Spherazole

Base Information

• Chemical Name: Spherazole
• CAS No.: 84625-61-6
• Deprecated CAS: 84604-65-9
• Molecular Formula: C35H38Cl2N8O4
• Molecular Weight: 705.644
• Hs Code.: 2934990002
• Nikkaji Number: J930.335I
• Wikipedia: Itraconazole
• Wikidata: Q104400456
• NCI Thesaurus Code: C1138
• RXCUI: 28031
• ChEMBL ID: CHEMBL882
• Mol file: 84625-61-6.mol

Synonyms:Itraconazole;Orungal;R 51211;R-51211;R51211;Sporanox

Chemical Property of Spherazole

Chemical Property:

• Appearance/Colour: off-white crystalline solid
• Melting Point: 166 ºC
• Boiling Point: 850 ºC at 760 mmHg
• PKA: 3.7(at 25℃)
• Flash Point: 467.9 ºC
• PSA: 104.70000
• Density: 1.4 g/cm³
• LogP: 5.70730
• Storage Temp.: 2-8°C
• Solubility.: chloroform: 50 mg/mL, clear, colorless
• Water Solubility.: Insoluble in water. Solube in chloroform at 50 mg/ml. Slightly soluble in ethanol or methanol
• XLogP3: 5.7
• Hydrogen Bond Donor Count: 0
• Hydrogen Bond Acceptor Count: 9
• Rotatable Bond Count: 11
• Exact Mass: 704.2393071
• Heavy Atom Count: 49
• Complexity: 1120

Purity/Quality:

above 98.5% ^*data from raw suppliers

Itraconazole-d3 ^*data from reagent suppliers

Safty Information:

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

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antifungal Agents
• Canonical SMILES: CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl
• Isomeric SMILES: CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OC[C@@H]5CO[C@@](O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl
• Recent ClinicalTrials: A Study in Healthy Men to Test How Itraconazole Influences the Amount of BI 1815368 in the Blood
• Recent EU Clinical Trials: Signal TrAnsduction Pathway activity analysis for OVarian cancER treatment. STAPOVER study
• Recent NIPH Clinical Trials: Clinical pharmacology study to evaluate the drug-drug interactions of TAS-115 in healthy subjects
• Uses: The imidazole antifungal agents for the triazole ring, through inhibiting the activation of cytochrome P-450, including oxidase and peroxidase, disable the 14, α-methyl sterols to be dehydrogenated and be converted to ergosterol, so that the growth and proliferation of fungi are inhibited. They have strong lipophilicity and penetrate through the biofilm to inhibit the binding of the membrane to the fungus. The antibacterial spectrum is similar to ketoconazole. It is effective in the treatment of superficial fungal diseases such as vaginal and oral candidiasis as well as skin mycosis. Furthermore, it is expected to become the highly-efficient and safe drugs for the treatment of deep fungal infections such as cryptococcal encephalitis (AIDS). It is used for the treatment of vulvovaginal candidiasis, pityriasis and skin fungal disease pityriasis caused by sensitive fungi. It can be used for the synthesis of broad-spectrum azole antifungal agents for the treatment of systemic infection caused by deep fungus. It can also be used for the treatment of candidiasis and aspergillosis. An orally active antimycotic structurally related to Ketoconazole. Antifungal vitamin, enzyme cofactor Anti Fungal. Used in the treatment of stomach upset/ indigestion and other gastrointestinal conditions For the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis. A traizole antifungal agent Itraconazole is a triazole antifungal agent. It is used to inhibit cytochrome P-450-dependent enzymes and ergosterol synthesis. It has been used against histoplasmosis, blastomycosis, cryptococcal meningitis, and aspergillosis. It?s different formulations are used to study Candida strains in murine invasive infections. It has been used to study proliferative changes of the forestomach mucosa in alloxan-induced diabetic rats..
• Production method: Starting from m-dichlorobenzene, compound (I) can be obtained through a reaction similar to ketoconazole. The compound (I) is further condensed with 1-acetyl-4-(4-hydroxyphenyl) piperazine, followed by hydrolysis to remove the acetyl group, condensation with p-nitrochlorobenzene, hydrogenation reduction, chloroformate esterification, and reaction with hydrazine hydrate. After cyclization and alkylation, itraconazole is finally obtained. The intermediate 1-acetyl-4-(4-hydroxyphenyl) piperazine can use piperazine as the starting material and prepared with the following reactions.
• Description: Itraconazole is an orally-active triazole antifungal indicated for use in the treatment of dermal, vaginal and systemic mycoses. In immunocompromised and AIDS patients, itraconazole has been shown to significantly reduce the incidence of relapses of cryptococcal meningitis.
• Indications: Itraconazole (Sporanox) is effective in the treatment of histoplasmosis, blastomycosis, candidiasis, and dermatophyte infection. Its efficacy in the treatment of tinea capitis in children is equal to griseofulvin, and it is usually better tolerated (21). It is metabolized by the cytochrome P-450 system and may increase the levels ofwarfarin, cyclosporine, and digoxin among others. Its use is contraindicated with certain medications. Itraconazole (Sporanox) is a triazole antifungal that is related to the imidazole ketoconazole. Similar to ketoconazole, it interferes with ergosterol synthesis and cell membrane integrity. It is clinically active against dimorphic fungi, yeast, dermatophytes, Blastomycetes, histoplasmosis, sporotrichosis, and Aspergillus. Itraconazole is a potent inhibitor of the cytochrome P450 3A enzyme system, which may elevate blood levels of other drugs metabolized by this system if taken concomitantly. Itraconazole levels may decrease in patients who are concurrently taking rifampin, phenobarbital, or phenytoin. Cyclosporine, felodipine, digoxin, warfarin, and oral hypoglycemic levels may increase when given in conjunction with itraconazole. Itraconazole, like ketoconazole, is contraindicated in patients taking cisapride. Itraconazole may induce torsades de pointes, ventricular arrhythmias, and congestive heart failure.
• Therapeutic Function: Antifungal
• Clinical Use: Aspergillosis Systemic mycoses with dimorphic fungi (blastomycosis, coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, penicilliosis) Subcutaneous mycoses (chromoblastomycosis, sporotrichosis) Mucosal and cutaneous candidosis. Dermatophytosis Phaeohyphomycosis Pityriasis versicolor
• Drug interactions: Potentially hazardous interactions with other drugs Aliskiren: concentration of aliskiren increased - avoid Analgesics: possibly inhibits alfentanil metabolism; concentration of fentanyl possibly increased; possibly increases methadone concentration - increased risk of ventricular arrhythmias. Anti-arrhythmics: avoid concomitant use with disopyramide and dronedarone. Antibacterials: metabolism accelerated by rifabutin and rifampicin - avoid; possibly increased rifabutin concentration - reduce rifabutin dose; clarithromycin can increase itraconazole concentration. Anticoagulants: avoid with apixiban and rivaroxaban; effect of coumarins enhanced; concentration of dabigatran possibly increased - avoid. Antidepressants: avoid concomitant use with reboxetine. Antidiabetics: can enhance effects of repaglinide. Antiepileptics: concentration reduced by carbamazepine, fosphenytoin, phenobarbital and phenytoin - avoid with phenytoin. Antihistamines: inhibits mizolastine metabolism - avoid. Antimalarials: avoid with piperaquine with artenimol and artemether/lumefantrine. Antimuscarinics: possibly increases solifenacin concentration. Antipsychotics: possibly increases haloperidol concentration; possibly inhibits metabolism of aripiprazole - reduce aripiprazole dose; increased risk of ventricular arrhythmias with pimozide - avoid; possibly increased quetiapine concentration - reduce quetiapine dose; possibly increases lurasidone concentration - avoid. Antivirals: concentration of daclatasvir increased - reduce daclatasvir dose; concentration of both drugs increased with dasabuvir, paritaprevir and simeprevir - avoid; concentration reduced by efavirenz and nevirapine; concentration of both drugs possibly increased by fosamprenavir; concentration of indinavir increased - may need to reduce indinavir dose; with ritonavir concentration of both drugs may be increased; concentration of saquinavir possibly increased; concentration possibly increased by telaprevir; concentration reduced by efavirenz. Anxiolytics and hypnotics: concentration of buspirone, midazolam and alprazolam increased - reduce buspirone dose.

Technology Process of Spherazole

There total 14 articles about Spherazole which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 90.5%

(-)-(R)-2,4dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol 3-one (106461-41-0) + Toluene-4-sulfonic acid (2R,4R)-2-(2,4-dichloro-phenyl)-2-[1,2,4]triazol-1-ylmethyl-[1,3]dioxolan-4-ylmethyl ester (113770-65-3) → itraconazole (84625-61-6,252964-65-1,873066-43-4)

Guidance literature:

(-)-(R)-2,4dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol 3-one; With hydrazine hydrate; sodium hydroxide; In N,N-dimethyl-formamide; at 40 ℃; for 0.666667h; Inert atmosphere;

Toluene-4-sulfonic acid (2R,4R)-2-(2,4-dichloro-phenyl)-2-[1,2,4]triazol-1-ylmethyl-[1,3]dioxolan-4-ylmethyl ester; In N,N-dimethyl-formamide; at 60 ℃; for 1.5h;

Reference yield: 69.0%

(-)-(R)-2,4dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol 3-one (106461-41-0) + 2RS,4RS-toluene-4-sulfonic acid (2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)methyl-1,3-dioxolan-4-yl)methyl ester (113770-65-3) → itraconazole (84604-65-9,84625-61-6,252964-65-1,873066-43-4)

Guidance literature:

With caesium carbonate; In dimethyl sulfoxide; at 80 ℃; for 16h; Inert atmosphere;

DOI:10.1021/acs.jmedchem.5b01718

Reference yield: 46.0%

s-butyl bromide (78-76-2,5787-31-5) + cis-4-<4-<4-<4-<<2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl>methoxy>phenyl>-1-piperazinyl>phenyl>-2,4-dihydro-3H-1,2,4-triazol-3-one (89848-41-9) → itraconazole (84625-61-6,252964-65-1,873066-43-4)

Guidance literature:

With potassium hydroxide; In dimethyl sulfoxide; for 14h;

DOI:10.1021/jm00373a015

upstream raw materials:

2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl ]-phenyl]-3H-1,2,4-triazol-3-one

2-(sec-butyl)-4-(4-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

(-)-(R)-2,4dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol 3-one

2RS,4RS-toluene-4-sulfonic acid (2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)methyl-1,3-dioxolan-4-yl)methyl ester

Refernces

• 1、 -. "Prepartion method of itraconazole". . . Retrieved 2017/04/29.
• 2、 -. "Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction". . . Retrieved 2008/06/13.