143782-20-1

Basic information

• Product Name: 4-(4,4-DiMethyl-2,5-dioxoiMidazolidin-1-yl)-2-trifluoroMethylbenzonitrile
• Synonyms: Benzonitrile, 4-(4,4-diMethyl-2,5-dioxo-1-iMidazolidinyl)-2-(trifluoroMethyl)-;RU 56279;2-(trifluoromethyl)-4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)benzonitrile;4-(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile
• CAS NO: 143782-20-1
• Molecular Formula: C₁₃H₁₀F₃N₃O₂
• Molecular Weight: 297
• Mol File: 143782-20-1.mol
• Article Data: 27

Chemical Properties

• Appearance: /
• Density: 1.46±0.1 g/cm3(Predicted)
• Storage Temp.: 2-8°C(protect from light)
• PKA: 7.69±0.70(Predicted)
• CAS DataBase Reference: 4-(4,4-DiMethyl-2,5-dioxoiMidazolidin-1-yl)-2-trifluoroMethylbenzonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 4-(4,4-DiMethyl-2,5-dioxoiMidazolidin-1-yl)-2-trifluoroMethylbenzonitrile(143782-20-1)
• EPA Substance Registry System: 4-(4,4-DiMethyl-2,5-dioxoiMidazolidin-1-yl)-2-trifluoroMethylbenzonitrile(143782-20-1)

Safety Data

• Hazardous Substances Data: 143782-20-1(Hazardous Substances Data)

Usage

Uses

4-(4,4-Dimethyl-2,5-dioxo-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile is an intermediate in the synthesis of Oxo-MDV 3100 (Oxo-enzalutamide) (O857800), which is an impurity of Enzalutamide (M199800), which is an androgen-receptor antagonist that blocks androgens from binding to the androgen receptor and prevents nuclear translocation and co-activator recruitment of the ligand-receptor complex. Enzalutamide has been shown to induce tumor cell apoptosis, and is used for the treatment of castration-resistant prostate cancer.

Synthetic route

4-iodo-2-(trifluoromethyl)benzonitrile (101066-87-9) + 5,5-dimethyl-imidazolidine-2,4-dione (77-71-4) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
With copper(I) oxide In N,N-dimethyl-formamide at 150℃; for 12h;	98%
With copper(I) oxide In N,N-dimethyl-formamide at 150℃; for 12h;	98%
With copper(I) oxide In N,N-dimethyl-formamide at 150℃; for 14h; Inert atmosphere; regioselective reaction;	82%

4-(4,4-Dimethyl-5-imino-2-oxo-1-imidazolidinyl)-2-trifluoromethyl-benzonitrile (143782-19-8) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
With hydrogenchloride; water for 0.583333h; Heating / reflux;	95%
With hydrogenchloride In water; isopropyl alcohol
With hydrogenchloride; water for 0.583333h; Reflux;
With hydrogenchloride; water In methanol for 0.5h; Reflux;

phosgene (75-44-5) + 4-amino-2-trifluoromethylbenzonitrile (654-70-6) + 2-amino-isobutyric acid tert-butyl ester hydrochloride (84758-81-6) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
Stage #1: phosgene; 4-amino-2-trifluoromethylbenzonitrile In toluene; acetonitrile at 70℃; Stage #2: 2-amino-isobutyric acid tert-butyl ester hydrochloride With triethylamine In toluene; acetonitrile at 20℃; Stage #3: With hydrogenchloride; water In toluene; acetonitrile at 70℃; for 1h;	90%
Stage #1: phosgene; 4-amino-2-trifluoromethylbenzonitrile In toluene; acetonitrile at 70℃; for 1h; Stage #2: 2-amino-isobutyric acid tert-butyl ester hydrochloride With triethylamine In acetonitrile at 20℃; Stage #3: With hydrogenchloride In water; acetonitrile at 70℃; for 1h;	90%

5,5-dimethyl-imidazolidine-2,4-dione (77-71-4) + 4-fluoro-2-(trifluoromethyl)benzonitrile (194853-86-6) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
Stage #1: 5,5-dimethyl-imidazolidine-2,4-dione With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 0.5h; Stage #2: 4-fluoro-2-(trifluoromethyl)benzonitrile In N,N-dimethyl-formamide for 5h; Heating;	79%
Stage #1: 5,5-dimethyl-imidazolidine-2,4-dione With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 0.5h; Stage #2: 4-fluoro-2-(trifluoromethyl)benzonitrile In N,N-dimethyl-formamide for 5h;	79%
With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 48h; Inert atmosphere;	74%

(4-cyano-3-(trifluoromethyl)phenyl)boronic acid + 5,5-dimethyl-imidazolidine-2,4-dione (77-71-4) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
With pyridine; oxygen; copper diacetate In dichloromethane for 168h;	79%

4-fluoro-2-(trifluoromethyl)benzonitrile (261952-05-0) + 5,5-dimethyl-imidazolidine-2,4-dione (77-71-4) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 45℃; for 24h;	74%

5,5-dimethyl-imidazolidine-2,4-dione (77-71-4) + 4-chloro-2-(trifluoromethyl)benzonitrile (320-41-2) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
With 18-crown-6 ether; sodium hydride In N,N-dimethyl-formamide at 140℃; for 60h;	55%

C24H9BiF9N3 + 5,5-dimethyl-imidazolidine-2,4-dione (77-71-4) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
With pyridine; copper diacetate In dichloromethane at 20℃;	8%

5,5-dimethyl-3-(4-iodo-3-(trifluoromethyl) phenyl) 2,4-imidazolidinedione → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
In N-methyl-acetamide; water; ethyl acetate

C17H20F3N3O3 → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
With hydrogenchloride; water In acetonitrile at 70℃; for 1h;
With hydrogenchloride In water; acetonitrile at 70℃; for 1h;
With hydrogenchloride; water In acetonitrile at 70℃; for 1h;

4-isocyanato-2-(trifluoromethyl)benzonitrile (143782-18-7) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 0.75 h / 20 °C 2: hydrogenchloride / acetonitrile; water / 1 h / 70 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / acetonitrile / 0.75 h / 20 °C 2: hydrogenchloride; water / acetonitrile / 1 h / 70 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / 1,1-dichloroethane / 5 - 20 °C 2: hydrogenchloride; water / 0.58 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 1 h / Reflux 2: water; hydrogenchloride / methanol / 0.5 h / Reflux View Scheme

4-amino-2-trifluoromethylbenzonitrile (654-70-6) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetonitrile / 70 °C 2: triethylamine / acetonitrile / 0.75 h / 20 °C 3: hydrogenchloride / acetonitrile; water / 1 h / 70 °C View Scheme
Multi-step reaction with 3 steps 1: toluene; acetonitrile / 70 °C 2: triethylamine / acetonitrile / 0.75 h / 20 °C 3: hydrogenchloride; water / acetonitrile / 1 h / 70 °C View Scheme
Multi-step reaction with 3 steps 1: ethyl acetate; toluene / 0.5 h / 0 - 5 °C 2: triethylamine / 1,1-dichloroethane / 5 - 20 °C 3: hydrogenchloride; water / 0.58 h / Reflux View Scheme
Multi-step reaction with 6 steps 1: potassium carbonate / 1,2-dichloro-ethane / 14 h / 20 °C 2: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 3: iron; hydrogenchloride / isopropyl alcohol; ethanol; water / 1 h / 90 °C 4: potassium carbonate / 1,2-dichloro-ethane / 14 h 5: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 6: N,N-dimethyl-formamide / 7 h / 110 °C View Scheme
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / dichloromethane; toluene / 2 h / 0 - 20 °C 2: triethylamine / tetrahydrofuran / 1 h / Reflux 3: water; hydrogenchloride / methanol / 0.5 h / Reflux View Scheme

2-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide (1259327-69-9) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 2: iron; hydrogenchloride / isopropyl alcohol; ethanol; water / 1 h / 90 °C 3: potassium carbonate / 1,2-dichloro-ethane / 14 h 4: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 5: N,N-dimethyl-formamide / 7 h / 110 °C View Scheme

N-[4-cyano-3-(tri-fluoromethyl)phenyl]-2-methyl-2-nitropropanamide → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: iron; hydrogenchloride / isopropyl alcohol; ethanol; water / 1 h / 90 °C 2: potassium carbonate / 1,2-dichloro-ethane / 14 h 3: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 4: N,N-dimethyl-formamide / 7 h / 110 °C View Scheme

2-amino-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methylpropanamide (208122-09-2) → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / 1,2-dichloro-ethane / 14 h 2: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 3: N,N-dimethyl-formamide / 7 h / 110 °C View Scheme

2-bromo-N-(1-{[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl}-1-methylethyl)-2-methylpropanamide → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium nitrite / N,N-dimethyl-formamide / 14 h / 20 °C 2: N,N-dimethyl-formamide / 7 h / 110 °C View Scheme

N-(1-{[4-cyano-3-(trifluoromethyl)phenyl]carbamoyl}-1-methylethyl)-2-methyl-2-nitropropanamide → 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1)

Conditions	Yield
In N,N-dimethyl-formamide at 110℃; for 7h;	587 mg

2-bromo-5-methoxybenzyl bromide (19614-12-1) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-[3-(2-bromo-5-methoxybenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile (1006898-70-9)

Conditions	Yield
With caesium carbonate In acetonitrile	98%

4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) + CH3X → 4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-2-trifluoromethyl-benzonitrile (143782-31-4)

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: CH3X In N,N-dimethyl-formamide at 20℃; for 3h;	95%

2-benzylbenzyl bromide (55276-42-1) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-[3-(2-benzylbenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile (1179803-73-6)

Conditions	Yield
With caesium carbonate In acetonitrile at 20℃; for 4h;	94%

(E)-1-(tri-n-butylstannyl)-3-chloro-1-propene + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → (E)-4-[4,4-dimethyl-2,5-dioxo-3-{1'-iodo-1'-propen-3'-yl}-1-imidazolidinyl]-2-trifluoromethylbenzonitrile

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: (E)-1-(tri-n-butylstannyl)-3-chloro-1-propene In N,N-dimethyl-formamide at 20℃; for 3h; Stage #3: With iodine In chloroform	91%

4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) + XCH2(m-I-Ph) → 4-[3-(3-iodo-benzyl)-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: XCH2(m-I-Ph) In N,N-dimethyl-formamide at 20℃; for 3h;	91%

4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) + X(CH2)3F → 4-[3-(3-fluoro-propyl)-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: X(CH2)3F In N,N-dimethyl-formamide at 20℃; for 3h;	90%

4-iodophenethyl 4-methylbenzenesulfonate + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-{3-[2-(4-iodo-phenyl)-ethyl]-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl}-2-trifluoromethyl-benzonitrile

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: toluene-4-sulfonic acid 2-(4-iodo-phenyl)-ethyl ester In N,N-dimethyl-formamide at 20℃; for 3h;	89%

4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) + X(CH2)2OCH3 → 4-(4,4-dimethyl-2,5-dioxo-3-(2-methoxyethyl)-1-imidazolidinyl) 2-trifluoromethyl-benzonitrile

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: X(CH2)2OCH3 In N,N-dimethyl-formamide at 20℃; for 3h;	89%

iodobenzene (591-50-4) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-1-phenylhydantoin

Conditions	Yield
With copper(l) iodide; potassium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine In toluene at 110℃; for 48h; Inert atmosphere;	88%

1-bromomethyl-4-iodobenzene (16004-15-2) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-[3-(4-iodo-benzyl)-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 1-bromomethyl-4-iodobenzene In N,N-dimethyl-formamide at 20℃; for 3h;	86%

4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) + X(CH2)4F → 4-[3-(4-fluoro-butyl)-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: X(CH2)4F In N,N-dimethyl-formamide at 20℃; for 3h;	86%

4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) + 1-Bromo-2-bromomethyl-benzene (3433-80-5) → 4-[3-(2-bromobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile (1006898-69-6)

Conditions	Yield
With potassium carbonate In acetonitrile at 20℃; for 5h;	86%
With potassium carbonate In acetonitrile at 20℃; for 5h;	86%
With potassium carbonate In acetonitrile at 20℃; for 5h;	86%

1,4-dibromo-butane (110-52-1) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-[3-(4-bromo-butyl)-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl]-2-trifluoromethylbenzonitrile (636595-83-0)

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: 1,4-dibromo-butane In N,N-dimethyl-formamide at 60℃; for 0.5h;	85%
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: 1,4-dibromo-butane In N,N-dimethyl-formamide at 60℃; for 0.5h;	85%

1,3-dibromo-propane (109-64-8) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → C16H15BrF3N3O2

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Cooling; Stage #2: 1,3-dibromo-propane In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;	85%
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;	85%

1,1'-oxybis(2-bromo-ethane) (5414-19-7) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-{3-[2-(2-bromoethoxy)ethyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (636595-85-2)

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: 1,1'-oxybis(2-bromo-ethane) In N,N-dimethyl-formamide at 60℃; for 0.5h;	82%

4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) + 6-(4-bromobut-2-ynyloxymethyl)-2,2-dimethyl-2,3-dihydrobenzo[e][1,3]oxazin-4-one (636595-66-9) → 4-{3-[4-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-ylmethoxy)but-2-ynyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (636595-74-9)

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 3h; Stage #2: 6-(4-bromobut-2-ynyloxymethyl)-2,2-dimethyl-2,3-dihydrobenzo[e][1,3]oxazin-4-one In N,N-dimethyl-formamide at 20℃; for 6h;	82%
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 3h; Stage #2: 6-(4-bromobut-2-ynyloxymethyl)-2,2-dimethyl-2,3-dihydrobenzo[e][1,3]oxazin-4-one In N,N-dimethyl-formamide at 20℃; for 6h;	82%

1,3-dibromo-propane (109-64-8) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → C16H15F3N6O2

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Inert atmosphere; Stage #2: 1,3-dibromo-propane In N,N-dimethyl-formamide; mineral oil at 55℃; for 2h; Inert atmosphere;	81%

4-Bromobutyl acetate (4753-59-7) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile (154992-24-2)

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.25h; Stage #2: 4-Bromobutyl acetate In N,N-dimethyl-formamide; mineral oil at 50℃; for 2h;	80%

ethyl bromoacetate (105-36-2) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → Ethyl3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-2,4-dioxo-1-imidazolidine-acetate (143782-22-3)

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h; Inert atmosphere; Stage #2: ethyl bromoacetate In N,N-dimethyl-formamide; mineral oil at 55℃; for 5h; Inert atmosphere;	80%

3-(4'-iodophenyl)-1-propyl tosylate + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-{3-[3-(4-iodo-phenyl)-propyl]-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl}-2-trifluoromethyl-benzonitrile

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 3-(4'-iodophenyl)-1-propyl tosylate In N,N-dimethyl-formamide at 20℃; for 3h;	78%

1-chloro-3-(2-tetrahydropyranyloxy)propane (42330-88-1) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-{4,4-Dimethyl-2,5-dioxo-3-[3-(tetrahydro-furan-2-yloxy)-propyl]-imidazolidin-1-yl}-2-trifluoromethyl-benzonitrile

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide for 0.5h; Stage #2: 1-chloro-3-(2-tetrahydropyranyloxy)propane With sodium iodide In N,N-dimethyl-formamide at 50℃; for 36h;	73%

4-bromo-2-fluoro-N-methylbenzanamide (749927-69-3) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide (1242137-18-3)

Conditions	Yield
With copper(l) iodide; potassium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine In toluene at 110℃; Reagent/catalyst; Inert atmosphere;	70%

4-ethynylbenzyl 4-methylbenzenesulfonate (1158998-68-5) + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-[3-[(4-ethynylphenyl)methyl]-4,4-dimethyl-2,5-dioxo-1-imidazolidinyl]-2-(trifluoromethyl)benzonitrile (1350841-19-8)

Conditions	Yield
Stage #1: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h; Inert atmosphere; Stage #2: 4-ethynylbenzyl 4-methylbenzenesulfonate In N,N-dimethyl-formamide; mineral oil at 53℃; for 11h;	69%

4-(hydroxymethyl)phenylmethyl(2-(methyl(2-phenylcyclopropyl)amino)ethyl)carbamate + 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (143782-20-1) → 4-((3-(4-cyano-3-(trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl)phenylmethyl2-(methyl(2-phenylcyclopropyl)amino)ethyl)carbamate

Conditions	Yield
Stage #1: 4-(hydroxymethyl)phenylmethyl(2-(methyl(2-phenylcyclopropyl)amino)ethyl)carbamate With thionyl chloride In dichloromethane at 20℃; for 1h; Stage #2: 4-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile With sodium hydride In N,N-dimethyl-formamide at 20℃; for 6h;	65.5%

Upstream product

• 261952-05-0 4-methyl-2-(trifluoromethyl)benzonitrile 
• 77-71-4 5,5-dimethyl-imidazolidine-2,4-dione 
• 101066-87-9 4-iodo-2-(trifluoromethyl)benzonitrile 
• 208122-09-2 2-amino-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-methylpropanamide 
• 1259327-69-9 2-bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-methylpropanamide 
• 75-44-5 phosgene 
• 654-70-6 4-amino-2-trifluoromethylbenzonitrile 
• 84758-81-6 2-amino-isobutyric acid tert-butyl ester hydrochloride 
• 143782-19-8 4-(4,4-Dimethyl-5-imino-2-oxo-1-imidazolidinyl)-2-trifluoromethyl-benzonitrile 
• 320-41-2 4-chloro-2-(trifluoromethyl)benzonitrile 
• 915299-32-0 (4-cyano-3-(trifluoromethyl)phenyl)boronic acid 
• 194853-86-6 4-fluoro-2-(trifluoromethyl)benzonitrile 
• 143782-18-7 4-isocyanato-2-(trifluoromethyl)benzonitrile 

Downstream Products

• 636595-83-0 4-[3-(4-bromo-butyl)-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl]-2-trifluoromethylbenzonitrile 
• 636595-74-9 4-{3-[4-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-ylmethoxy)but-2-ynyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile 
• 636595-68-1 4-(3-{2-[2-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-ylmethoxy)-ethoxy]-ethyl}-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-2-trifluoromethyl-benzonitrile 
• 636595-71-6 4-[3-(2-{2-[2-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[e][1,3]oxazin-6-ylmethoxy)-ethoxy]-ethoxy}-ethyl)-4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile 
• 143782-21-2 2-(5,5-dimethyl-3-(4-cyano-3-(trifluoromethyl)phenyl)-2,4-dioxoimidazolin-1-yl)acetic acid 
• 143782-22-3 2-(5,5-dimethyl-3-(4-cyano-3-(trifluoromethyl)phenyl)-2,4-dioxoimidazolin-1-yl) ethyl acetate 
• 1006898-69-6 4-[3-(2-bromobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile 
• 1006899-00-8 tert-Butyl {2-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]phenyl}carbamate 
• 1006898-92-5 4-[3-(2-aminobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile 
• 1178953-04-2 4-(4,4-dimethyl-2,5-dioxo-3-{2-[4-(2-oxopiperazin-1-ylmethyl)phenylamino]-benzyl}imidazolidin-1-yl)-2-trifluoromethylbenzonitrile 
• 1178953-41-7 benzyl 4-(4-{2-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-ylmethyl]phenylamino}benzyl)-3-oxopiperazine-1-carboxylate 
• 154992-24-2 4-[3-(4-hydroxybutyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 
• 1006898-70-9 4-[3-(2-bromo-5-methoxybenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile 
• 636595-88-5 4-{4,4-dimethyl-2,5-dioxo-3-[2-(2-piperazin-1-ylethoxy)ethoxy]imidazolidin-1-yl}-2-trifluoromethylbenzonitrile 

Relevant articles and documents

ARYL HYDANTOIN HETEROCYCLES AND METHODS OF USE

Disclosed is a compound of formula (I) in which R1, R2, R3, X1, X2, X2', X3, X4, ring A, m, n, and o are as described herein. The compound of formula (I) is useful for treating a disorder associated with androgen receptor malfunction, such as a hyperproliferative disorder, in a subject in need thereof.

The design, synthesis and anti-tumor mechanism study of new androgen receptor degrader

Targeted protein degradation using small molecules is a novel strategy for drug development. In order to solve the problem of drug resistance in the treatment of prostate cancer, proteolysis-targeting chimeras (PROTAC) was introduced into the design of anti-prostate cancer derivatives. In this work, we synthesized two series of selective androgen receptor degraders (SARDs) containing the hydrophobic degrons with different linker, and then investigated the structure-activity relationships of these hybrid compounds. Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Among them, compound A9 displayed potent inhibitory activity against LNCaP prostate cancer cell line with IC50 values of 1.75 μM, as well as excellent AR degradation activity. Primary mechanism studies elucidated compound A9 arrested cell cycle at G0/G1 phase and induced a mild apoptotic response in LNCaP cells. Further study indicated that the degradation of AR was mediated through proteasome-mediated process. For all these reasons, compound A9 held promising potential as anti-proliferative agent for the development of highly efficient SARDs for drug-resistance prostate cancer therapies.

Phthalimide selective androgen receptor degradation agent as well as preparation method and application thereof

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