873055-58-4

Basic information

• Product Name: 5-AMino-2,4-di-tert-butylphenol
• Synonyms: 5-AMino-2,4-di-tert-butylphenol;2,4-Di-tert-butyl-5-aMinophenyl Methyl carbonate;Phenol, 5-amino-2,4-bis(1,1-dimethylethyl)-;4,6-dichloropyridazin-4-ol
• CAS NO: 873055-58-4
• Molecular Formula: C₁₄H₂₃NO
• Molecular Weight: 221.33852
• EINECS: -0
• Mol File: 873055-58-4.mol
• Article Data: 24

Chemical Properties

• Boiling Point: 319.7±30.0 °C(Predicted)
• Appearance: /
• Density: 0.990±0.06 g/cm3(Predicted)
• Storage Temp.: 2-8°C(protect from light)
• PKA: 11.63±0.23(Predicted)
• CAS DataBase Reference: 5-AMino-2,4-di-tert-butylphenol(CAS DataBase Reference)
• NIST Chemistry Reference: 5-AMino-2,4-di-tert-butylphenol(873055-58-4)
• EPA Substance Registry System: 5-AMino-2,4-di-tert-butylphenol(873055-58-4)

Safety Data

• Hazardous Substances Data: 873055-58-4(Hazardous Substances Data)

Usage

Description

5-Amino-2,4-di-tert-butylphenol is an organic compound characterized by the presence of an amino group attached to a phenol ring, with two tert-butyl groups attached to the 2nd and 4th positions. This structure endows it with unique chemical properties and reactivity, making it a valuable intermediate in the synthesis of various pharmaceutical compounds.

Uses

Used in Pharmaceutical Industry:
5-Amino-2,4-di-tert-butylphenol is used as a key intermediate in the synthesis of ivacaftor, a medication designed to treat cystic fibrosis. It plays a crucial role in the condensation reaction with oxo dihydroquinoline carboxylic acid, leading to the formation of the final drug product. This application is significant as it contributes to the development of treatments for a genetic disorder that affects the respiratory and digestive systems, improving the quality of life for patients with cystic fibrosis.

Synthetic route

2,4-di-tert-butyl-5-nitro-phenol (873055-57-3) → 5-amino-2,4-di-tert-butyl-phenol (873055-58-4)

Conditions	Yield
With ammonium formate; 5%-palladium/activated carbon In ethanol for 2h; Heating / reflux;	100%
With ammonium formate; palladium on carbon In ethanol for 2h; Reflux;	100%
With 5%-palladium/activated carbon; ammonium formate In ethanol for 2h; Reflux;	100%

N-(2,4-di-tert-butyl-5-hydroxyphenyl)acetamide → 5-amino-2,4-di-tert-butyl-phenol (873055-58-4)

Conditions	Yield
With hydrogenchloride In ethanol; water for 6h; Reflux;	89%
With hydrogenchloride In ethanol; water for 12h; Reflux;	88%

2,4-di-tert-butyl-5-nitro-phenol (873055-57-3) + pyrographite (7440-44-0) → 5-amino-2,4-di-tert-butyl-phenol (873055-58-4)

Conditions	Yield
With ammonium formate In ethanol

carbonic acid 2,4-di(tert-butyl)-5-nitrophenyl ester methyl ester (873055-55-1) → 5-amino-2,4-di-tert-butyl-phenol (873055-58-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; KOH / methanol 2: ammonium formate / ethanol View Scheme
Multi-step reaction with 2 steps 1: potassium hydroxide / methanol 2: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1.1: potassium hydroxide / methanol / 2 h / 25 °C 1.2: pH 2 - 3 2.1: ammonium formate; 5%-palladium/activated carbon / ethanol / 2 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: methanol; potassium hydroxide / 2 h / 20 °C 1.2: pH 2 - 3 2.1: ammonium formate / 5% palladium over charcoal / ethanol / 2 h / Heating / reflux View Scheme

carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester (873055-54-0) → 5-amino-2,4-di-tert-butyl-phenol (873055-58-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: sulfuric acid; nitric acid; sodium sulfate / hexane; water 2: hydrogenchloride; KOH / methanol 3: ammonium formate / ethanol View Scheme
Multi-step reaction with 3 steps 1: nitric acid / (2S)-N-methyl-1-phenylpropan-2-amine hydrate; sulfuric acid 2: hydrogenchloride; KOH / methanol 3: ammonium formate / ethanol View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid; nitric acid / 2 h / 25 °C / Cooling 2.1: potassium hydroxide / methanol / 2 h / 25 °C 2.2: pH 2 - 3 3.1: ammonium formate; 5%-palladium/activated carbon / ethanol / 2 h / Reflux View Scheme

2,4-di-tert-Butylphenol (96-76-4) → 5-amino-2,4-di-tert-butyl-phenol (873055-58-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine; dmap / dichloromethane / 2 h / 0 - 5 °C 1.2: 1.5 h / 0 - 5 °C 2.1: potassium hydroxide / methanol 3.1: palladium 10% on activated carbon; hydrogen / methanol / 2 h / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: dmap; triethylamine / dichloromethane / 16 h / 0 - 25 °C 2.1: sulfuric acid; nitric acid / 2 h / 25 °C / Cooling 3.1: potassium hydroxide / methanol / 2 h / 25 °C 3.2: pH 2 - 3 4.1: ammonium formate; 5%-palladium/activated carbon / ethanol / 2 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: dmap; triethylamine / dichloromethane / 0 - 20 °C 2.1: sulfuric acid; nitric acid / 2 h / 50 °C / Cooling with ice 2.2: 2 h / 20 °C 3.1: 5%-palladium/activated carbon; ammonium formate / ethanol / 2 h / Reflux View Scheme

m-Hydroxyaniline (591-27-5) → 5-amino-2,4-di-tert-butyl-phenol (873055-58-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetic acid / 2 h / 60 °C 2: sulfuric acid / toluene / 12 h / 10 - 30 °C 3: hydrogenchloride / ethanol; water / 12 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: acetic acid / 2 h / 50 °C 2: sulfuric acid / dichloromethane / 48 h / 20 °C 3: hydrogenchloride / ethanol; water / 6 h / Reflux View Scheme

2,4-di-tert-butylphenyl ethyl carbonate → 5-amino-2,4-di-tert-butyl-phenol (873055-58-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sulfuric acid / 0 - 5 °C 1.2: 10 h / 0 - 10 °C 1.3: 0 - 30 °C 2.1: hydrogen / isopropyl alcohol / 20 °C / 3000.3 - 4500.45 Torr View Scheme

meta-hydroxyacetanilide (621-42-1) → 5-amino-2,4-di-tert-butyl-phenol (873055-58-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sulfuric acid / dichloromethane / 48 h / 20 °C 2: hydrogenchloride / ethanol; water / 6 h / Reflux View Scheme

trimethylsilylazide (4648-54-8) + 5-amino-2,4-di-tert-butyl-phenol (873055-58-4) → (5-azido-2,4-di-tert-butylphenoxy)trimethylsilane

Conditions	Yield
With tert.-butylnitrite In acetonitrile at 0 - 20℃; for 18h; Inert atmosphere;	73%

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) + 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (13721-01-2) → ivacaftor (873054-44-5)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide	71%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 25℃; for 12h;	71%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;	71%

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) + 4-chloroquinoline-3-carbonyl chloride (765222-35-3) → C24H27ClN2O2

Conditions	Yield
With triethylamine In tetrahydrofuran at 20℃; for 2h;	62%

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) + C10H5Br2NO → C24H27BrN2O2

Conditions	Yield
With triethylamine In tetrahydrofuran at 20℃; for 2h;	59%

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) → ivacaftor (873054-44-5)

Conditions	Yield
Stage #1: 4-oxo-1,4-dihydroquinoline-3-carboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 5-amino-2-4-di-tert-butyl-phenol In N,N-dimethyl-formamide at 20℃;	52%

formaldehyd (50-00-0) + 5-amino-2,4-di-tert-butyl-phenol (873055-58-4) → 2,4-di-tert-butyl-6-(N-methylamino)phenol (1085-21-8)

Conditions	Yield
With sodium cyanoborohydride In methanol for 3h; Reflux;	15%

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) + 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid (197367-75-2) → N-(2,4-di-tert-butyl-5-hydroxyphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide (1161024-91-4)

Conditions	Yield
Stage #1: 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid With triethylamine; HATU In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: 5-amino-2-4-di-tert-butyl-phenol In tetrahydrofuran at 65℃; for 16h;

7-ethyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-3-carboxylic acid (1161025-08-6) + 5-amino-2,4-di-tert-butyl-phenol (873055-58-4) → N-(2,4-di-tert-butyl-5-hydroxyphenyl)-7-ethyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-3-carboxamide (1161025-00-8)

Conditions	Yield
Stage #1: 7-ethyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-3-carboxylic acid With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In 2-methyltetrahydrofuran at 45℃; for 0.5h; Stage #2: 5-amino-2-4-di-tert-butyl-phenol In 2-methyltetrahydrofuran at 45℃; for 16h;

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) + 1-benzyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acide (35975-86-1) → N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (1622228-86-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 25 - 30℃; for 4h;	15.5 g

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) + methyl chloroformate (79-22-1) → 5-amino-2,4-di-tert-butylphenyl methyl carbonate (1182822-31-6)

Conditions	Yield
With triethylamine In diethyl ether at 0 - 20℃;

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) → 1-benzyl-3-(1-(2,4-di-tert-butyl-5-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)quinolin-4(1H)-one

Conditions	Yield
Multi-step reaction with 3 steps 1: tert.-butylnitrite / acetonitrile / 18 h / 0 - 20 °C / Inert atmosphere 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 3: copper(ll) sulfate pentahydrate; sodium L-ascorbate / water; dichloromethane; tert-butyl alcohol / 24 h / 60 °C / Inert atmosphere View Scheme

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) → 3-(1-(2,4-di-tert-butyl-5-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)quinolin-4(1H)-one

Conditions

Yield

Multi-step reaction with 4 steps 1: tert.-butylnitrite / acetonitrile / 18 h / 0 - 20 °C / Inert atmosphere 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere 3: copper(ll) sulfate pentahydrate; sodium L-ascorbate / water; dichloromethane; tert-butyl alcohol / 24 h / 60 °C / Inert atmosphere 4: palladium(II) hydroxide; ammonium formate / N,N-dimethyl-formamide / 8.5 h / 80 °C / Inert atmosphere View Scheme

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) → 5-azido-2,4-di-tertbutylphenol

Conditions	Yield
Multi-step reaction with 2 steps 1: tert.-butylnitrite / acetonitrile / 18 h / 0 - 20 °C / Inert atmosphere 2: tetrabutyl ammonium fluoride / tetrahydrofuran / 2 h / 0 - 20 °C / Inert atmosphere View Scheme

5-amino-2,4-di-tert-butyl-phenol (873055-58-4) + C18H14ClNO3 → N-(2,4-di-tert-butyl-5-hydroxyphenyl)-2-(3,4-dimethoxyphenyl)quinoline-4-carboxamide

Conditions	Yield
With dmap In N,N-dimethyl-formamide at 20℃;

Upstream product

• 873055-57-3 2,4-di-tert-butyl-5-nitro-phenol 
• 621-42-1 meta-hydroxyacetanilide 
• 591-27-5 m-Hydroxyaniline 
• 96-76-4 2,4-di-tert-Butylphenol 
• 873055-54-0 carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester 
• 873055-55-1 carbonic acid 2,4-di(tert-butyl)-5-nitrophenyl ester methyl ester 
• 7440-44-0 pyrographite 

Downstream Products

• 873054-44-5 ivacaftor 
• 1161024-91-4 N-(2,4-di-tert-butyl-5-hydroxyphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxamide 
• 1161025-00-8 N-(2,4-di-tert-butyl-5-hydroxyphenyl)-7-ethyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-3-carboxamide 
• 1182822-31-6 5-amino-2,4-di-tert-butylphenyl methyl carbonate 
• 1085-21-8 2,4-di-tert-butyl-6-(N-methylamino)phenol 
• 1622228-86-7 N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide 

Relevant articles and documents

METHODS OF TREATMENT FOR CYSTIC FIBROSIS

This application describes methods of treating cystic fibrosis or a CFTR mediated disease comprising administering Compound I or a pharmaceutically acceptable salt thereof. (I) The application also describes pharmaceutical compositions comprising Compound I or a pharmaceutically acceptable salt thereof and optionally comprising one or more additional CFTR modulating agents.

COMPOSITIONS AND METHODS FOR TREATMENT OF CYSTIC FIBROSIS

Compositions comprising Compound I of the formula (I) and methods of treating cystic fibrosis comprising administering Compound I. Compositions comprising a pharmaceutically acceptable salt of Compound I and methods of treating cystic fibrosis comprising administering a pharmaceutically acceptable salt of Compound I.

METHODS OF TREATMENT FOR CYSTIC FIBROSIS

Compound I of the formula (I) and/or pharmaceutically acceptable salt(s) of Compound I comprised in a pharmaceutical composition and methods of using the same to treat cystic fibrosis.