269055-15-4

Basic information

• Product Name: 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3, 5 –dimethylbenzonitrile
• Synonyms: 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3, 5 –dimethylbenzonitrile;Etravirine;Etravirine（TMC-125）;R 165335;TMC 125;4-(6-amino-5-bromo-2-(4-cyanobenzyl)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile, Etravirine;4-[[6-AMino-5-broMo-2-[(4-cyanophenyl)aMino]-4-pyriMidinyl]oxy]-3,5-diMethyl -;4-[[6-aMino-5-broMo-2-[(4-cyanophenyl)aMino]-4-pyriMidinyl]oxy]-3, 5 –diMethylbenzonitrile/Etravirine
• CAS NO: 269055-15-4
• Molecular Formula: C₂₀H₁₅BrN₆O
• Molecular Weight: 435.284
• EINECS: 1592732-453-0
• Product Categories: All Inhibitors;Inhibitors;Intermediates & Fine Chemicals;Non-nucleoside Reverse Transcriptase;Pharmaceuticals;Other APIs
• Mol File: 269055-15-4.mol

Chemical Properties

• Melting Point: .265°C (dec.)
• Boiling Point: 637.4 °C at 760 mmHg
• Flash Point: 339.3 °C
• Appearance: white to off-white solid
• Density: 1.57 g/cm³
• Vapor Pressure: 3.82E-16mmHg at 25°C
• Refractive Index: 1.702
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated, Sonicated)
• PKA: 1.23±0.10(Predicted)
• CAS DataBase Reference: 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3, 5 –dimethylbenzonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3, 5 –dimethylbenzonitrile(269055-15-4)
• EPA Substance Registry System: 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3, 5 –dimethylbenzonitrile(269055-15-4)

Safety Data

• Hazardous Substances Data: 269055-15-4(Hazardous Substances Data)

Usage

Uses

Used in Antiviral Applications:
Etravirine is used as an antiretroviral drug for the treatment of HIV-1 infection in treatment-experienced adult patients. It is particularly effective against HIV-1 strains that are resistant to other NNRTIs and antiretroviral agents. Etravirine is used in combination with other antiretroviral agents to delay the progression of HIV infection, improve the immune system (increase in CD4+ count), and protect against opportunistic infections. However, it does not cure AIDS or completely kill the HIV virus, and patients should still take precautions to prevent the transmission of the virus to others.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, Etravirine is used as a key component of combination regimens for treating HIV-1 infection. Its allosteric binding nature to the reverse transcriptase enzyme results in an improved safety profile, as there is no known human homolog for the drug-binding site of the enzyme. Etravirine is also synthesized through a series of nucleophilic substitution reactions, starting from 5-bromo-2,4,6-trichloropyrimidine, making it an important compound in the development of new antiretroviral drugs.
Brand Name:
Etravirine is marketed under the brand name Intelence.

Originator

Janssen (United States)

Acquired resistance

Various mutations are associated with a decreased virological response. Single codon substitutions at positions 100, 101 and 181 are considered major mutations. A single K103N mutation is not associated with resistance.

Pharmaceutical Applications

A comprehensive analysis of baseline resistance data from the DUET-1 and DUET-2 studies has identified a list of 17 etravirine resistance associated mutations: V901, A98G, L100L, K101E/H/I, V1061, E138A, V179D/F/T, Y181C/L/V, G190A/S, and M230L. A single K103N mutation is not associated with resistance to etravirine.

Mechanism of action

Etravirine binds directly to reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases alpha, beta, and gamma.

Pharmacokinetics

Oral absorption: Not known/available Cmax 200 mg oral twice daily: c. 959 ng/mL Cmin 200 mg oral twice daily: c. 469 ng/mL Plasma half-life: c. 36 h Volume of distribution: Not known/available Plasma protein binding: >99% Administration with food improves the bioavailability and reduces interpatient variability. It undergoes oxidative metabolism by cytochrome P450 systems. Around 93.7% and 1.2% of an administered dose can be retrieved in the feces and urine, respectively, mostly as unchanged drug. Details of distribution into CSF, semen and breast milk and recommendations for dose adjustment in patients with hepatic impairment are not yet available.

Clinical Use

Treatment of HIV-1 infection in adults (in combination with other antiretroviral drugs)

Side effects

In the phase III studies around 15% of patients experienced erythematous or maculopapular rashes of mild or moderate severity; most resolved with continued dosing, but treatment was discontinued in 2% of patients. Rare cases of Stevens– Johnson syndrome have been reported. Other common adverse events are diarrhea, nausea, headache and fatigue. Dyslipidemia and raised pancreatic amylase occur in some patients.

Synthesis

Only the discovery synthesis and small scale syntheses have been disclosed for 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3, 5 –dimethylbenzonitrile in the following scheme. The largest scale synthesis was initiated by the portionwise addition of cyanamide to a solution of the p-cyanoaniline hydrochloride salt 73. The mixture was refluxed in diglyme to give guanidine salt 74 in 85% yield after concentration of the reaction mixture and recrystallization from acetone. Reaction of guanidine 74 with diethylmalonate in the presence of sodium ethoxide in refluxing ethanol gave pyrimidine diol 75 in 57% yield, which upon refluxing in phosphorous oxychloride for 30 min gave dichloride 76 in 97% yield. Bromination of dichloride 76 with NBS in chloroform at room temperature provided bromide 77 in 55% yield. Heating a mixture of the dichlorobromide 77 with the sodium salt of 2,5-dimethyl-4-cyanophenol 78, generated by reaction with sodium hydride in situ) in diglyme and NMP at 155 °C gave the coupled product 79 in 45% yield. Finally, reaction of the chloride 79 with ammonia in refluxing dioxane (or iPrOH) in a sealed tube gave etravirine (IX) in 41% yield after purification.

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.

Metabolism

Etravirine is extensively metabolised by hepatic microsomal enzymes, mainly by the cytochrome P450 isoenzymes CYP3A4, CYP2C9, and CYP2C19, to substantially less active metabolites.Unchanged etravirine accounted for 81.2-86.4% of the administered dose in faeces. Unchanged etravirine was not detected in urine.

InChI:InChI=1/C20H15BrN6O/c1-11-7-14(10-23)8-12(2)17(11)28-19-16(21)18(24)26-20(27-19)25-15-5-3-13(9-22)4-6-15/h3-8H,1-2H3,(H3,24,25,26,27)

Synthetic route

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

Conditions	Yield
Stage #1: 4-{6-amino-2-[(4-cyanophenyl)amino]pyrimidin-4-yloxy}-3,5-dimethylbenzenecarbonitrile With bromine In propan-1-ol at 5 - 20℃; Stage #2: With sodium hydroxide In propan-1-ol; water at 0 - 20℃; Product distribution / selectivity;	92.82%
With bromine In dichloromethane at 0 - 5℃; for 4h;	80%
With bromine In dichloromethane at 0 - 5℃; for 5h;	80.2%

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)

Conditions	Yield
Stage #1: 3,5-dimethyl-4-hydroxybenzonitrile With potassium carbonate; potassium iodide In 1-methyl-pyrrolidin-2-one at 0 - 5℃; for 0.166667h; Inert atmosphere; Stage #2: 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;	89%
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 80℃; for 12h; Inert atmosphere;	10 g

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

Conditions	Yield
Stage #1: C25H22BrN5O3 With silver(II) fluoride Inert atmosphere; Glovebox; Stage #2: With ammonia In water; isopropyl alcohol at 80℃; for 0.5h; Stage #3: With hydrogenchloride In water at 0.25℃; for 0.5h;	56%

4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile (269055-76-7) → etravirine (269055-15-4)

Conditions	Yield
With ammonia In isopropyl alcohol	41%
In water	40.5%
In water	40.5%
With ammonia In 1,4-dioxane at 150℃; for 96h; Sealed tube;	0.44 g

4-((4,6-dichloropyrimidin-2-yl)amino)benzonitrile (329187-59-9) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 78 percent / Br2; NaHCO3 / H2O; methanol 2: 45 percent / N-methylpyrrolidine / dioxane 3: 41 percent / NH3 / propan-2-ol View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 12 h / 45 °C 2.1: ammonia / 1,4-dioxane; water / 12 h / 120 °C 3.1: bromine / dichloromethane / 4 h / 0 - 5 °C 3.2: pH 9 - 10 View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 12 h / 45 °C 2.1: ammonium hydroxide / water; 1,4-dioxane / 12 h / 120 °C 3.1: bromine / dichloromethane / 4 h / 0 - 5 °C 3.2: pH 9-10 View Scheme
Multi-step reaction with 3 steps 1: N-Bromosuccinimide / tetrahydrofuran / 20 °C 2: ammonia / 1,4-dioxane / 1 h / 50 °C / Sealed tube 3: potassium carbonate / 1-methyl-pyrrolidin-2-one / 12 h / 80 °C / Inert atmosphere View Scheme

4-((4,6-dihydroxypyrimidine-2-yl)amino)benzonitrile (374067-80-8) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 86 percent / POCl3 2: 78 percent / Br2; NaHCO3 / H2O; methanol 3: 45 percent / N-methylpyrrolidine / dioxane 4: 41 percent / NH3 / propan-2-ol View Scheme
Multi-step reaction with 4 steps 1.1: trichlorophosphate; N,N-dimethyl-aniline / 6 h / Reflux 2.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 12 h / 45 °C 3.1: ammonia / 1,4-dioxane; water / 12 h / 120 °C 4.1: bromine / dichloromethane / 4 h / 0 - 5 °C 4.2: pH 9 - 10 View Scheme
Multi-step reaction with 4 steps 1.1: trichlorophosphate; N,N-dimethyl-aniline / 6 h / Reflux 2.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 12 h / 45 °C 3.1: ammonium hydroxide / water; 1,4-dioxane / 12 h / 120 °C 4.1: bromine / dichloromethane / 4 h / 0 - 5 °C 4.2: pH 9-10 View Scheme
Multi-step reaction with 4 steps 1: trichlorophosphate / 12 h / 90 - 95 °C 2: N-Bromosuccinimide / tetrahydrofuran / 20 °C 3: ammonia / 1,4-dioxane / 1 h / 50 °C / Sealed tube 4: potassium carbonate / 1-methyl-pyrrolidin-2-one / 12 h / 80 °C / Inert atmosphere View Scheme

4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 45 percent / N-methylpyrrolidine / dioxane 2: 41 percent / NH3 / propan-2-ol View Scheme

4-cyanophenyl guanidine hydrochloride → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 76 percent / NaOEt / ethanol 2: 86 percent / POCl3 3: 78 percent / Br2; NaHCO3 / H2O; methanol 4: 45 percent / N-methylpyrrolidine / dioxane 5: 41 percent / NH3 / propan-2-ol View Scheme

4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile hydrobromide (1030633-38-5) → etravirine (269055-15-4)

Conditions	Yield
With sodium hydroxide In water at 20℃; for 1.25h;

4-{6-amino-2-[(4-cyanophenyl)amino]pyrimidin-4-yloxy}-3,5-dimethylbenzenecarbonitrile → 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile hydrobromide (1030633-38-5) + etravirine (269055-15-4)

Conditions	Yield
Stage #1: 4-{6-amino-2-[(4-cyanophenyl)amino]pyrimidin-4-yloxy}-3,5-dimethylbenzenecarbonitrile With bromine; acetic acid at 20 - 80℃; for 4.25h; Stage #2: With sodium hydroxide In water at 20℃;

etravirine phosphate (1253183-22-0) → etravirine (269055-15-4)

Conditions	Yield
With sodium hydroxide In water at 20℃; for 0.5h;

etravirine tosylatee salt (1030633-41-0) → etravirine (269055-15-4)

Conditions	Yield
With sodium hydroxide In water at 0 - 20℃; for 1.75h; Product distribution / selectivity;

3,5-dimethyl-4-hydroxybenzonitrile (4198-90-7) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water; acetone / 3 - 30 °C 1.2: 0.17 h / 10 °C / Inert atmosphere 1.3: 2 h / 10 °C 2.1: ammonia / 1-methyl-pyrrolidin-2-one; water / 19 h / 120 °C 3.1: bromine / propan-1-ol / 5 - 20 °C 3.2: 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 2 h / 70 °C / Large scale reaction 2: potassium tert-butylate / 1-methyl-pyrrolidin-2-one / 2 h / 0 - 5 °C / Large scale reaction 3: ammonia / 1,4-dioxane; water / 12 h / 120 °C / Autoclave; Large scale reaction 4: bromine / dichloromethane / 4 h / 0 - 5 °C View Scheme
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 70 °C 2.1: potassium tert-butylate / 1-methyl-pyrrolidin-2-one / 0 - 20 °C 3.1: ammonium hydroxide / 1,4-dioxane; water / 120 - 125 °C / autoclave 4.1: bromine / dichloromethane / 0 - 5 °C 4.2: 0 - 5 °C / pH 9 - 10 View Scheme

4-Aminobenzonitrile (873-74-5) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water; acetone / 3 - 30 °C 1.2: 0.17 h / 10 °C / Inert atmosphere 1.3: 2 h / 10 °C 2.1: ammonia / 1-methyl-pyrrolidin-2-one; water / 19 h / 120 °C 3.1: bromine / propan-1-ol / 5 - 20 °C 3.2: 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1: potassium tert-butylate / 1-methyl-pyrrolidin-2-one / 2 h / 0 - 5 °C / Large scale reaction 2: ammonia / 1,4-dioxane; water / 12 h / 120 °C / Autoclave; Large scale reaction 3: bromine / dichloromethane / 4 h / 0 - 5 °C View Scheme
Multi-step reaction with 6 steps 1.1: nitric acid / ethanol; water / 16 h / Reflux 2.1: ethanol; sodium / 12 h / Reflux 3.1: trichlorophosphate; N,N-dimethyl-aniline / 6 h / Reflux 4.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 12 h / 45 °C 5.1: ammonia / 1,4-dioxane; water / 12 h / 120 °C 6.1: bromine / dichloromethane / 4 h / 0 - 5 °C 6.2: pH 9 - 10 View Scheme

4-((2,6-dichloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (1225383-63-0) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium tert-butylate / 1-methyl-pyrrolidin-2-one / 2 h / 0 - 5 °C / Large scale reaction 2: ammonia / 1,4-dioxane; water / 12 h / 120 °C / Autoclave; Large scale reaction 3: bromine / dichloromethane / 4 h / 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / 1-methyl-pyrrolidin-2-one / 0 - 20 °C 2.1: ammonium hydroxide / 1,4-dioxane; water / 120 - 125 °C / autoclave 3.1: bromine / dichloromethane / 0 - 5 °C 3.2: 0 - 5 °C / pH 9 - 10 View Scheme
Multi-step reaction with 3 steps 1: 1-methyl-pyrrolidin-2-one; potassium tert-butylate / 2.5 h / 0 - 5 °C 2: ammonia; 1-methyl-pyrrolidin-2-one / water / 0.5 h / 130 °C / 6723.1 Torr / Microwave irradiation 3: bromine / dichloromethane / 5 h / 0 - 5 °C View Scheme

1-(4-cyanophenyl)guanidine (5637-42-3) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: ethanol; sodium / 12 h / Reflux 2.1: trichlorophosphate; N,N-dimethyl-aniline / 6 h / Reflux 3.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 12 h / 45 °C 4.1: ammonia / 1,4-dioxane; water / 12 h / 120 °C 5.1: bromine / dichloromethane / 4 h / 0 - 5 °C 5.2: pH 9 - 10 View Scheme
Multi-step reaction with 6 steps 1.1: potassium tert-butylate / butan-1-ol / 4 h / 60 - 93 °C 2.1: trichlorophosphate / 20 - 85 °C 2.2: pH 9 - 10 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / dmap / 1-methyl-pyrrolidin-2-one / 0.5 h 3.2: 4.5 h / 20 - 85 °C 4.1: N-Bromosuccinimide; ammonium acetate / dichloromethane / 4 h 4.2: pH 10 - 11 5.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 1 h / 20 °C 5.2: 24.5 h / 100 - 110 °C 6.1: sodium hydroxide; water / isopropyl alcohol / 5.5 h / 20 - 75 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium; ethanol / 12 h / Reflux 2.1: trichlorophosphate; N,N-dimethyl-aniline / 6 h / Reflux 3.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 12 h / 45 °C 4.1: ammonium hydroxide / water; 1,4-dioxane / 12 h / 120 °C 5.1: bromine / dichloromethane / 4 h / 0 - 5 °C 5.2: pH 9-10 View Scheme
Multi-step reaction with 6 steps 1: potassium tert-butylate / butan-1-ol / 4 h / 45 - 93 °C 2: trichlorophosphate / 7 h / 27 - 97 °C 3: dmap / acetonitrile / 7 h / 27 - 78 °C 4: bromine; acetic acid / dichloromethane / 11 h / 27 °C 5: 1,8-diazabicyclo[5.4.0]undec-7-ene; dmap / N,N-dimethyl-formamide / 5 h / 27 - 73 °C 6: lithium hydroxide monohydrate / acetonitrile; isopropyl alcohol / 10 h / 27 - 59 °C View Scheme
Multi-step reaction with 5 steps 1: sodium; methanol / methanol / 6 h / Reflux; Inert atmosphere 2: trichlorophosphate / 12 h / 90 - 95 °C 3: N-Bromosuccinimide / tetrahydrofuran / 20 °C 4: ammonia / 1,4-dioxane / 1 h / 50 °C / Sealed tube 5: potassium carbonate / 1-methyl-pyrrolidin-2-one / 12 h / 80 °C / Inert atmosphere View Scheme

4-((4-amino-6-chloropyrimidin-2-yl)amino)benzonitrile (1398507-08-8) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / dmap / 1-methyl-pyrrolidin-2-one / 0.5 h 1.2: 4.5 h / 20 - 85 °C 2.1: N-Bromosuccinimide; ammonium acetate / dichloromethane / 4 h 2.2: pH 10 - 11 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 1 h / 20 °C 3.2: 24.5 h / 100 - 110 °C 4.1: sodium hydroxide; water / isopropyl alcohol / 5.5 h / 20 - 75 °C View Scheme
Multi-step reaction with 2 steps 1.1: bromine / methanol / 2.17 h / 0 - 5 °C 2.1: potassium carbonate; potassium iodide / 1-methyl-pyrrolidin-2-one / 0.17 h / 0 - 5 °C / Inert atmosphere 2.2: 26.5 h / 10 - 120 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: dmap / acetonitrile / 7 h / 27 - 78 °C 2: bromine; acetic acid / dichloromethane / 11 h / 27 °C 3: 1,8-diazabicyclo[5.4.0]undec-7-ene; dmap / N,N-dimethyl-formamide / 5 h / 27 - 73 °C 4: lithium hydroxide monohydrate / acetonitrile; isopropyl alcohol / 10 h / 27 - 59 °C View Scheme

N-[6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yl]benzamide (1404118-66-6) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide; ammonium acetate / dichloromethane / 4 h 1.2: pH 10 - 11 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 1 h / 20 °C 2.2: 24.5 h / 100 - 110 °C 3.1: sodium hydroxide; water / isopropyl alcohol / 5.5 h / 20 - 75 °C View Scheme
Multi-step reaction with 3 steps 1: bromine; acetic acid / dichloromethane / 11 h / 27 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene; dmap / N,N-dimethyl-formamide / 5 h / 27 - 73 °C 3: lithium hydroxide monohydrate / acetonitrile; isopropyl alcohol / 10 h / 27 - 59 °C View Scheme

N-[5-bromo-6-(4-cyano-2,6-dimethylphenoxy)-2-(4-cyano-phenylamino)pyrimidin-4-yl]-benzamide (1404118-68-8) → etravirine (269055-15-4)

Conditions	Yield
With water; sodium hydroxide In isopropyl alcohol at 20 - 75℃; for 5.5h; Product distribution / selectivity;
With lithium hydroxide monohydrate In isopropyl alcohol; acetonitrile at 27 - 59℃; for 10h; Solvent; Time; Temperature; Reagent/catalyst;	75 mg

4-(4-amino-6-hydroxy-pyrimidin-2-ylamino)-benzonitrile (1398507-07-7) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: trichlorophosphate / 20 - 85 °C 1.2: pH 9 - 10 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / dmap / 1-methyl-pyrrolidin-2-one / 0.5 h 2.2: 4.5 h / 20 - 85 °C 3.1: N-Bromosuccinimide; ammonium acetate / dichloromethane / 4 h 3.2: pH 10 - 11 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 1 h / 20 °C 4.2: 24.5 h / 100 - 110 °C 5.1: sodium hydroxide; water / isopropyl alcohol / 5.5 h / 20 - 75 °C View Scheme
Multi-step reaction with 5 steps 1: trichlorophosphate / 7 h / 27 - 97 °C 2: dmap / acetonitrile / 7 h / 27 - 78 °C 3: bromine; acetic acid / dichloromethane / 11 h / 27 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene; dmap / N,N-dimethyl-formamide / 5 h / 27 - 73 °C 5: lithium hydroxide monohydrate / acetonitrile; isopropyl alcohol / 10 h / 27 - 59 °C View Scheme

5-bromo-2,6-dichloropyrimidin-4-amine (101012-11-7) + 3,5-dimethyl-4-hydroxybenzonitrile (4198-90-7) + 4-Aminobenzonitrile (873-74-5) → etravirine (269055-15-4)

Conditions	Yield
Stage #1: 5-bromo-2,6-dichloropyrimidin-4-amine With sodium hydride In ISOPROPYLAMIDE; mineral oil at 0 - 5℃; for 0.333333h; Inert atmosphere; Stage #2: 3,5-dimethyl-4-hydroxybenzonitrile In ISOPROPYLAMIDE; mineral oil at 10 - 80℃; for 19.5h; Stage #3: 4-Aminobenzonitrile

4-(6-amino-5-bromo-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (1415796-11-0) + 4-Aminobenzonitrile (873-74-5) → etravirine (269055-15-4)

Conditions	Yield
With zinc(II) chloride In 1,4-dioxane at 100℃; for 44h; Inert atmosphere;

4-(6-(acetylamino)-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: zinc(II) chloride / 1,4-dioxane / 43 h / 90 - 100 °C 2: potassium hydroxide; water / ethanol / 20 °C 3: bromine / N,N-dimethyl-formamide / 1 h / -10 - -5 °C View Scheme

4-(4-amino-6-chloropyrimidin-2-ylamino)benzonitrile hydrochloride → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / water; acetone / 3.08 h / 0 - 40 °C 2.1: bromine / methanol / 2.17 h / 0 - 5 °C 3.1: potassium carbonate; potassium iodide / 1-methyl-pyrrolidin-2-one / 0.17 h / 0 - 5 °C / Inert atmosphere 3.2: 26.5 h / 10 - 120 °C / Inert atmosphere View Scheme

4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]-amino]benzonitrile (269055-04-1) → etravirine (269055-15-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; hydrogenchloride; dmap / tetrahydrofuran; water / 1 h / 20 °C 2.1: silver(II) fluoride / acetonitrile / 2 h / 20 °C / Inert atmosphere; Glovebox; Sealed tube 3.1: ammonium hydroxide / isopropyl alcohol / 0.5 h / 80 °C / Inert atmosphere; Glovebox 3.2: 0.5 h / 20 °C / Inert atmosphere; Glovebox View Scheme

C25H21BrFN5O3 → etravirine (269055-15-4)

Conditions	Yield
Stage #1: C25H21BrFN5O3 With ammonium hydroxide In isopropyl alcohol at 80℃; for 0.5h; Inert atmosphere; Glovebox; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20℃; for 0.5h; Inert atmosphere; Glovebox;	122 mg

4-(5-bromo-2-chloro-pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (1039021-95-8) → etravirine (269055-15-4)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: 0.42 h / 165 °C / Inert atmosphere; Glovebox; Sealed tube 2.1: N-ethyl-N,N-diisopropylamine; hydrogenchloride; dmap / tetrahydrofuran; water / 1 h / 20 °C 3.1: silver(II) fluoride / acetonitrile / 2 h / 20 °C / Inert atmosphere; Glovebox; Sealed tube 4.1: ammonium hydroxide / isopropyl alcohol / 0.5 h / 80 °C / Inert atmosphere; Glovebox 4.2: 0.5 h / 20 °C / Inert atmosphere; Glovebox View Scheme

propargyl bromide (106-96-7) + etravirine (269055-15-4) → 4-((5-bromo-2-((4-cyanophenyl)amino)-6-(prop-2-yn-1-ylamino)pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 5h;	63%

etravirine (269055-15-4) → C20H15BrN6O2

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 0.5h; Heating / reflux;	33%

etravirine (269055-15-4) → 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile hydrobromide (1030633-38-5)

Conditions	Yield
With hydrogen bromide In dichloromethane; water

toluene-4-sulfonic acid (104-15-4) + etravirine (269055-15-4) → etravirine tosylatee salt (1030633-41-0)

Conditions	Yield
In acetone at 20℃; for 1h;
In nitromethane; ethanol

etravirine (269055-15-4) → etravirine phosphate (1253183-22-0)

Conditions	Yield
With phosphoric acid In water; acetone at 20℃; for 0.5h;

Upstream product

• 1030633-38-5 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile hydrobromide 
• 1253183-22-0 etravirine phosphate 
• 1030633-41-0 etravirine tosylatee salt 
• 4198-90-7 3,5-dimethyl-4-hydroxybenzonitrile 
• 873-74-5 4-Aminobenzonitrile 
• 1616667-63-0 C₂₅H₂₂BrN₅O₃ 
• 1039021-95-8 4-(5-bromo-2-chloro-pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile 
• 269055-04-1 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]-amino]benzonitrile 
• 1398507-09-9 4-((4-amino-5-bromo-6-chloropyrimidin-2-yl)amino)benzonitrile 
• 1415796-11-0 4-(6-amino-5-bromo-2-chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile 
• 101012-11-7 5-bromo-2,6-dichloropyrimidin-4-amine 
• 1398507-07-7 4-(4-amino-6-hydroxy-pyrimidin-2-ylamino)-benzonitrile 
• 1404118-68-8 N-[5-bromo-6-(4-cyano-2,6-dimethylphenoxy)-2-(4-cyano-phenylamino)pyrimidin-4-yl]-benzamide 
• 1404118-66-6 N-[6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yl]benzamide 

Downstream Products

• 1030633-41-0 etravirine tosylatee salt 
• 1253183-22-0 etravirine phosphate 
• 269055-19-8 4-[[4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]-benzonitrile 
• 1030633-39-6 etravirine hydrochloride salt 
• 1030633-38-5 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile hydrobromide 

Relevant articles and documents

A etravirine preparation method

The invention discloses a preparation method for etravirine. The method comprises the following steps: performing nucleophilic substitution on a pyrimidine ring to generate an intermediate IV under the action of an alkali by taking a compound II and a compound III as initial raw materials; performing the nucleophilic substitution on the intermediate IV and aminobenzonitrile under an alkaline condition to generate a key intermediate V; performing ammoniation on the key intermediate V in a microwave reactor to generate an intermediate VI; performing bromination on the intermediate VI to generate a target product, namely the etravirine I. The preparation method disclosed by the invention is high in reaction selectivity and easy to operate; compared with the original synthetic method, the reaction time is greatly shortened; the energy consumption is reduced; the reaction yield is improved; the overall yield reaches 38.5 percent; the preparation method is suitable for industrial large-scale production.

Process for the Synthesis of Etravirine and Its Intermediates

The invention discloses the synthesis of Etravirine via intermediate 4-((4-amino-5-bromo-6-chloropyrimidin-2-yl) amino)benzonitrile and process for the preparation of Etravirine of the formula-I.

C-H FLUORINATION OF HETEROCYCLES WITH SILVER (II) FLUORIDE

The present invention provides compositions and methods for the selective C-H fluorination of nitrogen-containing heteroarenes with AgF2, which has previously been considered too reactive for practical, selective C-H fluorination. Fluorinated heteroarenes are prevalent in numerous pharmaceuticals, agrochemicals and materials. However, the reactions used to introduce fluorine into these molecules require pre-functionalized substrates or the use of F2 gas. The present invention provides a mild and general method for the C-H fluorination of nitrogen-containing heteroarene compounds to 2-fluoro-heteroarenes with commercially available AgF2. In various embodiments, these reactions occur at ambient temperature within one hour and occur with exclusive selectivity for fluorination at the 2-position. Exemplary reaction conditions are effective for fluorinating diazine heteroarenes to form a single fluorinated isomer.

PRODRUGS OF HIV REPLICATION INHIBITING PYRIMIDINES

The present invention concerns compounds of formula (A1)(A2)N—R1 (I), the N-oxide forms, the pharmaceutically acceptable addition salts, the quaternary amines and stereochemically isomeric forms thereof, wherein R1 is substituted C1-6alkyl; —S(═O)—R8; —S(═O)2—R8; C7-12alkylcarbonyl; optionally substituted C1-6alkyloxycarbonylC1-6alkylcarbonyl; with R8 being C1-6alkyl, aryl1 or Het1; (A1)(A2)N— is the covalently bonded form of the corresponding intermediate of formula (A1)(A2)N—H, which is a HIV replication inhibiting pyrimidine of formula

Synthesis and late-stage functionalization of complex molecules through C-H fluorination and nucleophilic aromatic substitution

We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride. A diverse array of functionalities can be installed because of the mild reaction conditions revealed for nucleophilic aromatic substitutions (SNAr) of the 2-fluoroheteroarenes. An evaluation of the rates for substitution versus the rates for competitive processes provides a framework for planning this functionalization sequence. This process is illustrated by the modification of a series of medicinally important compounds, as well as the increase in efficiency of synthesis of several existing pharmaceuticals.

PROCESS FOR ETRAVIRINE INTERMEDIATE AND POLYMORPHS OF ETRAVIRINE

4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethyl-benzonitrile is a key intermediate for the preparation of etravirine. The present invention provides a process for preparation of 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile. The present invention also provides a novel process for the preparation of etravirine crystalline form I. The present invention further provides novel crystalline forms of etravirine, processes for their preparation and pharmaceutical compositions comprising them.

PROCESS FOR THE PREPARATION OF ETRAVIRINE AND INTERMEDIATES IN THE SYNTHESIS THEREOF

The present invention includes compounds of Formula (1) of the following structure: or salts thereof, wherein X is a halogen or a tosyl group. Processes for preparing the compounds of Formula (1) are disclosed in the patent application. The compounds of Formula I are useful as intermediates for preparation of Etravirine. The present invention is also directed toward processes for preparing Etravirine.

PROCESS FOR THE PRODUCTION OF ETRAVIRINE

A novel process for the preparation of Etravirine comprises the condensing of ethyl cyanoacetate with N-cyanophenylguanidine to obtain an —OH compound of formula (II), which is further converted to a leaving group of formula (III). The compound of formula (III) is optionally protected and brominated to yield compound of formula (IV). The condensation of formula (IV) with 3,5-dimethyl-4-hydroxybenzonitrile yields a compound of formula (VI), and an optional deprotection of the compound of formula (VI) results in Etravirine.

A PROCESS FOR ETRA VIRINE INTERMEDIATE AND POLYMORPHS OF ETRAVIRINE

4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethyl- benzonitrile is a key intermediate for the preparation of etravirine. The present invention provides a process for preparation of 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4- pyrimidinyl]oxy]-3,5-dimethylbenzonitrile. The present invention also provides a novel process for the preparation of etravirine crystalline form I. The present invention further provides novel crystalline forms of etravirine, processes for their preparation and pharmaceutical compositions comprising them.

PROCESS FOR THE PREPARATION OF ETRAVIRINE AND INTERMEDIATES IN THE SYNTHESIS THEREOF

The present patent application provides intermediates, e.g., 4-(6-(acetylamino)-2- chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile, for preparing Etravirine or the salts of Etravirine, and processes for preparing Etravirine or its salts as disclosed in the specification herein. The application also provides processes for preparing 4-(6-(acetylamino)-2- chloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile.