163597-57-7

Basic information

• Product Name: 3-Cyano-4-(2-methylpropoxy)benzenecarbothioamide
• Synonyms: 3-Cyano-4-(2-methylpropoxy)benzenecarbothioamide;3-Cyano-4-isobutyloxythiobenzamide;3-Cyano-4-isobutyloxyhthiobenzamide;BenzenecarbothioaMide,3-cyano-4-(2-Methylpropoxy)-;3-Cyano-4-isobutoxybenzothioaMide;Febuxostat Impurity E
• CAS NO: 163597-57-7
• Molecular Formula: C₁₂H₁₄N₂OS
• Molecular Weight: 234.32
• EINECS: 200-258-5
• Mol File: 163597-57-7.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 396.194 °C at 760 mmHg
• Flash Point: 193.411 °C
• Appearance: /
• Density: 1.18
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.593
• Storage Temp.: 2-8°C
• PKA: 12.49±0.29(Predicted)
• CAS DataBase Reference: 3-Cyano-4-(2-methylpropoxy)benzenecarbothioamide(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Cyano-4-(2-methylpropoxy)benzenecarbothioamide(163597-57-7)
• EPA Substance Registry System: 3-Cyano-4-(2-methylpropoxy)benzenecarbothioamide(163597-57-7)

Safety Data

• Hazardous Substances Data: 163597-57-7(Hazardous Substances Data)

Usage

Uses

3-?Cyano-?4-?isobutyloxythiobenza?mide is an impurity in the preparation of Febuxostat (F229000), a xanthine oxidase/xanthine dehydrogenase inhibitor. Used for treatment of hyperuricemia and chronic gout.

InChI:InChI=1/C12H14N2OS/c1-8(2)7-15-11-4-3-9(12(14)16)5-10(11)6-13/h3-5,8H,7H2,1-2H3,(H2,14,16)

Synthetic route

3-formyl-4-isobutoxythiobenzamide → 3-cyanoisobutoxybenzothioamide (163597-57-7)

Conditions	Yield
With formic acid; hydroxylamine hydrochloride; sodium acetate for 5h; Reagent/catalyst; Reflux;	90%

4-isobutoxyisophthalonitrile (161718-81-6) → 3-cyanoisobutoxybenzothioamide (163597-57-7)

Conditions	Yield
With hydrogenchloride; thioacetamide In N,N-dimethyl-formamide at 45℃; for 40h;	85%
With hydrogenchloride; thioacetamide In isopropyl alcohol at 40 - 45℃; for 14h;

4-nitrobenzonitrile (619-72-7) + methylmagnesium halide → 3-cyanoisobutoxybenzothioamide (163597-57-7)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

4-cyanophenol (767-00-0) → 3-cyanoisobutoxybenzothioamide (163597-57-7)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 steps 1: potassium iodide / N,N-dimethyl-formamide / 10 h / 60 °C 2: hydrogenchloride / N,N-dimethyl-formamide / 4 h / 80 °C 3: hexamethylenetetramine / 10 h / 75 °C 4: hydroxylamine hydrochloride; sodium acetate; formic acid / 5 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: potassium iodide / N,N-dimethyl-formamide / 10 h / 60 °C 2: magnesium chloride hexahydrate; sodium thiosulfate / N,N-dimethyl-formamide / 1.5 h / 20 °C 3: hexamethylenetetramine / 10 h / 75 °C 4: hydroxylamine hydrochloride; sodium acetate; formic acid / 5 h / Reflux View Scheme

2,4-dibromophenol (615-58-7) → 3-cyanoisobutoxybenzothioamide (163597-57-7)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme

3-bromo-4-hydroxybenzonitrile (2315-86-8) → 3-cyanoisobutoxybenzothioamide (163597-57-7)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

4-hydroxy-isophthalonitrile (34133-58-9) → 3-cyanoisobutoxybenzothioamide (163597-57-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / dimethyl sulfoxide / 16 h / 70 - 75 °C 2: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C View Scheme

3-bromo-4-isobutoxybenzonitrile (208665-95-6) → 3-cyanoisobutoxybenzothioamide (163597-57-7)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

4-(2-methylpropoxy)benzonitrile (5203-15-6) → 3-cyanoisobutoxybenzothioamide (163597-57-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / N,N-dimethyl-formamide / 4 h / 80 °C 2: hexamethylenetetramine / 10 h / 75 °C 3: hydroxylamine hydrochloride; sodium acetate; formic acid / 5 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: magnesium chloride hexahydrate; sodium thiosulfate / N,N-dimethyl-formamide / 1.5 h / 20 °C 2: hexamethylenetetramine / 10 h / 75 °C 3: hydroxylamine hydrochloride; sodium acetate; formic acid / 5 h / Reflux View Scheme

4-isobutoxybenzothioamide (221076-43-3) → 3-cyanoisobutoxybenzothioamide (163597-57-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hexamethylenetetramine / 10 h / 75 °C 2: hydroxylamine hydrochloride; sodium acetate; formic acid / 5 h / Reflux View Scheme

methyl chloroacetate (96-34-4) + 3-cyanoisobutoxybenzothioamide (163597-57-7) → methyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate

Conditions	Yield
In ethanol at 100℃; for 2h;	87%

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%

tert-Butyl chloroacetate (107-59-5) + 3-cyanoisobutoxybenzothioamide (163597-57-7) → tert-butyl 2-(3’-cyano-4’-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (1139901-88-4)

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

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;

3-cyanoisobutoxybenzothioamide (163597-57-7) → febuxostat

Conditions	Yield
Multi-step reaction with 2 steps 1: 306 mg / ethanol / 2 h / 100 °C 2: 35 percent / 1N NaOH / tetrahydrofuran; ethanol / 1 h / 60 °C View Scheme
Multi-step reaction with 2 steps 1: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C 2: sodium hydroxide; ethanol / tetrahydrofuran / 1 h / 60 °C View Scheme
Multi-step reaction with 2 steps 1: ethanol / 2 h / 100 °C 2: sodium hydroxide; water / methanol / 60 °C View Scheme

ethyl 2-chloro-3-oxo-butyrate (609-15-4) + 3-cyanoisobutoxybenzothioamide (163597-57-7) → febuxostat

Conditions	Yield
Stage #1: ethyl 2-chloro-3-oxo-butyrate; 3-cyano-4-(2-methylpropoxy)benzothiamide In ethanol at 100℃; for 2h; Stage #2: With ethanol; sodium hydroxide In tetrahydrofuran at 60℃; for 1h; Stage #3: With hydrogenchloride In tetrahydrofuran; water

3-cyanoisobutoxybenzothioamide (163597-57-7) → 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: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C 2: sodium hydroxide; ethanol / tetrahydrofuran / 1 h / 60 °C 3: ethyl acetate; cyclohexane; methanol / 3 h View Scheme
Multi-step reaction with 2 steps 1.1: ethanol / 2 h / 100 °C 1.2: 1 h / 60 °C 2.1: ethyl acetate; cyclohexane; methanol / 3 h View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → 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: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C 2: sodium hydroxide; ethanol / tetrahydrofuran / 1 h / 60 °C 3: toluene / 10 h View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → (E)-2-(3-cyano-4-isobutoxyphenyl)-N’-(4-hydroxybenzylidene)-4-methylthiazole-5-carbohydrazide

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → (E)-2-(3-cyano-4-isobutoxyphenyl)-N’-(4-methoxybenzylidene)-4-methylthiazole-5-carbohydrazide

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → (E)-2-(3-cyano-4-isobutoxyphenyl)-4-methyl-N’-((5-(2-nitrophenyl)furan-2-yl)methylene)thiazole-5-carbohydrazide

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → (E)-2-(3-cyano-4-isobutoxyphenyl)-4-methyl-N’-((5-methylfuran-2-yl)methylene)thiazole-5-carbohydrazide

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → (E)-2-(3-cyano-4-isobutoxyphenyl)-4-methyl-N’-((5-nitrofuran-2-yl)methylene)thiazole-5-carbohydrazide

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carbohydrazide

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → (E)-2-(3-cyano-4-isobutoxyphenyl)-N’-(4-fluoro-3-phenoxybenzylidene)-4-methylthiazole-5-carbohydrazide

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → C24H24N4O4S

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → C24H24N4O4S

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → C25H26N4O4S

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → (E)-2-(3-cyano-4-isobutoxyphenyl)-4-methyl-N’-(4-nitrobenzylidene)thiazole-5-carbohydrazide

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

3-cyanoisobutoxybenzothioamide (163597-57-7) → (E)-2-(3-cyano-4-isobutoxyphenyl)-4-methyl-N’-(2-methylbenzylidene)thiazole-5-carbohydrazide

Conditions	Yield
Multi-step reaction with 3 steps 1: ethanol / 5 h / Reflux 2: hydrazine hydrate / ethanol / 5 h / Reflux 3: acetic acid / ethanol / 8 h / Reflux View Scheme

Upstream product

• 221076-43-3 4-isobutoxybenzothioamide 
• 5203-15-6 4-(2-methylpropoxy)benzonitrile 
• 208665-95-6 3-bromo-4-isobutoxybenzonitrile 
• 34133-58-9 4-hydroxy-isophthalonitrile 
• 2315-86-8 3-bromo-4-hydroxybenzonitrile 
• 615-58-7 2,4-dibromophenol 
• 767-00-0 4-cyanophenol 
• 619-72-7 4-nitrobenzonitrile 
• 161718-81-6 4-isobutoxyisophthalonitrile 

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 
• 160844-75-7 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester 
• 923942-34-1 methyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate 
• 1139901-88-4 tert-butyl 2-(3’-cyano-4’-isobutoxyphenyl)-4-methylthiazole-5-carboxylate 

Relevant articles and documents

Preparation method of febuxostat intermediate, and application thereof in preparation of febuxostat

The invention provides a preparation method of a compound of structural formula II. The method comprises the following steps: 1) reacting a compound of structural formula VII under the action of an alkylating agent and an alkali to obtain a compound of structural formula VI; 2) reacting the compound of structural formula VI to obtain a compound of structural formula V; 3) reacting the compound ofthe structural formula V with urotropine under an acidic condition in the absence of a solvent to obtain a compound of structural formula IV; 4) reacting the compound of the structural formula IV withhydroxylamine hydrochloride in the presence of an alkali, and dehydrating the obtained reaction product to obtain a compound of structural formula III; and 5) performing a ring closing reaction on the compound of the structural formula III and the compound of the structural formula VIII to obtain the compound of structural formula II. The invention also provides an application of the preparationmethod in the synthesis of febuxostat. The method has the advantages of simplicity in operation, high yield, few side reactions and no highly toxic substances, and is suitable for industrial production as a novel method for preparing the febuxostat intermediate. R in the formulas is a C1-C4 alkyl group.

A facile one-pot synthesis of 4-alkoxy-1,3-benzenedicarbonitrile

2-(3-Cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxlic acid (TEI-6720) was prepared. The introduction of cyano group to 4-nitrobenzonitrile with KCN in dry DMSO followed by quenching with alkyl halide afforded the key intermediates, 4-alkoky-1,3-benzenedicarbonitriles, in good yield. The reaction was completed in dry DMSO, while no reaction occurred in dry DMF. This observation can be suggested by the participation of DMSO in the reaction.