160844-75-7

Basic information

• Product Name: Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate
• Synonyms: 5-Thiazolecarboxylicacid, 2-[3-cyano-4-(2-Methylpropoxy)phenyl]-4-Methyl-, ethyl ester;Febuxostat Impurity 3;2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate;Febuxostat Ethyl Ester;ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl;Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate;Ethyl> 2-(3-cyano-4-isobutoxyphenyl)-4-Methyl-5-th;5-carboxylato-2-[3-cyano-4-(2-Methylpropoxy)phenyl]-1-ethyl-4-Methyl-1H-1$l^{4},3-thiazol-1-yl
• CAS NO: 160844-75-7
• Molecular Formula: C₁₈H₂₀N₂O₃S
• Molecular Weight: 344.43
• EINECS: 1592732-453-0
• Product Categories: Febuxostat Intermediates;Febuxostat intermediate
• Mol File: 160844-75-7.mol
• Article Data: 36

Chemical Properties

• Melting Point: 176 °C
• Boiling Point: 497.149 °C at 760 mmHg
• Flash Point: 254.467 °C
• Appearance: /
• Density: 1.22
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.57
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: DMSO (Slightly, Heated), Methanol (Very Slightly, Heated)
• PKA: 1.02±0.10(Predicted)
• CAS DataBase Reference: Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate(160844-75-7)
• EPA Substance Registry System: Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate(160844-75-7)

Safety Data

• Hazardous Substances Data: 160844-75-7(Hazardous Substances Data)

Usage

Chemical Properties

White crystalline powder

Uses

Ethyl 2-(3-Cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate is an impurity of Febuxostat (F229000), a xanthine oxidase/xanthine dehydrogenase inhibitor. Used for treatment of hyperuricemia and chronic gout. 40-120 mg/day febuxostat was proven effective in lowering serum urate levels when administered to manage hyperuricemia in patients with gout.

InChI:InChI=1/C18H20N2O3S/c1-5-22-18(21)16-12(4)20-17(24-16)13-6-7-15(14(8-13)9-19)23-10-11(2)3/h6-8,11H,5,10H2,1-4H3

Synthetic route

5-bromo-2-isobutoxy-benzonitrile (876918-26-2) + ethyl 4-methylthiazole-5-carboxylate (20582-55-2) → C22H24N2O2 (1240593-43-4) + diethyl 4,4-dimethyl-2,2-bithiazole-5,5-dicarboxylate (3944-31-8) + 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
With di-tert-butyl(cyclohexyl)phosphine; potassium carbonate; palladium dichloride In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 24h; Reagent/catalyst; Inert atmosphere;	A n/a B n/a C 100%
With potassium carbonate; di-tert-butyl(cyclohexyl)phosphine; palladium diacetate In xylene at 120℃; for 5h; Product distribution / selectivity; Inert atmosphere;

2-(3-bromo-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (144060-96-8) + copper(l) cyanide → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
With copper(l) iodide In N,N-dimethyl-formamide at 130 - 140℃; for 16h;	98.5%

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

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
With ammonium hydroxide; sodium persulfate; sodium iodide; iron(II) chloride In 1,2-dichloro-ethane at 20 - 50℃; for 16h; Reagent/catalyst; Solvent; Temperature;	98%
With hydroxylamine hydrochloride; sodium formate In formic acid for 3h; Product distribution / selectivity; Reflux;	96%
With formic acid; hydroxylamine hydrochloride; sodium formate at 100℃; for 7h;	95.2%

5-bromo-2-isobutoxy-benzonitrile (876918-26-2) + ethyl 4-methylthiazole-5-carboxylate (20582-55-2) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
With di-tert-butyl(cyclohexyl)phosphine; potassium hydrogencarbonate; isobutyric Acid; copper(I) bromide; palladium dichloride In toluene at 25℃; for 21h; Reagent/catalyst; Time; Inert atmosphere; Reflux;	93%
With potassium carbonate; di-tert-butyl(cyclohexyl)phosphine; palladium diacetate In xylene at 20℃; for 24.5h; Product distribution / selectivity; Reflux;	82%
With di-tert-butyl(cyclohexyl)phosphine; copper(I) bromide dimethylsulfide complex; potassium carbonate; isobutyric Acid; palladium dichloride In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 24h; Inert atmosphere; Sealed tube;	98.2 %Chromat.

ethyl 4-methylthiazole-5-carboxylate (20582-55-2) + 2-methyl-propan-1-ol (78-83-1) + 5-Bromo-2-fluoro-benzonitrile (179897-89-3) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Stage #1: 2-methyl-propan-1-ol With potassium tert-butylate In toluene Stage #2: 5-Bromo-2-fluoro-benzonitrile at 20℃; for 2h; Stage #3: ethyl 4-methylthiazole-5-carboxylate With di-tert-butyl(cyclohexyl)phosphine; potassium hydrogencarbonate; isobutyric Acid; copper(I) bromide; palladium dichloride In toluene for 15h; Inert atmosphere; Reflux;	91%

chloroacetic acid ethyl ester (105-39-5) + 3-cyanoisobutoxybenzothioamide (163597-57-7) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
In ethanol at 100℃; for 2h;	85%

Isobutyl bromide (78-77-3) + ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate (161798-01-2) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Stage #1: ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate With hydroxylamine hydrochloride In dimethyl sulfoxide at 40℃; for 0.5h; Stage #2: With acetyl chloride In dimethyl sulfoxide at 70 - 80℃; Stage #3: Isobutyl bromide With potassium carbonate In dimethyl sulfoxide at 20 - 80℃;	84%
Stage #1: ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate With hydroxylamine hydrochloride In dimethyl sulfoxide for 0.5h; Stage #2: With acetyl chloride In dimethyl sulfoxide at 70 - 80℃; Stage #3: Isobutyl bromide With potassium carbonate In dimethyl sulfoxide at 70 - 80℃; for 5h;	84%

(2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester) (161797-99-5) + Isobutyl bromide (78-77-3) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Stage #1: (2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester); Isobutyl bromide; N,N-dimethyl-formamide With potassium carbonate at 90 - 95℃; Stage #2: With trichlorophosphate at 0 - 60℃; for 2h; Stage #3: With ammonia; iodine at 10 - 20℃; for 2h; Temperature; Solvent;	83%

5-bromo-2-isobutoxy-benzonitrile (876918-26-2) + 2-boronic acid-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 80℃; for 12h; Reagent/catalyst; Temperature; Suzuki Coupling; Inert atmosphere; Green chemistry;	79%

ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (22900-83-0) + 5-iodo-2-isobutoxy-benzonitrile (1139901-87-3) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 20℃; for 36h; Reagent/catalyst; Solvent;	61%

ethyl 2-chloro-3-oxo-butyrate (609-15-4) + 3-cyanoisobutoxybenzothioamide (163597-57-7) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
In ethanol at 100℃; for 2h;	306 mg
In toluene Product distribution / selectivity; Reflux;
In ethyl acetate; N,N-dimethyl-formamide at 80 - 85℃; for 22h;
In ethanol for 5h; Reflux;

4-isobutoxyisophthalonitrile (161718-81-6) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 85 percent / thioacetamide, HCl / dimethylformamide / 40 h / 45 °C 2: 306 mg / ethanol / 2 h / 100 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 2: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C View Scheme

4-nitrobenzonitrile (619-72-7) + methylmagnesium halide → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 2.) K2CO3 / 1.) DMSO, 100 deg C, 1 h, 2.) 6 h; 70 deg C 2: 85 percent / thioacetamide, HCl / dimethylformamide / 40 h / 45 °C 3: 306 mg / ethanol / 2 h / 100 °C View Scheme

2-(3-bromo-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (144060-96-8) + potassium ferrocyanide trihydrate → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
With sodium carbonate; palladium diacetate In 1-methyl-pyrrolidin-2-one at 145℃; for 48h; Inert atmosphere;

ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate (161798-01-2) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 4 h / 70 °C 2: hydroxylamine hydrochloride; sodium formate / formic acid / 3 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 0.5 h / 70 - 75 °C 1.2: 5 h 2.1: hydroxylamine hydrochloride; sodium formate; formic acid / 100 °C View Scheme
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium formate; formic acid / 8 h / 100 °C 2: potassium carbonate / N,N-dimethyl-formamide / 8 h / 75 °C View Scheme

ethyl 2-chloro-3-oxo-butyrate (609-15-4) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 0.25 h / 70 °C 2: copper(ll) bromide; tert.-butylnitrite / acetonitrile / 1 h / 60 °C 3: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / toluene; water / 1 h / 70 - 75 °C View Scheme
Multi-step reaction with 4 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 4: potassium carbonate / N,N-dimethyl-formamide / 8 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1.1: isopropyl alcohol / 25 - 85 °C 2.1: trifluoroacetic acid / 24 h / 80 °C 2.2: 0.17 h 3.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 5.08 h / 25 - 85 °C 4.1: sodium formate; formic acid; hydroxylamine / 2.17 h / 25 - 100 °C View Scheme

5-bromosalicyclaldehyde (1761-61-1) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 2 h / 75 - 80 °C 2.1: hydroxylamine hydrochloride; sodium formate / formic acid / 7 h / 99 - 100 °C 3.1: n-butyllithium / hexane; tetrahydrofuran / 3 h / -45 - -40 °C 3.2: -20 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / toluene; water / 1 h / 70 - 75 °C View Scheme

(3-cyano-4-isobutoxyphenyl)boronic acid (876918-32-0) + ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (22900-83-0) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
With sodium carbonate; tetrakis(triphenylphosphine) palladium(0) In water; toluene at 70 - 75℃; for 1h;

ethyl-2-amino-4-methylthiazole-5-carboxylate (7210-76-6) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: copper(ll) bromide; tert.-butylnitrite / acetonitrile / 1 h / 60 °C 2: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / toluene; water / 1 h / 70 - 75 °C View Scheme

5-bromo-2-isobutoxybenzaldehyde (222315-01-7) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; sodium formate / formic acid / 7 h / 99 - 100 °C 2.1: n-butyllithium / hexane; tetrahydrofuran / 3 h / -45 - -40 °C 2.2: -20 °C 3.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / toluene; water / 1 h / 70 - 75 °C View Scheme

5-bromo-2-isobutoxy-benzonitrile (876918-26-2) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 3 h / -45 - -40 °C 1.2: -20 °C 2.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / toluene; water / 1 h / 70 - 75 °C View Scheme

4-cyanophenol (767-00-0) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: N-Bromosuccinimide; trifluorormethanesulfonic acid / acetonitrile / -15 - 30 °C 2: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 12 h / 70 - 75 °C 3: sodium carbonate / palladium diacetate / N,N-dimethyl-formamide / 18 h / 140 - 145 °C 4: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 5: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C View Scheme
Multi-step reaction with 7 steps 1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 6 h / 80 °C 2: aluminum (III) chloride / nitromethane / 5.5 h / 0 - 5 °C 3: iron(III) sulfate; water / toluene / 0.7 h / 110 °C 4: tetrabutylammomium bromide; sodium hypochlorite / ethyl acetate; water / 0 - 5 °C 5: sodium hydrogen sulfide; magnesium(II) chloride hexahydrate / N,N-dimethyl-formamide / 4 h / 80 °C 6: N,N-dimethyl-formamide / 4 h / 60 °C 7: hydroxylamine hydrochloride; sodium formate; formic acid / 4.17 h / 25 - 100 °C View Scheme
Multi-step reaction with 7 steps 1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 6 h / 80 °C 2: aluminum (III) chloride / nitromethane / 5.5 h / 0 °C 3: iron(III) sulfate; water / toluene / 0.7 h / 110 °C 4: tetrabutylammomium bromide; sodium hypochlorite / ethyl acetate; water / 0 - 5 °C 5: sodium hydrogen sulfide; magnesium(II) chloride hexahydrate / N,N-dimethyl-formamide / 4 h / 80 °C 6: N,N-dimethyl-formamide / 4 h / 60 °C 7: hydroxylamine hydrochloride; sodium formate; formic acid / 4.17 h / 25 - 100 °C View Scheme

2,4-dibromophenol (615-58-7) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: palladium diacetate / dimethyl sulfoxide / 4 h / 40 - 45 °C 2: potassium carbonate; potassium iodide / dimethyl sulfoxide / 16 h / 70 - 75 °C 3: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 4: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C View Scheme
Multi-step reaction with 4 steps 1: sodium carbonate / palladium diacetate / N,N-dimethyl-formamide / 18 h / 140 - 145 °C 2: potassium carbonate; potassium iodide / dimethyl sulfoxide / 16 h / 70 - 75 °C 3: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 4: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C View Scheme

3-bromo-4-hydroxybenzonitrile (2315-86-8) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 12 h / 70 - 75 °C 2: sodium carbonate / palladium diacetate / N,N-dimethyl-formamide / 18 h / 140 - 145 °C 3: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 4: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrogenchloride / isopropyl alcohol / 0.25 h 1.2: 2 h / 50 - 55 °C 2.1: isopropyl alcohol / 5 h / 80 - 85 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 80 - 85 °C 4.1: copper(l) iodide / N,N-dimethyl-formamide / 16 h / 130 - 140 °C View Scheme

4-hydroxy-isophthalonitrile (34133-58-9) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate; potassium iodide / dimethyl sulfoxide / 16 h / 70 - 75 °C 2: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 3: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C View Scheme

3-bromo-4-isobutoxybenzonitrile (208665-95-6) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium carbonate / palladium diacetate / N,N-dimethyl-formamide / 18 h / 140 - 145 °C 2: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 3: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C View Scheme

5-Bromo-2-fluoro-benzonitrile (179897-89-3) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0 - 20 °C 1.2: 15 h / 0 - 20 °C 2.1: potassium carbonate / palladium diacetate; di-tert-butyl(cyclohexyl)phosphine / xylene / 24.5 h / 20 °C / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 4 h / 0 °C 1.2: 21 h / 0 - 20 °C 2.1: palladium dichloride; isobutyric Acid; di-tert-butyl(cyclohexyl)phosphine; potassium carbonate / 5,5-dimethyl-1,3-cyclohexadiene / 8 h / Reflux; Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 4 h / 0 °C 1.2: 21 h / 0 - 20 °C 2.1: palladium dichloride; isobutyric Acid; copper(I) bromide dimethylsulfide complex; di-tert-butyl(cyclohexyl)phosphine; potassium carbonate / 5,5-dimethyl-1,3-cyclohexadiene / 24 h / 140 °C / Inert atmosphere; Sealed tube View Scheme

5-Bromo-2-fluoro-benzonitrile (179897-89-3) → C22H24N2O2 (1240593-43-4) + 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0 - 20 °C 1.2: 15 h / 0 - 20 °C 2.1: potassium carbonate / palladium diacetate; di-tert-butyl(cyclohexyl)phosphine / xylene / 5 h / 120 °C / Inert atmosphere View Scheme

(2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester) (161797-99-5) → 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: methanesulfonic acid / 10 h / 75 °C 2: hydroxylamine hydrochloride; sodium formate; formic acid / 8 h / 100 °C 3: potassium carbonate / N,N-dimethyl-formamide / 8 h / 75 °C View Scheme
Multi-step reaction with 3 steps 1: trifluoroacetic acid / 40 h / Reflux 2: potassium carbonate; N,N-dimethyl-formamide / 4 h / 87 - 93 °C 3: hydroxylamine hydrochloride; sodium formate; formic acid / 5 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: trifluoroacetic acid / 24 h / 80 °C 1.2: 0.17 h 2.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 5.08 h / 25 - 85 °C 3.1: sodium formate; formic acid; hydroxylamine / 2.17 h / 25 - 100 °C View Scheme

2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7) → 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carbohydrazide

Conditions	Yield
With hydrazine hydrate In ethanol for 5h; Reflux;	99%

2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7) → febuxostat

Conditions	Yield
With water; sodium hydroxide In tetrahydrofuran; ethanol at 40℃; for 5h;	98%
With methanol; sodium hydroxide In tetrahydrofuran at 20℃; for 5h; Green chemistry;	96%
Stage #1: 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester With water; sodium hydroxide In methanol at 45 - 60℃; for 1h; Stage #2: With hydrogenchloride In methanol pH=2; Product distribution / selectivity;	95.8%

2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7) → febuxostat sodium (1140907-13-6)

Conditions	Yield
With sodium hydroxide In water; isopropyl alcohol at 35 - 75℃; for 0.5h; Concentration; Temperature; Time;	79%

2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7) → ethyl 4-methyl-2-(4-(2-methylpropyloxy)-3-cyanophenyl)-5-thiazolecarboxylate hydrochloride

Conditions	Yield
With hydrogenchloride In acetone at 30 - 50℃; for 0.75h;	61.5%

(3-cyano-4-isobutoxyphenyl)boronic acid (876918-32-0) + 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (160844-75-7) → febuxostat

Conditions	Yield
Stage #1: (3-cyano-4-isobutoxyphenyl)boronic acid; 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester With sodium carbonate; tetrakis(triphenylphosphine) palladium(0) In water; toluene at 70 - 75℃; for 1h; Stage #2: With sodium hydroxide In tetrahydrofuran for 5h; Inert atmosphere; Reflux; Stage #3: With hydrogenchloride In water

Upstream product

• 34133-58-9 4-hydroxy-isophthalonitrile 
• 208665-95-6 3-bromo-4-isobutoxybenzonitrile 
• 179897-89-3 5-Bromo-2-fluoro-benzonitrile 
• 22900-83-0 ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate 
• 1139901-87-3 5-iodo-2-isobutoxy-benzonitrile 
• 351003-36-6 2-fluoro-5-iodobenzonitrile 
• 2042-37-7 o-cyanobromobenzene 
• 876918-26-2 5-bromo-2-isobutoxy-benzonitrile 
• 20582-55-2 ethyl 4-methylthiazole-5-carboxylate 
• 78-83-1 2-methyl-propan-1-ol 
• 1271738-74-9 ethyl 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate 
• 64-17-5 ethanol 
• 144060-53-7 febuxostat 
• 161798-01-2 ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate 

Downstream Products

• 144060-53-7 febuxostat 
• 1350352-71-4 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid methylamine 
• 1350352-72-5 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid tert-butylamine 
• 1239233-86-3 2-[3-carbamoyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazole carboxylic acid 
• 1239233-87-4 2-(3-carboxy-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid 
• 1140907-13-6 febuxostat sodium 
• 1140907-14-7 febuxostat potassium 

Relevant articles and documents

Synthesis, structural elucidation and larvicidal activity of novel arylhydrazones

The present study focuses on a series of novel hydrazones of 2- [3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carbohydrazide (5a-l) for their larvicidal activity against Anopheles arabiensis. The synthesis of the title compounds was achieved by the conventional reflux method, and structures of the novel compounds were ascertained by FT-IR, NMR (1H &13C), LC-MS, and elemental analysis. Compound (5l) was studied by single crystal X-ray diffraction for intra and intermolecular interactions. Title compounds (E)-2-(3-cyano-4-isobutoxyphenyl)-N'-(4-fluoro-3-phenoxybenzylidene)-4-methylthiazole-5-carbohydrazide (5a) and (E)-N'-(4-Chlorobenzylidene)-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carbohydrazide (5g) emerged as promising larvicidal agents against Anopheles arabiensis.

Pd/Cu-Catalyzed C-H/C-H Cross Coupling of (Hetero)Arenes with Azoles through Arylsulfonium Intermediates

A highly efficient method for the selective formal C-H/C-H cross-coupling of azoles and (hetero)arenes was established through arylsulfonium intermediates under transition-metal catalysis, which produced a variety of 2-(hetero)aryl azoles in good to excellent yields. Advantages of the reaction included mildness, a good functional group tolerance, a wide range of substrates, a high regio- and chemoselectivity, one-pot procedures, and the late-stage functionalization of complex molecules without the use of oxidants, offering a promising strategy for the transition-metal-catalyzed C-H arylation of azoles.

Synthesis, molecular docking, DFT study of novel N-benzyl-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxamide derivatives and their antibacterial activity

A series of febuxostat based new chemical entities was synthesized using microwave method and characterized by NMR, mass and FT-IR spectral studies. Molecular docking of febuxostat amide nucleus substitution compounds 8c (-7.91kcal/mol), 8g (-7.94 kcal/mol) exhibiting high binding energy against ALK receptors. Theoretical investigation of MEPs, HOMO, LUMO and energy gap of HOMO-LUMO were calculated by B3LYP/6-31G method. Among the tested compounds, methoxy substituted compound 8g showed highest antibacterial activity against S. aereus and B. subtilis.