171228-49-2

Basic information

• Product Name: Posaconazole
• Synonyms: Pcz;Pos;Posconazole;4-{4-[4-(4-{[(3S,5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylMethyl)oxolan-3-yl]Methoxy}phenyl)piperazin-1-yl]phenyl}-1-[(2S,3S)-2-hydroxypentan-3-yl]-4,5-dihydro-1H-1,2,4-triazol-5-one;4-(4-(4-(4-(((3R,5R)-5-(3,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-yl)tetrahydrofuran-3-yl)Methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-1H-1,2,4-triazol-5(4H)-one;Pasaconazole;4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-Triazol-1-yl)Methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)Methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-1H-1,2,4-triazol-5(4H)-one;D-threo-Pentitol,2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]Methyl]-1-(1H-1,2,4-triazol-1-yl)-
• CAS NO: 171228-49-2
• Molecular Formula: C₃₇H₄₂F₂N₈O₄
• Molecular Weight: 700.78
• EINECS: 200-659-6
• Product Categories: API;Noxafil;Inhibitors;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;POSACONAZOLE ada@tuskwei.com
• Mol File: 171228-49-2.mol
• Article Data: 27

Chemical Properties

• Melting Point: 170-1720C
• Boiling Point: 850.7 °C at 760 mmHg
• Flash Point: 9℃
• Appearance: White solid
• Density: 1.36 g/cm³
• Vapor Pressure: 8.76E-31mmHg at 25°C
• Refractive Index: 1.657
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 14.72±0.20(Predicted)
• Merck: 14,7602
• CAS DataBase Reference: Posaconazole(CAS DataBase Reference)
• NIST Chemistry Reference: Posaconazole(171228-49-2)
• EPA Substance Registry System: Posaconazole(171228-49-2)

Safety Data

• Hazard Codes: F,T
• Statements: 11-23/24/25-39/23/24/25
• Safety Statements: 7-16-36/37-45
• RIDADR: UN1230 - class 3 - PG 2 - Methanol, solution
• WGK Germany: 3
• RTECS: XZ5481020
• Hazardous Substances Data: 171228-49-2(Hazardous Substances Data)

Usage

Description

Posaconazole, also known by its brand name Noxafil, is a triazole antifungal drug belonging to the azole class of antifungal agents. It is a white solid and is the newest member to reach the market. Posaconazole is indicated for the treatment and prophylaxis of a range of invasive fungal infections, including aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidiomycosis in patients who are refractory to, or intolerant of, standard therapy with amphotericin B and/or itraconazole. In the US, it is approved for the prophylaxis of invasive Aspergillus and Candida infections in patients aged 13 years and older who are at high risk of developing these infections due to being severely immunocompromised. Additionally, it is approved for the treatment of oropharyngeal candidiasis. Posaconazole has an expanded spectrum of activity over other members of the azole antifungals, demonstrating potent activity against refractory cases of aspergillosis and fluconazole-resistant Candida, as well as activity against Zygomycetes.

Uses

Used in Antifungal Treatments:
Posaconazole is used as an orally active triazole antifungal for the treatment and prophylaxis of various invasive fungal infections, such as aspergillosis, fusariosis, chromoblastomycosis, mycetoma, and coccidiomycosis, particularly in patients who are refractory to or intolerant of standard therapies.
Used in Invasive Fungal Infection Prophylaxis:
Posaconazole is used as a prophylactic agent for invasive Aspergillus and Candida infections in patients aged 13 years and older who are at high risk of developing these infections due to severe immunocompromise.
Used in Oropharyngeal Candidiasis Treatment:
Posaconazole is used as an antifungal agent for the treatment of oropharyngeal candidiasis.
Used in Antifungal Susceptibility Testing:
Posaconazole is used as a lanosterol 14α-demethylase (CYP51)-specific inhibitor in antifungal susceptibility testing of Aspergillus terreus to study its effects on membrane permeability in Candida albicans cells and its effects on promastigotes.
Used in Sterol C14α Demethylase Inhibition:
Posaconazole is used as a sterol C14α demethylase inhibitor with an IC50 of 0.25 nM, playing a crucial role in the inhibition of fungal cell membrane synthesis and growth.

Pharmacological effects

Posaconazole (posaconazole) is derived from itraconazole. It is currently subject to III phase clinical trials. Its pharmacological effects are similar with azoles, but compared with itraconazole, it has a stronger inhibitory effect on the C14 demethylation of steroid, especially for Aspergillus.

Pharmacokinetics

Studies on dosage and dosage protocol have shown that the rate of absorption and elimination rate is in line with the single-compartment model. There are significant differences on the relative bioavailability of different doses of oral suspension. It can be taken separately (every 12 hours or every 6 hours) which can significantly improve the bioavailability with the protein binding rate of 98% to 99%. With respect to tablets, the bioavailability of suspensions increase and food can significantly improve the speed and extent of absorption of drug absorption. An investigation of renal dysfunction on the pharmacokinetics of the drug study results has showed that the drug can’t be removed by hemodialysis without being affected by hemodialysis. Single-dose study has showed that patients with varying degrees of chronic kidney disease have no necessity for dosage adjustment. The Half-life of this is about 25 hours which can be primarily metabolized by the liver.

Pharmacokinetics

Cmax 200 mg oral: 0.5 mg/L after 4 h Plasma half-life: 35 h Volume of distribution: 1774 L Plasma protein binding: >98% Absorption Oral absorption is slow. Absorption from the gastrointestinal tract is improved if the drug is given with a high-fat meal. Blood concentrations increase in proportion to dosage up to 800 mg. Distribution It is extensively distributed into body tissues. Metabolism and excretion It is not as extensively metabolized by the hepatic cytochrome P450 system as other triazole antifungals. More than 70% of an administered dose is eliminated in the feces, predominantly as unchanged drug. The remainder is excreted as glucuronidated derivatives in the urine. Posaconazole is a substrate for intestinal P-glycoprotein,an adenosine triphosphate-dependent plasma membrane transporter responsible for drug efflux from cells. Multiple peaks in blood concentrations have been observed, suggesting that effluxed drug is reabsorbed into the systemic circulation.

Clinical indications and usage

It can be clinically used for the treatment of aspergillosis, zygnmycosis, and fusariumsis and can also be used for infection caused by part of fluconazole-resistant Candida genus. Studies have shown that posaconazole can widely and effectively applied to the treatment of phaeohyphomycosis and improve the infection survival rate of dermatitidis infection in a dose-dependent manner. The drug, as second-line drugs, has an effective rate of 44% to 78% against the invasive aspergillosis which is resistant to amphotericin B and itraconazole. It also has an effective rate of 71% against the zygomycete fungi. The drug is an oral suspension with the recommended dose of 200mg and 4 times per day with meals and taken orally for 7 to 10 days. This dose can also be maintained or changed to 400mg with oral administration of 2 times per day. The steady-state plasma concentration can reach within 7 to 10 days. The above information is edited by the lookchem of Dai Xiongfeng.

Originator

Schering-Plough (US)

Antimicrobial activity

The spectrum includes dimorphic fungi (Blast. dermatitidis, Coccidioides spp., Hist. capsulatum, Pen. marneffei, and Spor. schenckii), molds (Aspergillus spp., Mucor spp., Rhizomucor spp. and Rhizopus spp.), some dematiaceous fungi and yeasts (Candida spp. and Cryptococcus spp.).

Pharmaceutical Applications

A synthetic triazole available for oral administration.

Biochem/physiol Actions

Posaconazole is a highly potent broadspectrum antifungal agent against the yeast infection caused especially by Candida sp. It blocks the growth of fungi by inhibiting the enzyme?lanosterol?14α-demethylase (CYP51). In contrast to other antifungal azoles, posaconazole has been reported not to induce the efflux pump mechanism. Posaconazole exhibits antichagasic effects against different strains of Trypanosoma cruzi causing Chagas disease.

Clinical Use

Invasive aspergillosis Fusarium infection Chromoblastomycosis and mycetoma Coccidioidomycosis Oropharyngeal candidosis Prophylaxis of invasive fungal infections in patients at serious risk With the exception of oropharyngeal candidosis and prophylaxis, use is presently restricted to patients with disease that is refractory to other antifungal drugs, or who are intolerant to them.

Side effects

It is generally well tolerated even for long periods. Unwanted effects include gastrointestinal discomfort and mild to moderate, transient abnormalities of liver enzymes. Rare side effects include cholestasis and hepatic failure.

Synthesis

Several routes to the synthesis of posaconazole have been published in the literature. The most likely route to large scale synthesis uses convergent synthesis of a key chiral THF subunit 101 and aryl piperazine amine 102 followed by introduction of the triazole subunit at the end.The readily accessible allyl alcohol 94 was brominated (PBr3) to give bromide 95 which was alkylated with sodium diethylmalonate and the resulting diester was reduced with NaBH4/LiCl, to give the key diol 97 in very good yields. After scanning many hydrolases to desymmetrize the diol via selective acylation, hydrolase SP 435 was found to be suitable. Thus reaction of the diol 97 in the presence of SP 435 with vinyl acetate in acetonitrile gave monoacetate 98 in greater than 90% yield. Iodine mediated cyclization of the monoacetate 98 with iodine in dichloromethane gave chiral iodide 99 in 86% yield. The iodide was converted to triazole (sodiumtriazole, DMF: DMPU) and immediately followed by hydrolysis of the acetate with sodium hydroxide to provide alcohol 100. Activation of the alcohol to the pchlorobenzene sulfonate 101 proceeded in 76% yield which was then coupled with commercially available amino alcohol piperazine 102 with aqueous sodium hydroxide in DMSO to give amine intermediate 103 in 96% yield. The amine was reacted with benzoyl chloride to give benzoate 104 (97%), which was subsequently converted to triazine of posaconazole.For the preparation of chiral hydrazine 107, intermediate needed to make the triazolone, lactam 105 was reduced with Red-Al to give (S)-2-benzyloxy propanal 106 (94%) which was then reacted with formyl hydrazine to give hydrazone 107 in 81% yield. Addition of EtMgBr directly to formyl hydrozones 107 gave mixture of (S,S)stereoisomer 109 and (S,R)-diastereomer 110 in relative good diastereoselectivity (94:6) in 55% yield. However, protection of the formyl group as TBDMS ether 108 followed by treatment of the EtMgCl gave 95% yield of the (S,S)-diastereomer 109 and (S,R)-diastereomer 110 in 99:1 ratio.For finishing off the synthesis, the formyl hydrazine 109 was coupled with the phenyl carbamate 104 in toluene at 75 - 85°C for 12 – 24 hrs. After the completion of coupling, the intermediate was heated at 100 – 110°C for 24 – 48 hrs to completely cyclize to the benzyloxy triazolone 108, which was deprotected with 5% Pd/C and formic acid at room temperature overnight and 40°C for 24 h to give posaconazole (XV) in 80% overall yield.

Drug interactions

Potentially hazardous interactions with other drugs Analgesics: concentration of fentanyl possibly increased. Anti-arrhythmics: avoid concomitant use with dronedarone. Antibacterials: rifamycins may reduce posaconazole concentration; avoid unless benefit outweighs risk; rifabutin concentration increased. Anticoagulants: avoid with apixiban and rivaroxaban. Antidepressants: avoid concomitant use with reboxetine. Antidiabetics: posaconazole can decrease glucose concentrations, monitor glucose levels in diabetic patients; possibly enhances hypoglycaemic effect of glipizide. Antiepileptics: phenytoin, fosphenytoin, carbamazepine, phenobarbital and primidone may reduce posaconazole concentration - avoid unless benefit outweighs risk. Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol. Antipsychotics: increased risk of ventricular arrhythmias with pimozide - avoid; possibly increase quetiapine levels - reduce dose of quetiapine; possibly increases lurasidone concentration - avoid. Antivirals: concentration of atazanavir increased and possibly daclatasvir and simeprevir (reduce dose of daclatasvir, avoid with simeprevir); concentration reduced by efavirenz and possibly fosamprenavir; possibly increases saquinavir levels; increased risk of ventricular arrhythmias with telaprevir; concentration of both drugs increased with dasabuvir and paritaprevir - avoid. Anxiolytics and hypnotics: increases midazolam levels. Ciclosporin: increases posaconazole concentration; posaconazole can increase ciclosporin concentration - dose reduction may be required. Cytotoxics: concentration of bosutinib increased - avoid or reduce dose of bosutinib; possibly increased everolimus concentration - avoid; avoid with lapatinib; reduce dose of panobinostat and ruxolitinib; possibly inhibits metabolism of vinblastine and vincristine, increased risk of neurotoxicity. Ergot alkaloids: may increase ergot alkaloid concentration leading to ergotism - avoid. Guanfacine: possibly increases guanfacine concentration - halve guanfacine dose. Ivacaftor: possibly increased concentration of ivacaftor. Lipid-lowering drugs: avoid with lomitapide; possibly increased risk of myopathy with atorvastatin or simvastatin - avoid.1 Lumacaftor: posaconazole concentration possibly reduced - reduce dose of lumacaftor with ivacaftor. Ranolazine: possibly increased ranolazine concentration - avoid. Sirolimus: may increase concentration of sirolimus - adjust sirolimus dose as required according to levels. Sulphonylureas: posaconazole can decrease glucose concentrations, monitor glucose levels in diabetic patients. Tacrolimus: increases Cmax and AUC of tacrolimus by 121% and 358% respectively - reduce tacrolimus dose to about a third of current dose and adjust as required. Ulcer-healing drugs: cimetidine may reduce posaconazole concentration by 39% - avoid unless benefit outweighs risk; avoid with histamine H2- antagonists and proton pump inhibitors.

Metabolism

Limited metabolism, most circulating metabolites are glucuronide conjugates with only small amounts of oxidative metabolites. The main elimination route of posaconazole is via the faeces (77%) where 66% of a dose is excreted unchanged. About 14% of a dose is excreted in the urine with only trace amounts excreted unchanged.

references

[1] hanan k. munayyer, paul a. mann, andrew s. chau, taisa yarosh-tomaine, jonathan r. greene, roberta s. hare, larry heimark, robert e. palermo, david loebenberg and paul m. mcnicholas. posaconazole is a potent inhibitor of sterol 14α-demethylation in yeasts and molds. antimicrobial agents and chemotherapy. 2004; 48(10): 3690-3696[2] daryl s. schiller and horatio b. fung. posaconazole: an extended-spectrum triazole antifungal agent. clinical therapeutics. 2007; 29(9): 1862-1886

InChI:InChI=1/C37H42F2N8O4/c1-3-35(26(2)48)47-36(49)46(25-42-47)31-7-5-29(6-8-31)43-14-16-44(17-15-43)30-9-11-32(12-10-30)50-20-27-19-37(51-21-27,22-45-24-40-23-41-45)33-13-4-28(38)18-34(33)39/h4-13,18,23-27,35,48H,3,14-17,19-22H2,1-2H3/t26-,27?,35-,37-/m0/s1

Upstream product

• 170985-86-1 4-(4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-1-((2S,3S)-2-(benzyloxy)pentan-3-yl)-1H-1,2,4-triazol-5(4H)-one 
• 185961-30-2 2-((1S,2S)-2-Benzyloxymethoxy-1-ethyl-propyl)-4-[4-(4-{4-[(3R,5R)-5-(2,4-difluoro-phenyl)-5-[1,2,4]triazol-1-ylmethyl-tetrahydro-furan-3-ylmethoxy]-phenyl}-piperazin-1-yl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-one 
• 171228-61-8 (2S,3R)-2-Benzyloxymethoxy-pentan-3-ol 
• 170985-80-5 4-Bromo-benzenesulfonic acid (1R,2S)-2-benzyloxymethoxy-1-ethyl-propyl ester 
• 161532-56-5 4-[4-(4-{4-[(3R,5R)-5-(2,4-Difluoro-phenyl)-5-[1,2,4]triazol-1-ylmethyl-tetrahydro-furan-3-ylmethoxy]-phenyl}-piperazin-1-yl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-one 
• 106-41-2 4-bromo-phenol 
• 454479-36-8 1-[(2R,4R)-4-(4-Bromo-phenoxymethyl)-2-(2,4-difluoro-phenyl)-tetrahydro-furan-2-ylmethyl]-1H-[1,2,4]triazole 
• 454479-39-1 2-((1S,2S)-2-Benzyloxy-1-ethyl-propyl)-4-(4-piperazin-1-yl-phenyl)-2,4-dihydro-[1,2,4]triazol-3-one 
• 175712-02-4 ((3S,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl 4-chlorobenzenesulfonate 
• 221615-76-5 4-Hydroxy-butyric acid (1S,2S)-2-{4-[4-(4-{4-[(3R,5R)-5-(2,4-difluoro-phenyl)-5-[1,2,4]triazol-1-ylmethyl-tetrahydro-furan-3-ylmethoxy]-phenyl}-piperazin-1-yl)-phenyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}-1-methyl-butyl ester 
• 51336-94-8 2-chloro-1-(2,4-dichlorophenyl)ethanone 
• 74853-08-0 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine 
• 165115-73-1 2-[2-(2,4-difluorophenyl)-2-propene-1-yl]-1, 3-propanediol 
• 192448-07-0 2-methylpropanoic acid [(2S)-4-(2,4-difluorophenyl)-2-hydroxymethyl-4-penten-1-yl] ester 

Downstream Products

• 221615-79-8 4-Benzyloxy-butyric acid (1S,2S)-2-{4-[4-(4-{4-[(3R,5R)-5-(2,4-difluoro-phenyl)-5-[1,2,4]triazol-1-ylmethyl-tetrahydro-furan-3-ylmethoxy]-phenyl}-piperazin-1-yl)-phenyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}-1-methyl-butyl ester 
• 221615-80-1 C₄₁H₄₇BrF₂N₈O₅ 
• 1038994-53-4 C₄₁H₄₆F₂N₈O₈ 
• 1370642-06-0 C₄₅H₅₇F₂N₉O₆ 
• 1370642-04-8 C₄₀H₄₉F₂N₉O₄ 
• 200346-83-4 2,5,-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[1-[(1S,2S)-1-ethyl-2-[1-oxo-4-(phosphonooxy)butoxy]propyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1yl)-D-threopentitol 
• 221615-78-7 C₅₅H₆₁F₂N₈O₉P 
• 1488301-79-6 C₄₁H₄₆F₂N₈O₇ 

Relevant articles and documents

Thiourea modified polyacrylnitrile fibers as efficient Pd(II) scavengers

A series of thiourea modified fibers were prepared and characterized. The N-(2-aminoethyl)thiourea functionalized polyacrylonitrile fiber (AETU-PANF) was then evaluated for palladium absorption. The absorption process follows a pseudo-second-order model and the equilibrium data fit well to the Langmuir isotherm model. The maximum absorption capacity according to the Langmuir model was 169.2 mg g-1 with an absorption limit of 0.03 ppm. Wetted AETU-PANFs exhibited excellent absorption properties in organic solutions and the sorption rates were higher in organic solvents than in aqueous solutions. This is due to a special microenvironment that is formed inside the AETU-PANFs. The AETU-PANFs were also used to remove palladium from an organic solution containing active pharmaceutical ingredients. The Pd content was reduced from 310 ppm to 0.07 ppm.

Synthetic method of high-purity posaconazole

The invention discloses a synthetic method of high-purity posaconazole. The synthetic method comprises the following steps: S1, reacting a compound with a compound 2 to generate a compound 3; S2, removing anisole from the compound 3 under the action of hydrochloric acid to generate a compound required by the patent, namely posaconazole; and S3, carrying out primary refining on the obtained posaconazole crude product to obtain a medicinal high-purity posaconazole finished product.

Preparation method of posaconazole

The invention discloses a preparation method of posaconazole. According to the preparation method, in the presence of ammonium formate and a catalyst, in an organic solvent, a compound (I) carries outdebenzylation reactions to obtain a compound (A). The preparation method has the advantages of high yield, high purity, mild conditions, and simple operation.