161798-03-4

Basic information

• Product Name: ETHYL 2-(3-FORMYL-4-ISOBUTOXYPHENYL)-4-METHYLTHIAZOLE-5-CARBOXYLATE
• Synonyms: 2-(3-forMyl;5-Thiazolecarboxylicacid, 2-[3-forMyl-4-(2-Methylpropoxy)phenyl]-4-Methyl-, ethyl ester;ethyl-2-[3-forMyl-4-(2-Methylpropoxy)phenyl]-4-Methyl-5-thiazolecarboxylate;Febuxostat Impurity 2;Febuxostat Impurity G;2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate;Ethyl 2-(3-formyl-4-isobutoxyphenyl);ETHYL 2-(3-FORMYL-4-ISOBUTOXYPHENYL)-4-METHYLTHIAZOLE-5-CARBOXYLATE
• CAS NO: 161798-03-4
• Molecular Formula: C₁₈H₂₁NO₄S
• Molecular Weight: 347.43
• EINECS: 1592732-453-0
• Product Categories: Febuxostat intermediate
• Mol File: 161798-03-4.mol
• Article Data: 19

Chemical Properties

• Boiling Point: 495.9 °C at 760 mmHg
• Flash Point: 253.7 °C
• Appearance: /
• Density: 1.183
• Vapor Pressure: 5.68E-10mmHg at 25°C
• Refractive Index: 1.566
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly, Sonicated)
• PKA: 1.39±0.10(Predicted)
• CAS DataBase Reference: ETHYL 2-(3-FORMYL-4-ISOBUTOXYPHENYL)-4-METHYLTHIAZOLE-5-CARBOXYLATE(CAS DataBase Reference)
• NIST Chemistry Reference: ETHYL 2-(3-FORMYL-4-ISOBUTOXYPHENYL)-4-METHYLTHIAZOLE-5-CARBOXYLATE(161798-03-4)
• EPA Substance Registry System: ETHYL 2-(3-FORMYL-4-ISOBUTOXYPHENYL)-4-METHYLTHIAZOLE-5-CARBOXYLATE(161798-03-4)

Safety Data

• Hazardous Substances Data: 161798-03-4(Hazardous Substances Data)

Usage

Uses

Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate is an impurity of Febuxostat (F229000), which is a xanthine oxidase/xanthine dehydrogenase inhibitor, used for treatment of hyperuricemia and chronic gout.

Synthesis

Preparation of Compound of formula III)[0094] A compound of formula II (10.0 gr, 34.33 mmol) was reacted with iso- butyl bromide (18.9 gr, 137.3 mmol) in the presence of potassium carbonate (19.0 gr, 137.3 mmol) and potassium iodide (2.3 gr, 13.7 mmol) in 60 ml dimethylformamide. The reaction was performed at about 70°C during 4 hours. The reaction mixture was extracted at 70°C using 300 ml ethyl acetate and 600 ml water. The separated aqueous phase was washed twice with 100 ml ethyl acetate. The combined organic phase was washed twice with 100 ml water and then concentrated to dryness. The resulting solid residue was re- crystallized from 70 ml ethyl acetate, filtered and dried under reduced pressure at about 40°C to provide a compound of formula III (8.9 gr, yield - 83percent). The Compound of formula III purity is 99.1percent (by HPLC).

InChI:InChI=1/C18H21NO4S/c1-5-22-18(21)16-12(4)19-17(24-16)13-6-7-15(14(8-13)9-20)23-10-11(2)3/h6-9,11H,5,10H2,1-4H3

Synthetic route

3-formyl-4-isobutoxythiobenzamide + ethyl 2-chloro-3-oxo-butyrate (609-15-4) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
In N,N-dimethyl-formamide at 60℃; for 4h;	97%

Isobutyl bromide (78-77-3) + ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate (161798-01-2) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 75 - 85℃; for 6h;	94.7%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;	90%
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide	90%

ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate (161798-01-2) + isobutyl p-toluenesulfonate (4873-56-7) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 100 - 110℃; Temperature;	92.7%

isobutyl methanesulfonate (16156-53-9) + ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate (161798-01-2) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 95 - 100℃; Temperature;	85.5%

ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate (161798-01-2) + isobutyl benzenesulfonate (24698-43-9) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 95 - 100℃;	84.4%

(2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester) (161797-99-5) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: trifluoroacetic acid / 40 h / Reflux 2: potassium carbonate; N,N-dimethyl-formamide / 4 h / 87 - 93 °C View Scheme
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: magnesium chloride; triethylamine / tetrahydrofuran / 0.17 h / Microwave irradiation 2: potassium carbonate / acetonitrile / 0.17 h / Microwave irradiation View Scheme

ethyl 2-chloro-3-oxo-butyrate (609-15-4) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

4-hydroxythiobenzamide (25984-63-8) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 steps 1: phosphoric acid / water; ethanol / 30 - 80 °C 2: sulfuric acid / 60 - 120 °C 3: potassium carbonate / N,N-dimethyl-formamide / 60 - 115 °C View Scheme
Multi-step reaction with 3 steps 1: PPA / 0.25 h / Microwave irradiation 2: magnesium chloride; triethylamine / tetrahydrofuran / 0.17 h / Microwave irradiation 3: potassium carbonate / acetonitrile / 0.17 h / Microwave irradiation View Scheme
Multi-step reaction with 3 steps 1: ethanol / 2 h / Reflux 2: water; trifluoroacetic acid; acetic acid / 2.5 h / 100 °C 3: potassium carbonate; potassium iodide / N,N-dimethyl-formamide View Scheme

C12H15NO2 → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrabutylammomium bromide; sodium hypochlorite / ethyl acetate; water / 0 - 5 °C 2: sodium hydrogen sulfide; magnesium(II) chloride hexahydrate / N,N-dimethyl-formamide / 4 h / 80 °C 3: N,N-dimethyl-formamide / 4 h / 60 °C View Scheme

C12H13NO2 → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogen sulfide; magnesium(II) chloride hexahydrate / N,N-dimethyl-formamide / 4 h / 80 °C 2: N,N-dimethyl-formamide / 4 h / 60 °C View Scheme

4-cyanophenol (767-00-0) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 6 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 View Scheme
Multi-step reaction with 4 steps 1: polyphosphoric acid / water / 40 - 80 °C 2: phosphoric acid / water; ethanol / 30 - 80 °C 3: sulfuric acid / 60 - 120 °C 4: potassium carbonate / N,N-dimethyl-formamide / 60 - 115 °C View Scheme
Multi-step reaction with 4 steps 1: sodium hydrogensulfide; magnesium chloride monohydrate / 3 h / 20 °C 2: PPA / 0.25 h / Microwave irradiation 3: magnesium chloride; triethylamine / tetrahydrofuran / 0.17 h / Microwave irradiation 4: potassium carbonate / acetonitrile / 0.17 h / Microwave irradiation View Scheme

4-(2-methylpropoxy)benzonitrile (5203-15-6) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: aluminum (III) chloride / nitromethane / 5.5 h / 0 - 5 °C 2: iron(III) sulfate; water / toluene / 0.7 h / 110 °C 3: tetrabutylammomium bromide; sodium hypochlorite / ethyl acetate; water / 0 - 5 °C 4: sodium hydrogen sulfide; magnesium(II) chloride hexahydrate / N,N-dimethyl-formamide / 4 h / 80 °C 5: N,N-dimethyl-formamide / 4 h / 60 °C View Scheme
Multi-step reaction with 5 steps 1: aluminum (III) chloride / nitromethane / 5.5 h / 0 °C 2: iron(III) sulfate; water / toluene / 0.7 h / 110 °C 3: tetrabutylammomium bromide; sodium hypochlorite / ethyl acetate; water / 0 - 5 °C 4: sodium hydrogen sulfide; magnesium(II) chloride hexahydrate / N,N-dimethyl-formamide / 4 h / 80 °C 5: N,N-dimethyl-formamide / 4 h / 60 °C View Scheme

3-chloromethyl-4-isobutoxybenzonitrile → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: iron(III) sulfate; water / toluene / 0.7 h / 110 °C 2: tetrabutylammomium bromide; sodium hypochlorite / ethyl acetate; water / 0 - 5 °C 3: sodium hydrogen sulfide; magnesium(II) chloride hexahydrate / N,N-dimethyl-formamide / 4 h / 80 °C 4: N,N-dimethyl-formamide / 4 h / 60 °C View Scheme

2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester hydrochloride → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: phosphoric acid / 70 - 95 °C 2: potassium carbonate / N,N-dimethyl-formamide / 100 - 110 °C View Scheme
Multi-step reaction with 2 steps 1: phosphoric acid / 70 - 95 °C 2: potassium carbonate / N,N-dimethyl-formamide / 95 - 100 °C View Scheme
Multi-step reaction with 2 steps 1: phosphoric acid / 70 - 95 °C 2: potassium carbonate / N,N-dimethyl-formamide / 95 - 100 °C View Scheme

ethyl bromide (74-96-4) + 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (144060-62-8) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 20h;

ethyl 2-bromoacetoacetate (84911-18-2, 609-13-2) → 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 2 h / Reflux 2: water; trifluoroacetic acid; acetic acid / 2.5 h / 100 °C 3: potassium carbonate; potassium iodide / N,N-dimethyl-formamide View Scheme

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%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + aniline (62-53-3) + phosphonic acid diethyl ester (762-04-9) → ethyl 2-(3-((diethoxyphosphoryl)(phenylamino)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With β-cyclodextrin supported sulfonic acid In neat (no solvent) at 50℃; for 0.5h; Catalytic behavior; Reagent/catalyst; Solvent; Temperature; Kabachnik-Fields Reaction; Green chemistry;	96%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + 4-methoxy-aniline (104-94-9) + phosphonic acid diethyl ester (762-04-9) → ethyl 2-(3-((diethoxyphosphoryl)((4-methoxyphenyl)amino)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With β-cyclodextrin supported sulfonic acid In neat (no solvent) at 50℃; for 0.5h; Kabachnik-Fields Reaction; Green chemistry;	96%

4-aminophenyl phenyl sulfide (1135-14-4) + 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + phosphonic acid diethyl ester (762-04-9) → ethyl 2-(3-((diethoxyphosphoryl)((4-(phenylthio)phenyl)amino)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With β-cyclodextrin supported sulfonic acid In neat (no solvent) at 50℃; for 0.5h; Kabachnik-Fields Reaction; Green chemistry;	96%

4-trifluoromethylphenylamine (455-14-1) + 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + phosphonic acid diethyl ester (762-04-9) → ethyl 2-(3-((diethoxyphosphoryl)((4-(trifluoromethyl)phenyl)amino)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With β-cyclodextrin supported sulfonic acid In neat (no solvent) at 50℃; for 0.5h; Kabachnik-Fields Reaction; Green chemistry;	95%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + phosphonic acid diethyl ester (762-04-9) + 4-fluoroaniline (371-40-4) → ethyl 2-(3-((diethoxyphosphoryl)((4-fluorophenyl)amino)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With β-cyclodextrin supported sulfonic acid In neat (no solvent) at 50℃; for 0.5h; Kabachnik-Fields Reaction; Green chemistry;	94%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + phosphonic acid diethyl ester (762-04-9) + 2-iodo-4-(trifluoromethyl)aniline (163444-17-5) → ethyl 2-(3-((diethoxyphosphoryl)((2-iodo-4-(trifluoromethyl)phenyl)amino)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With β-cyclodextrin supported sulfonic acid In neat (no solvent) at 50℃; for 0.5h; Kabachnik-Fields Reaction; Green chemistry;	94%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + phosphonic acid diethyl ester (762-04-9) + 3-chloro-aniline (108-42-9) → ethyl 2-(3-(((3-chlorophenyl)amino)(diethoxyphosphoryl)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With β-cyclodextrin supported sulfonic acid In neat (no solvent) at 50℃; for 0.5h; Kabachnik-Fields Reaction; Green chemistry;	92%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + 4-nitro-aniline (100-01-6) + phosphonic acid diethyl ester (762-04-9) → ethyl 2-(3-((diethoxyphosphoryl)((4-nitrophenyl)amino)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With β-cyclodextrin supported sulfonic acid In neat (no solvent) at 50℃; for 0.5h; Kabachnik-Fields Reaction; Green chemistry;	92%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + 2-iodophenylamine (615-43-0) + phosphonic acid diethyl ester (762-04-9) → ethyl 2-(3-((diethoxyphosphoryl)((2-iodophenyl)amino)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With β-cyclodextrin supported sulfonic acid In neat (no solvent) at 50℃; for 0.5h; Kabachnik-Fields Reaction; Green chemistry;	91%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + thiosemicarbazide (79-19-6) + para-bromophenacyl bromide (99-73-0) → ethyl 2-(3-((2-(4-(4-bromophenyl)thiazol-2-yl)hydrazono)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With acetic acid In ethanol for 3h; Reflux; Green chemistry;	90%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + phosphonic acid diethyl ester (762-04-9) + 4-bromo-aniline (106-40-1) → ethyl 2-(3-(((4-bromophenyl)amino)(diethoxyphosphoryl)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With β-cyclodextrin supported sulfonic acid In neat (no solvent) at 50℃; for 0.5h; Kabachnik-Fields Reaction; Green chemistry;	90%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + thiosemicarbazide (79-19-6) + 4-chlorobenzoylmethyl bromide (536-38-9) → ethyl 2-(3-((2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazono)methyl)-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With acetic acid In ethanol for 4h; Reflux; Green chemistry;	88%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + thiosemicarbazide (79-19-6) + α-bromoacetophenone (70-11-1) → ethyl 2-(4-isobutoxy-3-((2-(4-phenylthiazol-2-yl)hydrazono)methyl)phenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With acetic acid In ethanol for 3h; Reflux; Green chemistry;	86%

3-bromoacetylcoumarin (29310-88-1) + 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + thiosemicarbazide (79-19-6) → ethyl 2-(4-isobutoxy-3-((2-(4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl)hydrazono)methyl)phenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With acetic acid In ethanol for 4h; Reflux; Green chemistry;	86%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + 2-(2-bromoacetyl)-3H-benzo[f]chromen-3-one (88735-43-7) + thiosemicarbazide (79-19-6) → ethyl 2-(4-isobutoxy-3-((2-(4-(3-oxo-3H-benzo[f]chromen-2-yl)thiazol-2-yl)hydrazono)methyl)phenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With acetic acid In ethanol for 3h; Reflux; Green chemistry;	83%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) + 4-Nitrophenacyl bromide (99-81-0) + thiosemicarbazide (79-19-6) → ethyl 2-(4-isobutoxy-3-((2-(4-(4-nitrophenyl)thiazol-2-yl)hydrazono)methyl)phenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
With acetic acid In ethanol for 4h; Reflux; Green chemistry;	81%

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) → febuxostat

Conditions	Yield
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium formate; formic acid / 100 °C 2: sodium hydroxide; ethanol / tetrahydrofuran / 1 h / 60 °C View Scheme
Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride / methanol / 65 °C 2.1: sodium hydroxide; water / methanol / 0.5 h / 75 °C 2.2: hydrose / 5 h / 25 °C / pH 2 - 3 3.1: sodium formate; formic acid / 100 °C View Scheme
With formic acid; hydroxylamine hydrochloride; sodium formate for 5h; Reflux;

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) → 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid (144060-62-8)

Conditions	Yield
Stage #1: 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester With water; sodium hydroxide In methanol at 75℃; for 0.5h; Stage #2: With hydrogenchloride In methanol; water at 25℃; for 5h; pH=2 - 3;
Stage #1: 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester With sodium hydroxide In ethanol at 80℃; for 4h; Stage #2: With hydrogenchloride In ethanol; water pH=~ 3;
Stage #1: 2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester With water; potassium carbonate In methanol for 3h; Reflux; Stage #2: With hydrogenchloride In water at 40℃; pH=5.3 - 5.7; Product distribution / selectivity;

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) → ethyl 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate (1271738-74-9)

Conditions	Yield
With hydroxylamine hydrochloride In methanol at 65℃;
With formic acid; hydroxylamine hydrochloride; sodium formate at 100 - 110℃;

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) → 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid (1350352-70-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydroxylamine hydrochloride / methanol / 65 °C 2.1: sodium hydroxide; water / methanol / 0.5 h / 75 °C 2.2: hydrose / 5 h / 25 °C / pH 2 - 3 View Scheme

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) → 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid methylamine (1350352-71-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium formate; formic acid / 100 °C 2: sodium hydroxide; ethanol / tetrahydrofuran / 1 h / 60 °C 3: ethyl acetate; cyclohexane; methanol / 3 h View Scheme
Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride / methanol / 65 °C 2.1: sodium hydroxide; water / methanol / 0.5 h / 75 °C 2.2: hydrose / 5 h / 25 °C / pH 2 - 3 3.1: sodium formate; formic acid / 100 °C 4.1: ethyl acetate; cyclohexane; methanol / 3 h View Scheme

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) → 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid tert-butylamine (1350352-72-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium formate; formic acid / 100 °C 2: sodium hydroxide; ethanol / tetrahydrofuran / 1 h / 60 °C 3: toluene / 10 h View Scheme
Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride / methanol / 65 °C 2.1: sodium hydroxide; water / methanol / 0.5 h / 75 °C 2.2: hydrose / 5 h / 25 °C / pH 2 - 3 3.1: sodium formate; formic acid / 100 °C 4.1: toluene / 10 h View Scheme

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) → 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid methylamine (1350352-73-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide; water / methanol / 0.5 h / 75 °C 1.2: hydrose / 5 h / 25 °C / pH 2 - 3 2.1: ethyl acetate; cyclohexane; methanol / 3 h View Scheme

2-(3-formyl-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (161798-03-4) → 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid n-butylamine (1350352-74-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide; water / methanol / 0.5 h / 75 °C 1.2: hydrose / 5 h / 25 °C / pH 2 - 3 2.1: toluene / 10 h View Scheme

Upstream product

• 84911-18-2 ethyl 2-bromoacetoacetate 
• 74-96-4 ethyl bromide 
• 144060-62-8 2-[3-formyl-4-(2-methylpropoxy)phenyl]-4-methyl-5-thiazolecarboxylic acid 
• 161798-01-2 ethyl 2‐(3‐formyl‐4‐hydroxyphenyl)‐4‐methylthiazole‐5‐carboxylate 
• 4873-56-7 isobutyl p-toluenesulfonate 
• 24698-43-9 isobutyl benzenesulfonate 
• 16156-53-9 isobutyl methanesulfonate 
• 399017-10-8 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylic acid ethyl ester hydrochloride 
• 5203-15-6 4-(2-methylpropoxy)benzonitrile 
• 767-00-0 4-cyanophenol 
• 609-15-4 ethyl 2-chloro-3-oxo-butyrate 
• 25984-63-8 4-hydroxythiobenzamide 
• 161797-99-5 (2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester) 
• 78-77-3 Isobutyl bromide 

Downstream Products

• 160844-75-7 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester 
• 1350352-76-9 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid n-butylamine 
• 1350352-75-8 2-[3-((hydroxyimino)methyl)-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid methylamine 

Relevant articles and documents

Design, synthesis, cytotoxic evaluation and molecular docking studies of novel thiazolyl α-aminophosphonates

Abstract: A new class of thiazolyl α-aminophosphonate derivatives was synthesized by one-pot Kabachnik–Fields reaction of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate with various aryl amines and diethyl phosphite under solvent-free conditions using β-cyclodextrin supported sulfonic acid (β-CD-SO3H) as an efficient, reusable and heterogeneous solid acid catalyst. The products were obtained in good to excellent yields at shorter reaction time. All the title compounds were screened for cytotoxic activity against human breast cancer (MCF-7 and MDA-MB-231), prostate cancer (DU-145) liver cancer (HepG2) and HeLa cancer cell lines using sulfarodamine-B (SRB assay). Compounds (8b, –4OMe), (8h, –4NO2) and (8j, –2I, –4CF3) showed better anticancer activity when compared with standard drug Adriamycin. Further in-silico target hunting reveals the anticancer activity of the designed compounds by inhibiting DNA topoisomerase II. Graphical abstract: [Figure not available: see fulltext.].

Synthesis method of febuxostat impurity

The invention provides a synthesis method of a febuxostat impurity, which is characterized in that 2-[3-formyl-4-isobutoxyphenyl]-4-methylthiazole-5-formic acid is used as a raw material, and the febuxostat impurity is prepared by a four-step synthesis method. The synthesis process provided by the invention has the advantages of mild reaction conditions, no need of special chemical reagents, highyield and purity up to 99%, and can be used as a standard substance or a reference substance for quality control of febuxostat series products.

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.