Atovaquone

Base Information

• Chemical Name: Atovaquone
• CAS No.: 95233-18-4
• Molecular Formula: C22H19ClO3
• Molecular Weight: 366.844
• Hs Code.: 29147000
• Mol file: 95233-18-4.mol

Synonyms:1,4-Naphthalenedione,2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-, trans-;Acuvel;Mepron;Mepron (antipneumocystic);Wellvone;

Chemical Property of Atovaquone

Chemical Property:

• Appearance/Colour: yellow to orange crystalline solid
• Vapor Pressure: 0mmHg at 25°C
• Melting Point: 216-219 °C
• Refractive Index: 1.653
• Boiling Point: 542.2 °C at 760 mmHg
• PKA: 5.01±0.10(Predicted)
• Flash Point: 281.7 °C
• PSA: 54.37000
• Density: 1.349 g/cm³
• LogP: 5.50510
• Storage Temp.: -20°C Freezer
• Solubility.: DMSO: >10mg/mL

Purity/Quality:

99% HPLC, ^*data from raw suppliers

Atovaquone >98.0%(HPLC)(T) ^*data from reagent suppliers

Safty Information:

• Pictogram(s): N
• Hazard Codes: N
• Statements: 50/53
• Safety Statements: 60-61

MSDS Files:

SDS file from LookChem

Total 1 MSDS from other Authors

Useful:

• Description: Atovaquone is an orally active antiprotozoal agent indicated for patients with mild to moderate AIDS-associated Pneumocystis carinii pneumonia who are intolerant to the fist-line therapy of trimethoprim-sulfamethoxazole. It is also under investigation as a treatment for malaria and AIDS-associated toxoplasmosis.
• Uses: Atovaquone inhibits the cytochrome bc(1) complex via interactions with the Rieske iron-sulfur protein and cytochrome b in the ubiquinol oxidation pocket. In addition to its use as a treatment for toxoplasmosis, atovaquone has antimalarial properties and prevents pneumocystis pneumonia post-renal transplant.
• Indications: Atovaquone is a naphthoquinone whose mechanism of action involves inhibition of the mitochondrial electron transport system in the protozoa. Malaria parasites depend on de novo pyrimidine biosynthesis through dihydroorotate dehydrogenase coupled to electron transport. Plasmodia are unable to salvage and recycle pyrimidines as do mammalian cells. Atovaquone is poorly absorbed from the gastrointestinal tract, but absorption is increased with a fatty meal. Excretion of the drug, mostly unchanged, occurs in the feces.The elimination half-life is 2 to 3 days. Low plasma levels persist for several weeks. Concurrent administration of metoclopramide, tetracycline, or rifampin reduces atovaquone plasma levels by 40 to 50%. Atovaquone has good initial activity against the blood but not the hepatic stage of P. vivax and P. ovale malaria parasites. It is effective against erythrocytic and exoerythrocytic P. falciparum, and therefore, daily suppressive doses need to be taken for only 1 week upon leaving endemic areas.When used alone, it has an unacceptable (30%) rate of recrudescence and selects for resistant organisms. It and proguanil are synergistic when combined and no atovaquone resistance is seen. This combination (Malarone) is significantly more effective than mefloquine, amodiaquine, chloroquine, and combinations of chloroquine, pyrimethamine, and sulfadoxine. In addition to using the combination of atovaquone and proguanil for the treatment and prophylaxis of P. falciparum malaria, atovaquone is also used for the treatment and prevention of P. carinii pneumonia and babesiosis therapy. Atovaquone is well tolerated and produces only rare instances of nausea, vomiting, diarrhea, abdominal pain, headache, and rash of mild to moderate intensity.
• Clinical Use: 3-[4-(4-Chlorophenyl)-cyclohexyl]-2-hydroxy-1,4-naphthoquinone(Mepron) is a highly lipophilic, water-insolubleanalog of ubiquinone 6, an essential component of the mitochondrialelectron transport chain in microorganisms. Thestructural similarity between atovaquone and ubiquinonesuggests that the former may act as an antimetabolite for thelatter and thereby interfere with the function of electrontransport enzymes.Atovaquone was originally developed as an antimalarialdrug, but Plasmodium falciparum was found to developa rapid tolerance to its action. More recently, the effectivenessof atovaquone against P. carinii was discovered. Itis a currently recommended alternative to trimethoprimsulfamethoxazole(TMP-SMX) for the treatment and prophylaxisof PCP in patients intolerant to this combination.Atovaquone was also shown to be effective in eradicatingT. gondii in preclinical animal studies.The oral absorption of atovaquone is slow and incomplete,in part because of the low water solubility of the drug.Aqueous suspensions provide significantly better absorptionthan do tablets. Food, especially if it has a high fat content,increases atovaquone absorption. Significant enterohepaticrecycling of atovaquone occurs, and most (nearly 95%) ofthe drug is excreted unchanged in the feces. In vivo, atovaquoneis largely confined to the plasma, where it is extensivelyprotein bound ( 99.9%). The half-life of the drugranges from 62 to 80 hours. The primary side effect is gastrointestinalintolerance. Pn. jirovecii pneumonia; alternative therapy for mild to moderate illness (prophylaxis and treatment) Prophylaxis and treatment of malaria in combination with proguanil It has also been used in cerebral toxoplasmosis in AIDS patients and in a few cases of human babesiosis.
• Drug interactions: Potentially hazardous interactions with other drugs Antibacterials: avoid with rifabutin, concentration of both drugs reduced; avoid with rifampicin, concentration reduced and rifampicin concentration increased; concentration reduced by tetracycline. Antivirals: concentration reduced by efavirenz - avoid; concentration of indinavir possibly reduced; concentration of zidovudine increased. Metoclopramide: significant reduction in plasma atovaquone levels.

Technology Process of Atovaquone

There total 19 articles about Atovaquone 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: 94.0%

2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-1,4-naphthoquinone (129719-64-8,153977-22-1) → atovaquone (95233-18-4)

Guidance literature:

With potassium hydroxide; In methanol; Heating;

DOI:10.1016/S0040-4039(98)01691-8

Reference yield: 90.0%

2-[trans-4-(4-chlorophenyl)cyclohexyl]-2,3-dihydronaphthalene-1,4-dione → atovaquone (95233-18-4)

Guidance literature:

2-[trans-4-(4-chlorophenyl)cyclohexyl]-2,3-dihydronaphthalene-1,4-dione; With hydrogen bromide; dihydrogen peroxide; In 1,2-dichloro-ethane; at 30 - 40 ℃; for 6h;

With sodium hydroxide; In water; 1,2-dichloro-ethane; at 50 - 65 ℃; for 7h; Temperature;

Reference yield: 85.0%

cis-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione (137732-39-9) → atovaquone (95233-18-4)

Guidance literature:

With sulfuric acid; at 15 - 16 ℃; for 0.333333h;

upstream raw materials:

2-[4-(4-chlorophenyl)-cyclohexyl]-3-chloro-1,4-naphthoquinone

2-chloro-1,4-naphthoquinone

trans-4-(p-chlorophenyl)cyclohexane carboxylic acid

atovaquone

Downstream raw materials:

3-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyloxy-2-trans-[(4-chlorophenyl)cyclohexyl][1,4]naphthoquinone

3-((1r,4r)-4-(4-chlorophenyl)cyclohexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate

Refernces

• 1、 Gutiérrez-Bonet, álvaro,Remeur, Camille,Matsui, Jennifer K.,Molander, Gary A.. "Late-Stage C-H Alkylation of Heterocycles and 1,4-Quinones via Oxidative Homolysis of 1,4-Dihydropyridines". supporting information. p. 12251 - 12258. Retrieved 2017/09/12.
• 2、 -. "IMPROVED SYNTHESIS OF 2-(4-(4-CHLOROPHENYL) CYCLOHEX-1-ENYL) -3, 4-DIHYDRONAPHTHALEN-1 (2H)-ONE; AN INTERMEDIATE FOR ATOVAQUONE". Page/Page column 27; 28. . Retrieved 2013/03/26.