Etravirine

Base Information

• Chemical Name: Etravirine
• CAS No.: 269055-15-4
• Deprecated CAS: 394729-17-0
• Molecular Formula: C20H15BrN6O
• Molecular Weight: 435.283
• European Community (EC) Number: 682-331-6
• UNII: 0C50HW4FO1
• DSSTox Substance ID: DTXSID30181412
• Nikkaji Number: J1.588.786I
• Wikipedia: Etravirine
• Wikidata: Q414762
• NCI Thesaurus Code: C73195
• RXCUI: 475969
• Metabolomics Workbench ID: 62857
• ChEMBL ID: CHEMBL308954
• Mol file: 269055-15-4.mol

Synonyms:4-((6-amino-5-bromo-2-((4-cyanophenyl)amino)-4-pyrimidinyl)oxy)-3,5-dimethyl-benzonitrile;benzonitrile, 4-((6-amino-5-bromo-2-((4-cyanophenyl)amino)-4-pyrimidinyl)oxy)-3,5-dimethyl-;etravirine;Intelence;R165335;TMC 125;TMC-125;TMC125 cpd

Chemical Property of Etravirine

Chemical Property:

• Appearance/Colour: white to off-white solid
• Vapor Pressure: 3.82E-16mmHg at 25°C
• Melting Point: 265oC (dec.)
• Refractive Index: 1.702
• Boiling Point: 637.4 °C at 760 mmHg
• PKA: 1.23±0.10(Predicted)
• Flash Point: 339.3 °C
• Density: 1.57 g/cm³
• Storage Temp.: -20°C Freezer
• Solubility.: DMSO (Slightly), Methanol (Slightly, Heated, Sonicated)
• XLogP3: 4.5
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 7
• Rotatable Bond Count: 4
• Exact Mass: 434.04907
• Heavy Atom Count: 28
• Complexity: 609

Purity/Quality:

99% ^*data from raw suppliers

Etravirine ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antiviral Agents
• Canonical SMILES: CC1=CC(=CC(=C1OC2=NC(=NC(=C2Br)N)NC3=CC=C(C=C3)C#N)C)C#N
• Recent ClinicalTrials: TMC125-TiDP35-C239 - Continued Access to Etravirine (ETR) in Treatment Experienced HIV-1 Infected Participants
• Recent EU Clinical Trials: Clinical trial - phase II - to test safety and efficay of Etravirine's treatment in Friedreich Ataxia's patients
• Description: Etravirine is a second-generation NNRTI. It is indicated for use in combination with other antiretroviral agents for treating HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to the currently available NNRTIs and other antiretroviral agents. The NNRTIs, along with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs), are important components of the combination regimens currently used to treat HIV-1 infection. The NRTIs/NtRTIs act by competing with the natural nucleotide substrates of reverse transcriptase for incorporation into viral DNA and subsequent chain termination. By contrast, the NNRTIs bind to an allosteric site of the enzyme and disrupt the DNA polymerase function by inducing conformational changes to the catalytic site. The allosteric binding nature of NNRTIs generally results in improved safety profile since there is no known human homolog for the drug-binding site of the enzyme.As with other NNRTIs, etravirine has many drug–drug interactions. It is a substrate of CYP3A4, CYP2C9, and CYP2C19, an inducer of 3A4, and an inhibitor of 2C9 and 2C19. Caution should be used with co-administration of inducers, inhibitors, or substrates of these enzymes. Etravirine can be synthesized starting from 5-bromo-2,4,6-trichloropyrimidine through three successive nucleophilic substitution reactions. Initial displacement with 4-aminobenzonitrile using Hu¨nig’s base, followed by reaction with sodium salt of 4-hydroxy-3,5- dimethylbenzonitrile, and subsequent ammonolysis reaction with ammonia in dioxane under pressure affords etravirine. .
• Uses: Etravirine is a novel HIV reverse transcriptase inhibitor useful in treatment of HIV infection. Etravirine is an antiretroviral (anti-HIV) drug that is part of the non nucleoside reverse transcriptase inhibitor (NNRTIs or Non Nukes) family. It is used together with other antiretrovirals in treatment-experienced adult patients, who have failed previous therapy, and have HIV-1 strains which are resistant to other retrovirals and NNRTIs. Etravirine is used to delay the progression of HIV infection. By using etravirine, your immune system should improve (increase in CD4 + count) and you will be better protected against opportunistic infections.Etravirine does not cure AIDS or completely kill the HIV virus, but helps to prevent further damage by slowing down the production of new viruses. Treatment with etravirine does not reduce the risk of passing infection on to others. You will still be able to pass HIV by sexual contact, by blood transfer or by sharing needles. You should always use appropriate precautions to prevent passing HIV on to others. Etravirine (TMC125) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used for the treatment of HIV.
• Clinical Use: Treatment of HIV-1 infection in adults (in combination with other antiretroviral drugs)
• Drug interactions: Potentially hazardous interactions with other drugs Antibacterials: concentration increased by clarithromycin, also concentration of clarithromycin reduced; concentration of both drugs reduced with rifabutin; avoid concomitant use with rifampicin. Antivirals: concentration possibly reduced by efavirenz and nevirapine - avoid concomitant use; concentration of fosamprenavir increased, consider reducing fosamprenavir dose; possibly reduces bosutinib and indinavir concentration - avoid concomitant use; concentration of dolutegravir reduced; possibly reduces concentration of maraviroc; concentration reduced by tipranavir and tipranavir concentration increased - avoid concomitant use. Clopidogrel: possibly reduced antiplatelet effect. Guanfacine: possibly reduces concentration of guanfacine - increase guanfacine dose. Orlistat: absorption possibly reduced by orlistat.

Technology Process of Etravirine

There total 28 articles about Etravirine 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: 92.82%

4-{6-amino-2-[(4-cyanophenyl)amino]pyrimidin-4-yloxy}-3,5-dimethylbenzenecarbonitrile → etravirine (269055-15-4,394729-17-0)

Guidance literature:

4-{6-amino-2-[(4-cyanophenyl)amino]pyrimidin-4-yloxy}-3,5-dimethylbenzenecarbonitrile; With bromine; In propan-1-ol; at 5 - 20 ℃;

With sodium hydroxide; In propan-1-ol; water; at 0 - 20 ℃; Product distribution / selectivity;

Reference yield: 89.0%

4-((4-amino-5-bromo-6-chloropyrimidin-2-yl)amino)benzonitrile (1398507-09-9) + 3,5-dimethyl-4-hydroxybenzonitrile (4198-90-7) → etravirine (269055-15-4,394729-17-0)

Guidance literature:

3,5-dimethyl-4-hydroxybenzonitrile; With potassium carbonate; potassium iodide; In 1-methyl-pyrrolidin-2-one; at 0 - 5 ℃; for 0.166667h; Inert atmosphere;

4-((4-amino-5-bromo-6-chloropyrimidin-2-yl)amino)benzonitrile; In 1-methyl-pyrrolidin-2-one; at 10 - 120 ℃; for 26.5h; Time; Temperature; Reagent/catalyst; Concentration; Inert atmosphere;

Reference yield: 56.0%

C25H22BrN5O3 (1616667-63-0) → etravirine (269055-15-4,394729-17-0)

Guidance literature:

C₂₅H₂₂BrN₅O₃; With silver(II) fluoride; Inert atmosphere; Glovebox;

With ammonia; In water; isopropyl alcohol; at 80 ℃; for 0.5h;

With hydrogenchloride; In water; at 0.25 ℃; for 0.5h;

upstream raw materials:

4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile

4-(4,6-dichloropyrimidine-2-yl-amino)benzonitrile

4-((4,6-dihydroxypyrimidine-2-yl)amino)benzonitrile

4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile

Downstream raw materials:

etravirine tosylatee salt

etravirine phosphate

4-[[4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile

Refernces

• 1、 -. "PRODRUGS OF HIV REPLICATION INHIBITING PYRIMIDINES". Paragraph 0099. . Retrieved 2015/11/28.
• 2、 -. "C-H FLUORINATION OF HETEROCYCLES WITH SILVER (II) FLUORIDE". . . Retrieved 2015/02/19.