161798-02-3

Basic information

• Product Name: Ethyl 2-(3-Cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate
• Synonyms: Ethyl 2-(3-Cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate;2-(3-Cyano-4-hydroxyphenyl)-4-Methyl-1,3-thiazole-5-carboxylicacidethylester;Febuxostat Impurity 5;2-(3-Cyano-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester;2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate;Ethyl 2-(3-cyano-4-oxocyclohexa-2,5-dien-1-ylidene)-4-methyl-3H-1,3-thiazole-5-carboxylate;Febuxostat 4-Hydroxy Ethyl Ester;Ethyl 2-(3-cyano-4-hydroxyphenyl)
• CAS NO: 161798-02-3
• Molecular Formula: C₁₄H₁₂N₂O₃S
• Molecular Weight: 288.32
• EINECS: 1308068-626-2
• Product Categories: Pharmaceutical Intermediates;Febuxostat intermediate
• Mol File: 161798-02-3.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 475.3±55.0 °C(Predicted)
• Appearance: /
• Density: 1.38
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 5.80±0.20(Predicted)
• CAS DataBase Reference: Ethyl 2-(3-Cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl 2-(3-Cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate(161798-02-3)
• EPA Substance Registry System: Ethyl 2-(3-Cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate(161798-02-3)

Safety Data

• Hazardous Substances Data: 161798-02-3(Hazardous Substances Data)

Usage

Uses

2-(3-Cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic Acid Ethyl Ester, can be used for the synthesis of Febuxostat (F229000), an antipodagrics.

Synthetic route

ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate (161798-01-2) → ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3)

Conditions	Yield
Stage #1: ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate With hydroxylamine hydrochloride In N,N-dimethyl-formamide for 0.5h; Stage #2: With acetyl chloride In N,N-dimethyl-formamide at 90℃;	99%
Stage #1: ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate With hydroxylamine hydrochloride In N,N-dimethyl-formamide for 0.5h; Stage #2: With acetyl chloride In N,N-dimethyl-formamide at 90℃;	99%
With formic acid; hydroxylamine hydrochloride; sodium acetate at 100 - 105℃; for 10h;	97.6%

ethyl 2-[4-(benzyloxy)-3-cyanophenyl]-4-methyl-1,3-thiazole-5-carboxylate (934470-15-2) → ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3)

Conditions	Yield
palladium-carbon In tetrahydrofuran; ethanol
With hydrogen; palladium on activated charcoal In tetrahydrofuran; ethanol at 20℃;

ethyl 2-chloro-3-oxo-butyrate (609-15-4) → ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: spirit / 2.5 h / 60 - 65 °C 2: methanesulfonic acid / 10 h / 75 °C 3: hydroxylamine hydrochloride; sodium formate; formic acid / 8 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1: ethanol / Reflux 2: phosphorus pentoxide 3: hydroxylamine hydrochloride; sodium acetate; formic acid View Scheme

(2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester) (161797-99-5) → ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanesulfonic acid / 10 h / 75 °C 2: hydroxylamine hydrochloride; sodium formate; formic acid / 8 h / 100 °C View Scheme
Multi-step reaction with 2 steps 1: phosphorus pentoxide 2: hydroxylamine hydrochloride; sodium acetate; formic acid View Scheme

4-hydroxythiobenzamide (25984-63-8) → ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: spirit / 2.5 h / 60 - 65 °C 2: methanesulfonic acid / 10 h / 75 °C 3: hydroxylamine hydrochloride; sodium formate; formic acid / 8 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1: ethanol / Reflux 2: phosphorus pentoxide 3: hydroxylamine hydrochloride; sodium acetate; formic acid View Scheme

C19H18N2O5S → ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3)

Conditions	Yield
With hydrogen

4-(benzyloxy)-3-cyanobenzenecarbothioamide (934470-14-1) → ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 75 °C 2: hydrogen / palladium on activated charcoal / tetrahydrofuran; ethanol / 20 °C View Scheme

4-benzyloxyisophthalonitrile (206533-18-8) → ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / 1,4-dioxane; N,N-dimethyl-formamide / 60 °C 2: ethanol / 75 °C 3: hydrogen / palladium on activated charcoal / tetrahydrofuran; ethanol / 20 °C View Scheme

C14H14N2O3S → ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3)

Conditions	Yield
With sodium chlorite In ethanol for 2h; Inert atmosphere; Green chemistry;	0.69 g

Isobutyl bromide (78-77-3) + ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
With potassium carbonate; potassium iodide In ethyl acetate at 65 - 70℃; for 5h; Temperature; Solvent; Reagent/catalyst;	98.2%
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 8h;	92.9%
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 90℃; for 3h;	88%
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 90℃; for 3h;	88%
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 15h;	2.28 g

3-bromo-2-methyl propan-1-ol (40145-08-2) + ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3) → ethyl 2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate

Conditions	Yield
Stage #1: ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 80℃; for 0.5h; Stage #2: 3-bromo-2-methyl propan-1-ol In N,N-dimethyl-formamide at 80℃; for 4h;	63%

2-methyl-1,2-epoxypropane (558-30-5) + ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3) → ethyl 2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate

Conditions	Yield
With sodium dihydrogenphosphate; potassium carbonate In water; acetonitrile at 150℃; for 12h; Sealed tube;	48%

ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3) → febuxostat

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 3 h / 90 °C 2: sodium hydroxide; water / methanol / 1 h / 45 - 60 °C View Scheme

ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3) → 2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 0.5 h / 80 °C 1.2: 4 h / 80 °C 2.1: sodium hydroxide; water / ethanol; tetrahydrofuran / 1.5 h / 60 °C View Scheme

ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3) → 2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate; sodium dihydrogenphosphate / water; acetonitrile / 12 h / 150 °C / Sealed tube 2: sodium hydroxide; water / ethanol; tetrahydrofuran / 1.5 h / 60 °C View Scheme

ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3) → 3-{2-cyano-4-[5-(ethoxycarbonyl)-4-methylthiazol-2-yl]phenoxy}-2-methylpropanoic acid

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 0.5 h / 80 °C 1.2: 4 h / 80 °C 2.1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite; sodium chlorite / water; acetonitrile; aq. phosphate buffer / 6 h / 35 °C / pH 6.7 View Scheme

ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3) → 2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methylthiazole-5-carboxylic acid

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 0.5 h / 80 °C 1.2: 4 h / 80 °C 2.1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hypochlorite; sodium chlorite / water; acetonitrile; aq. phosphate buffer / 6 h / 35 °C / pH 6.7 3.1: sodium hydroxide; water / ethanol; tetrahydrofuran / 1.5 h / 60 °C View Scheme

ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (161798-02-3) + methyl 2-(bromomethyl)propenoate (4224-69-5) → C19H18N2O5S

Conditions	Yield
With caesium carbonate In acetonitrile at 80℃;

Upstream product

• 206533-18-8 4-benzyloxyisophthalonitrile 
• 934470-14-1 4-(benzyloxy)-3-cyanobenzenecarbothioamide 
• 161798-01-2 ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate 
• 25984-63-8 4-hydroxythiobenzamide 
• 161797-99-5 (2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester) 
• 609-15-4 ethyl 2-chloro-3-oxo-butyrate 
• 934470-15-2 ethyl 2-[4-(benzyloxy)-3-cyanophenyl]-4-methyl-1,3-thiazole-5-carboxylate 

Downstream Products

• 160844-75-7 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester 
• 407582-47-2 2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid 
• 407582-49-4 2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methylthiazole-5-carboxylic acid 
• 144060-53-7 febuxostat 

Relevant articles and documents

A practical oxidative conversion of aldehydes into N-chloroaldimines

A novel method for the preparation of N-chloroaldimines from commonly available aromatic aldehydes has been developed. The reaction proceeded effectively by two steps: aldehydes were initially transformed into imines and then chloro-substitution with NaClO2 gave the N-chloroaldimines. This simple protocol allows for the preparation of a variety of aromatic N-chloroaldimines in moderate to excellent yields without the isolation of the imine intermediate. We also found that 3-nitrobenzaldehyde and 4-cyanobenzaldehyde were converted into the related benzonitrile directly under the standard conditions.

Synthesis of the major metabolites of febuxostat

Total synthesis of three Febuxostat metabolites, named 67M-1, 67M-2, and 67M-4,is described in this article. Through condensation of the key intermediate compound A with different side chains, and then oxidation and hydrolysis, we obtained three target compounds with an overall yield of 19.5%-28.0%.

PROCESS FOR THE PREPARATION OF 2-ARYLTHIAZOLE DERIVATIVES

The present invention relates an improved process for the preparation of 2-arylthiazole derivatives which are intermediates of Febuxostat and further conversion to Febuxostat or pharmaceutically acceptable salts thereof.