269055-75-6

Basic information

• Product Name: BENZONITRILE, 4-[(5-BROMO-4,6-DICHLORO-2-PYRIMIDINYL)AMINO]-
• Synonyms: 4-(5-BROMO-4,6-DICHLOROPYRIMIDIN-2-YLAMINO)BENZONITRILE;BENZONITRILE, 4-[(5-BROMO-4,6-DICHLORO-2-PYRIMIDINYL)AMINO]-;4-[(5-Bromo-4,6-dichloro-2-pyrimidinyl)amino]benzonitrile
• CAS NO: 269055-75-6
• Molecular Formula: C₁₁H₅BrCl₂N₄
• Molecular Weight: 343.999
• EINECS: 1312995-182-4
• Product Categories: Amines;Aroamtics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 269055-75-6.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 524.308 °C at 760 mmHg
• Flash Point: 270.892 °C
• Appearance: /
• Density: 1.823 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.696
• Storage Temp.: 2-8°C
• PKA: -3.08±0.10(Predicted)
• CAS DataBase Reference: BENZONITRILE, 4-[(5-BROMO-4,6-DICHLORO-2-PYRIMIDINYL)AMINO]-(CAS DataBase Reference)
• NIST Chemistry Reference: BENZONITRILE, 4-[(5-BROMO-4,6-DICHLORO-2-PYRIMIDINYL)AMINO]-(269055-75-6)
• EPA Substance Registry System: BENZONITRILE, 4-[(5-BROMO-4,6-DICHLORO-2-PYRIMIDINYL)AMINO]-(269055-75-6)

Safety Data

• Hazardous Substances Data: 269055-75-6(Hazardous Substances Data)

Usage

Uses

Intermediate in the preparation of HIV replication inhibitors

InChI:InChI=1/C11H5BrCl2N4/c12-8-9(13)17-11(18-10(8)14)16-7-3-1-6(5-15)2-4-7/h1-4H,(H,16,17,18)

Synthetic route

4-((4,6-dichloropyrimidin-2-yl)amino)benzonitrile (329187-59-9) → 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6)

Conditions	Yield
With bromine; sodium hydrogencarbonate In methanol; water	78%
With N-Bromosuccinimide In tetrahydrofuran at 20℃;	9 g

N-Bromosuccinimide (128-08-5) + 4-((4,6-dichloropyrimidin-2-yl)amino)benzonitrile (329187-59-9) → 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6)

Conditions	Yield
Stage #1: 4-(4,6-dichloropyrimidine-2-yl-amino)benzonitrile In chloroform for 0.5h; Stage #2: N-Bromosuccinimide In chloroform at 20℃; for 40.5h;	55%

4-((4,6-dihydroxypyrimidine-2-yl)amino)benzonitrile (374067-80-8) → 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 86 percent / POCl3 2: 78 percent / Br2; NaHCO3 / H2O; methanol View Scheme
Multi-step reaction with 2 steps 1: trichlorophosphate / 12 h / 90 - 95 °C 2: N-Bromosuccinimide / tetrahydrofuran / 20 °C View Scheme

4-cyanophenyl guanidine hydrochloride → 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 76 percent / NaOEt / ethanol 2: 86 percent / POCl3 3: 78 percent / Br2; NaHCO3 / H2O; methanol View Scheme

1-(4-cyanophenyl)guanidine (5637-42-3) → 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium; methanol / methanol / 6 h / Reflux; Inert atmosphere 2: trichlorophosphate / 12 h / 90 - 95 °C 3: N-Bromosuccinimide / tetrahydrofuran / 20 °C View Scheme

4-Aminobenzonitrile (873-74-5) → 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: nitric acid / methanol; water / 8 h / 10 - 65 °C 2: sodium; methanol / methanol / 6 h / Reflux; Inert atmosphere 3: trichlorophosphate / 12 h / 90 - 95 °C 4: N-Bromosuccinimide / tetrahydrofuran / 20 °C View Scheme

4-hydroxy-3,5-[(2)H6]dimethylbenzonitrile (1316315-42-0) + 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) → 4-(5-bromo-6-chloro-2-(4-cyanophenylamino)-pyrimidin-4-yloxy)-3,5-[(2)H6]dimethylbenzonitrile (1316315-43-1)

Conditions	Yield
Stage #1: 4-hydroxy-3,5-[(2)H6]dimethylbenzonitrile With sodium hydride In 1,4-dioxane at 20℃; for 0.0333333h; Stage #2: With 1-methyl-pyrrolidin-2-one In 1,4-dioxane at 20℃; for 0.166667h; Stage #3: 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile In 1,4-dioxane at 155℃; for 6h;	83.6%

N-ethyl-N,N-diisopropylamine (7087-68-5) + 2,4,6-trimethylaniline (88-05-1) + 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) → 4-[[5-bromo-4-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile (269055-38-1)

Conditions	Yield
In 1,4-dioxane	54.9%
In 1,4-dioxane	54.9%

2,4,6-trimethylaniline (88-05-1) + 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) → 4-[[5-bromo-4-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile (269055-38-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 120 - 150℃; for 297.84h; Sealed tube;	54.9%

4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) + sodium 4-cyano-2,6-dimethylphenolate → 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile (269055-76-7)

Conditions	Yield
With 1-Methylpyrrolidine In 1,4-dioxane	45%

3,5-dimethyl-4-hydroxybenzonitrile (4198-90-7) + 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) → 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile (269055-76-7)

Conditions	Yield
Stage #1: 3,5-dimethyl-4-hydroxybenzonitrile With sodium hydride In 1,4-dioxane for 0.0333333h; Stage #2: With 1-methyl-pyrrolidin-2-one In 1,4-dioxane for 0.166667h; Stage #3: 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile In 1,4-dioxane at 155℃; for 16h;	45%

2,6-d2-4-hydroxy-3,5-bis(methyl-d3)benzonitrile (1142096-16-9) + 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) → 4-(5-bromo-6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-2,6-d2-3,5-bis(methyl-d3)benzonitrile (1142096-20-5)

Conditions	Yield
Stage #1: 2,6-d2-4-hydroxy-3,5-bis(methyl-d3)benzonitrile With sodium hydride In 1,4-dioxane at 20℃; for 0.0333333h; Stage #2: With 1-methyl-pyrrolidin-2-one In 1,4-dioxane at 20℃; for 0.166667h; Stage #3: 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile In 1,4-dioxane at 155℃; for 16h;	27%

4-amino-2,6-dimethyl-3,4-benzonitrile + N-ethyl-N,N-diisopropylamine (7087-68-5) + 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) → 4-[[5-bromo-4-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (269055-40-5)

Conditions	Yield
	5%

4-amino-2,5-dimethyl-3,4-benzonitrile + N-ethyl-N,N-diisopropylamine (7087-68-5) + 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) → 4-[[5-bromo-4-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (269055-40-5)

Conditions	Yield
	5%

2,6-dimethyl-4-aminobenzonitrile (114820-10-9) + 4-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) → 4-[[5-bromo-4-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (269055-40-5)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine at 155 - 160℃; for 36h; Sealed tube;	5%

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-[[(5-bromo-4,6-dichloro)-2-pyrimidinyl]amino]benzonitrile (269055-75-6) → 4-((4-amino-5-bromo-6-chloropyrimidin-2-yl)amino)benzonitrile (1398507-09-9)

Conditions	Yield
With ammonia In 1,4-dioxane at 50℃; for 1h; Sealed tube;	11 g

Upstream product

• 5637-42-3 1-(4-cyanophenyl)guanidine 
• 873-74-5 4-Aminobenzonitrile 
• 128-08-5 N-Bromosuccinimide 
• 329187-59-9 4-(4,6-dichloropyrimidine-2-yl-amino)benzonitrile 
• 373690-68-7 4-cyanophenyl guanidine hydrochloride 
• 374067-80-8 4-((4,6-dihydroxypyrimidine-2-yl)amino)benzonitrile 

Downstream Products

• 269055-15-4 etravirine 
• 269055-38-1 4-[[5-bromo-4-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile 
• 269055-40-5 4-[[5-bromo-4-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile 
• 269055-76-7 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile 
• 1398507-09-9 4-((4-amino-5-bromo-6-chloropyrimidin-2-yl)amino)benzonitrile 
• 1316315-43-1 4-(5-bromo-6-chloro-2-(4-cyanophenylamino)-pyrimidin-4-yloxy)-3,5-[⁽²⁾H₆]dimethylbenzonitrile 
• 1142096-20-5 4-(5-bromo-6-chloro-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-2,6-d2-3,5-bis(methyl-d3)benzonitrile 

Relevant articles and documents

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.

Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues

The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.