277299-70-4

Basic information

• Product Name: 2-(3,4-Dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one
• Synonyms: 2-(3,4-Dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one;2-(3,4-Dimethylphenyl)-5-methyl-1H-pyrazol-3(2H)-one;2-(3,4-dimethylphenyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one;Eltrombopag Intermediate 1;EltroMbopag II;2-Oxo-2,4,5,6,7,7a-Hexahydrothieno [3,2-c] Pyridine;1-(3,4-diMethylphenyl)-3-Methyl-1H-pyrazol-5-ol;1H-pyrazol-3(2H)-one,2-(3,4-Dimethylphenyl)-5-methyl-
• CAS NO: 277299-70-4
• Molecular Formula: C₁₂H₁₄N₂O
• Molecular Weight: 202.25
• EINECS: 1592732-453-0
• Mol File: 277299-70-4.mol
• Article Data: 4

Chemical Properties

• Melting Point: 121.0 to 125.0 °C
• Boiling Point: 338.5±52.0 °C(Predicted)
• Appearance: /
• Density: 1.121
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 0.79±0.40(Predicted)
• CAS DataBase Reference: 2-(3,4-Dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one(CAS DataBase Reference)
• NIST Chemistry Reference: 2-(3,4-Dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one(277299-70-4)
• EPA Substance Registry System: 2-(3,4-Dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one(277299-70-4)

Safety Data

• Hazardous Substances Data: 277299-70-4(Hazardous Substances Data)

Usage

Uses

2-(3,4-Dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one, is an impurity of Eltrombopag (E508000), which is agonist of the Thrombopoietin (Tpo) receptor, used as treatment for thrombocytopenia.

Synthetic route

ethyl acetoacetate (141-97-9) + 3,4-dimethylphenylhydrazine hydrochloride (60481-51-8, 86746-50-1) → 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4)

Conditions	Yield
With sodium bicarbonate; sodium acetate In diethyl ether; acetic acid	76%
With sodium acetate In acetic acid for 24h; Heating / reflux;	76%
With sodium acetate; acetic acid for 24h; Reflux;	76%

ethyl acetoacetate (141-97-9) + 3,4-dimethylphenylhydrazine (13636-53-8) → 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4)

Conditions	Yield
In acetic acid	64%

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) + 2-amino-6-bromophenol (28165-50-6) → 1-(3,4-dimethylphenyl)-3-methyl-4-(3-bromo-2-hydroxyphenyl)hydrazono-5-pyrazolone

Conditions	Yield
Stage #1: 2-amino-6-bromophenol With hydrogenchloride; sodium nitrite In ethanol; water at 0 - 10℃; Stage #2: 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one With triethylamine In ethanol; water at 20 - 30℃; for 2h; Reagent/catalyst;	98%

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) + 3'-amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid hydrochloride (376591-97-8) → 3’-{N’-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-di-hydropyrazol-4-ylidene]hydrazino}-2’-hydroxybiphenyl-3-carboxylic acid (376591-99-0)

Conditions	Yield
Stage #1: 3'-amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid hydrochloride With hydrogenchloride; sodium nitrite In methanol; water for 2.5h; pH=1-2; Stage #2: 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one With sodium hydrogencarbonate In methanol; water at 20℃; for 12h; pH=8; Stage #3: With hydrogenchloride In methanol; water at 0 - 20℃; for 3h; pH=1-2;	90%

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) + 3-amino-4-hydroxybenzoic acid (1571-72-8) → 3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-4-hydroxybenzoic acid

Conditions	Yield
	82%

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) → 4-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic acid

Conditions	Yield
	82%

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) + 3′-amino-2′-hydroxy biphenyl-3-carboxylic acid (376592-93-7) + triethylamine (121-44-8) → eltrombopag triethylamine salt

Conditions	Yield
Stage #1: 3'-amino-2'-hydroxy-1,1'-biphenyl-3-carboxylic acid With hydrogenchloride; sodium nitrite In methanol; water at 0 - 10℃; for 1.25h; Stage #2: 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one; triethylamine at 0 - 60℃; for 4h; pH=6 - 8; pH-value;	76%

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) + 2-amino-phenol (95-55-6) → eltrombopag olamine

Conditions	Yield
Stage #1: 2-amino-phenol With hydrogenchloride; sodium nitrite In methanol; water at 75 - 80℃; for 24h; Stage #2: 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one With triethylamine In methanol; water at 0 - 25℃; for 2.5h;	68%

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) + C13H11NO3*ClH (376591-78-5) → 4'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-3'-hydroxybiphenyl-4-carboxylic acid (376591-84-3)

Conditions	Yield
Stage #1: C13H11NO3*ClH With hydrogenchloride; sodium nitrite In water at 5℃; for 0.166667h; Stage #2: 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one With sodium hydrogencarbonate In ethanol; water at 20℃; for 24h; pH=7 - 8;	35%

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) + 2-amino-4-chlorophenol-6-sulfonic acid (88-23-3) → 5-chloro-3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-2-hydroxybenzenesulfonic acid

Conditions	Yield
	34%

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) + 3-aminosalicylic acid (570-23-0) → 3-{[1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-2-hydroxybenzoic acid

Conditions	Yield
	32%

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) + 3′-amino-2′-hydroxy biphenyl-3-carboxylic acid (376592-93-7) → eltrombopag olamine

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride; sodium nitrite / methanol; water / 1.25 h / 0 - 10 °C 1.2: 4 h / 0 - 60 °C / pH 6 - 8 2.1: methanol / 7.5 h / 25 - 60 °C View Scheme

2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one (277299-70-4) + 2-bromo-6-nitro-phenol (13073-25-1) + 3-Carboxyphenylboronic acid (25487-66-5) → Eltrombopag

Conditions	Yield
Stage #1: 2-bromo-6-nitro-phenol With benzyl bromide; potassium carbonate In acetonitrile at 90℃; for 3h; Stage #2: 3-Carboxyphenylboronic acid With potassium carbonate; palladium dichloride In 1,4-dioxane; water at 50℃; under 7500.75 Torr; for 4h; Inert atmosphere; Stage #3: 2-(3,4-dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one Further stages;

Upstream product

• 141-97-9 ethyl acetoacetate 
• 13636-53-8 3,4-dimethylphenylhydrazine 
• 60481-51-8 3,4-dimethylphenylhydrazine hydrochloride 

Downstream Products

• 376591-84-3 4'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-3'-hydroxybiphenyl-4-carboxylic acid 
• 376591-99-0 3’-{N’-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-di-hydropyrazol-4-ylidene]hydrazino}-2’-hydroxybiphenyl-3-carboxylic acid 

Relevant articles and documents

CRYSTALLINE FORM OF ELTROMBOPAG FREE ACID

The present invention relates to crystalline form of Eltrombopag free acid and its process for preparation.

Thrombopoietin mimetics

Invented are non-peptide TPO mimetics. Also invented are novel processes and intermediates used in the preparation of the presently invented compounds. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a selected hydroxy-1-azobenzene derivative.