6 1-(4-chloro-5-fluoropyrimidin-6-yl)bromoethane 
• 86404-63-9 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone 
• 107-02-8 acrolein 
• 112-55-0 1-dodecylthiol 
• 759-67-1 2-fluoro-3-oxopentanoic acid ethyl ester 
• 137234-87-8 6-Ethyl-5-fluoropyrimidin-4(3H)-one 
• 137234-74-3 4-chloro-6-ethyl-5-fluoropyrimidine 
• 848469-32-9 (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 
• 188416-34-4 (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (1R)-10-camphorsulfonate 
• 182230-43-9 2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol 
• 1289559-75-6 C₆H₅FN₂O 
• 1289559-65-4 1-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethanone 
• 1289559-66-5 1-(5-fluoropyrimidin-4-yl)ethanol 
• 51336-94-8 2-chloro-1-(2,4-dichlorophenyl)ethanone 

Relevant articles and documents

Process development of voriconazole: A novel broad-spectrum triazole antifungal agent

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.

Improved voriconazole racemate preparation method

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.

Voriconazole synthesis method

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.