161718-81-6

Basic information

• Product Name: 4-(2-Methylpropoxy)-1,3-benzenedicarbonitrile
• Synonyms: 4-(2-Methylpropoxy)-1,3-benzenedicarbonitrile;4-Isobutyloxy-1,3-benzenedicarbonitrile;4-isobutoxy-3-cyanobenzonitrile;4-Isobutoxyisophthalonitrile;1,3-Benzenedicarbonitrile,4-(2-Methylpropoxy)-;4-(2-methylpropoxy)benzene-1,3-dicarbonitrile
• CAS NO: 161718-81-6
• Molecular Formula: C₁₂H₁₂N₂O
• Molecular Weight: 200.24
• EINECS: 213-210-4
• Mol File: 161718-81-6.mol

Chemical Properties

• Melting Point: 128-132 ºC
• Boiling Point: 345.478 °C at 760 mmHg
• Flash Point: 140.646 °C
• Appearance: /
• Density: 1.09
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.528
• Storage Temp.: 2-8°C
• CAS DataBase Reference: 4-(2-Methylpropoxy)-1,3-benzenedicarbonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 4-(2-Methylpropoxy)-1,3-benzenedicarbonitrile(161718-81-6)
• EPA Substance Registry System: 4-(2-Methylpropoxy)-1,3-benzenedicarbonitrile(161718-81-6)

Safety Data

• Hazardous Substances Data: 161718-81-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
4-(2-Methylpropoxy)-1,3-benzenedicarbonitrile is used as an intermediate compound for the synthesis of febuxostat (F229000), a non-purine xanthine oxidase inhibitor. Febuxostat is utilized as a treatment for hyperuricaemia and chronic gout, helping to regulate uric acid levels in the body and alleviate symptoms associated with these conditions.
The compound's role in the preparation of febuxostat highlights its importance in the development of medications that address specific health concerns, making it a valuable component in the pharmaceutical sector.

InChI:InChI=1/C12H12N2O/c1-9(2)8-15-12-4-3-10(6-13)5-11(12)7-14/h3-5,9H,8H2,1-2H3

Synthetic route

4-hydroxy-isophthalonitrile (34133-58-9) + isobutyl halide → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide for 6h; Inert atmosphere;	88.1%

3-bromo-4-isobutoxybenzonitrile (208665-95-6) + potassium ferrocyanide → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
With sodium carbonate; palladium diacetate In N,N-dimethyl-formamide at 140 - 145℃; for 18h;

Isobutyl bromide (78-77-3) + 4-nitrobenzonitrile (619-72-7) → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
Stage #1: 4-nitrobenzonitrile With potassium cyanide In dimethyl sulfoxide at 100℃; for 1h; Heating; Stage #2: Isobutyl bromide With potassium carbonate at 80℃; for 2h;

Isobutyl bromide (78-77-3) + 4-hydroxy-isophthalonitrile (34133-58-9) → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
With potassium carbonate; potassium iodide In dimethyl sulfoxide at 70 - 75℃; for 16h; Product distribution / selectivity;

2,4-dibromophenol (615-58-7) → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium diacetate / dimethyl sulfoxide / 4 h / 40 - 45 °C 2: potassium carbonate; potassium iodide / dimethyl sulfoxide / 16 h / 70 - 75 °C View Scheme
Multi-step reaction with 2 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 View Scheme

4-cyanophenol (767-00-0) → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme

3-bromo-4-hydroxybenzonitrile (2315-86-8) → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

salicylaldehyde (90-02-8) → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water / 1 h / 20 °C 1.2: 8 h 2.1: acetic acid; hexamethylenetetramine / water / 1 h / Reflux 3.1: hydroxylamine hydrochloride; sodium formate; formic acid / 1-methyl-pyrrolidin-2-one / 6 h / Reflux 4.1: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 6 h / Inert atmosphere View Scheme

5-formyl-2-hydroxybenzaldehyde (3328-70-9) → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium formate; formic acid / 1-methyl-pyrrolidin-2-one / 6 h / Reflux 2: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 6 h / Inert atmosphere View Scheme

5-(chloromethyl)salicylaldehyde (23731-06-8) → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetic acid; hexamethylenetetramine / water / 1 h / Reflux 2: hydroxylamine hydrochloride; sodium formate; formic acid / 1-methyl-pyrrolidin-2-one / 6 h / Reflux 3: potassium carbonate; potassium iodide / N,N-dimethyl-formamide / 6 h / Inert atmosphere View Scheme

Isobutyl bromide (78-77-3) + potassium cyanide (151-50-8) + 4-nitrobenzonitrile (619-72-7) → 4-isobutoxyisophthalonitrile (161718-81-6)

Conditions	Yield
With potassium carbonate 1.) DMSO, 100 deg C, 1 h, 2.) 6 h; 70 deg C; Yield given. Multistep reaction;

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-isobutoxyisophthalonitrile (161718-81-6) → febuxostat

Conditions	Yield
Multi-step reaction with 3 steps 1: 85 percent / thioacetamide, HCl / dimethylformamide / 40 h / 45 °C 2: 306 mg / ethanol / 2 h / 100 °C 3: 35 percent / 1N NaOH / tetrahydrofuran; ethanol / 1 h / 60 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 2: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C 3: sodium hydroxide; ethanol / tetrahydrofuran / 1 h / 60 °C View Scheme
Multi-step reaction with 2 steps 1.1: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 2.1: ethanol / 2 h / 100 °C 2.2: 1 h / 60 °C View Scheme

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-isobutoxyisophthalonitrile (161718-81-6) → 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid methylamine (1350352-71-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 2: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C 3: sodium hydroxide; ethanol / tetrahydrofuran / 1 h / 60 °C 4: ethyl acetate; cyclohexane; methanol / 3 h View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 2.1: ethanol / 2 h / 100 °C 2.2: 1 h / 60 °C 3.1: ethyl acetate; cyclohexane; methanol / 3 h View Scheme

4-isobutoxyisophthalonitrile (161718-81-6) → 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid tert-butylamine (1350352-72-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 2: ethyl acetate; N,N-dimethyl-formamide / 22 h / 80 - 85 °C 3: sodium hydroxide; ethanol / tetrahydrofuran / 1 h / 60 °C 4: toluene / 10 h View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride; thioacetamide / isopropyl alcohol / 14 h / 40 - 45 °C 2.1: ethanol / 2 h / 100 °C 2.2: 1 h / 60 °C 3.1: toluene / 10 h View Scheme

4-isobutoxyisophthalonitrile (161718-81-6) → 3-cyano-4-isobutoxybenzimidamide hydrochloride

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol / 20 °C 2: ammonium chloride / 50 °C View Scheme

4-isobutoxyisophthalonitrile (161718-81-6) → ethyl 2-(3-cyano-4-isobutoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylate

Conditions	Yield
Multi-step reaction with 3 steps 1: methanol / 20 °C 2: ammonium chloride / 50 °C 3: sodium hydride / ethanol / 2 h / 80 °C View Scheme

4-isobutoxyisophthalonitrile (161718-81-6) → 2-(3-cyano-4-isobutoxyphenyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid

Conditions	Yield
Multi-step reaction with 4 steps 1: methanol / 20 °C 2: ammonium chloride / 50 °C 3: sodium hydride / ethanol / 2 h / 80 °C 4: lithium hydroxide / ethanol; water; tetrahydrofuran / 50 °C View Scheme

sodium methylate (124-41-4) + 4-isobutoxyisophthalonitrile (161718-81-6) → C13H16N2O2

Conditions	Yield
In methanol at 20℃;

Upstream product

• 23731-06-8 5-(chloromethyl)salicylaldehyde 
• 34133-58-9 4-hydroxy-isophthalonitrile 
• 3328-70-9 5-formyl-2-hydroxybenzaldehyde 
• 90-02-8 salicylaldehyde 
• 2315-86-8 3-bromo-4-hydroxybenzonitrile 
• 208665-95-6 3-bromo-4-isobutoxybenzonitrile 
• 615-58-7 2,4-dibromophenol 
• 78-77-3 Isobutyl bromide 
• 767-00-0 4-cyanophenol 
• 619-72-7 4-nitrobenzonitrile 
• 151-50-8 potassium cyanide 

Downstream Products

• 577778-48-4 3-(3-cyano-4-isobutoxyphenyl)-5-(4-pyridyl)-1,2,4-triazole 
• 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 
• 163597-57-7 3-cyanoisobutoxybenzothioamide 
• 160844-75-7 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester 
• 144060-53-7 febuxostat 

Relevant articles and documents

Preparation method of febuxostat intermediate

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of an important febuxostat intermediate. The preparation method comprises the following steps of: by taking dimethyl 4-isobutoxy isophthalate as a raw material, carrying out ammonolysis on ester groups under the action of a catalyst to obtain acylamino, and further dehydrating the acylamino to obtain 4-isobutoxybenzene-1, 3-dinitrile. According to the method, cyano groups are introduced in ammonolysis and dehydration modes, cyanide with high toxicity is avoided, a traditional catalyst is replaced with a green catalyst, the reaction is milder, economical and environmentally friendly, the yield is high, and the method is suitable for industrial production.

Febuxostat intermediate compound

The invention belongs to the technical field of medicine synthesis, and particularly relates to a febuxostat intermediate compound III. The febuxostat intermediate compound III is 4-isobutoxy isophthalamide. The preparation method of the new intermediate compound comprises the step of reacting dimethyl 4-isobutoxy isophthalate with an ammonia solution to obtain the new intermediate compound 4-isobutoxy isophthalamide. The invention also provides a method for synthesizing an important febuxostat intermediate 4-isobutoxybenzene-1, 3-dinitrile by using the intermediate. The new compound III is used as a key intermediate, and cyano groups are formed through amide dehydration. The conditions are mild, the use of highly toxic limited reagents is avoided, and the safety and applicability of industrial production are greatly improved. The method is milder in reaction, economical, environmentally friendly, high in yield and suitable for industrial production.

Preparation method and use of 2-phenyl-1,6-dihydropyrimidine-5-carboxylic acid derivative

The invention belongs to the technical field of medicines, and relates to a preparation method and a use of a 2-phenyl-1,6-dihydropyrimidine-5-carboxylic acid derivative. The invention provides the 2-phenyl-1,6-dihydropyrimidine-5-carboxylic acid derivative represented by general formula I, or a pharmaceutically acceptable salt, an isomer, a polymorph and a medicinal solvate thereof, and further provides an intermediate for preparing the 2-phenyl-1,6-dihydropyrimidine-5-carboxylic acid derivative or the pharmaceutically acceptable salt thereof. The structure of the intermediate is representedby general formula II, III or IV; and in the formulas, R, R and R are as defined in claims and the description.

Design, synthesis and biological evaluation of 2-(4-alkoxy-3-cyano)phenyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives as novel xanthine oxidase inhibitors

In our previous study, we reported a series of 1-hydroxy-2-phenyl-1H-imidazole-5-carboxylic acid derivatives that presented excellent in vitro xanthine oxidase (XO) inhibitory potency. To further investigate the structure-activity relationships of these compounds, the imidazole ring was transformed to a pyrimidine ring to design 2-(4-alkoxy-3-cyano)phenyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (8a-8j), 2-(4-alkoxy-3-cyano)phenyl-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (9c, 9e, 9j, 9l) and 2-(4-alkoxy-3-cyano)phenyl-6-imino-1,6-dihydropyrimidine-5-carboxylic acids (10c, 10e, 10j, 10l). These compounds exhibited remarkable in vitro XO inhibitory potency with IC50 values ranging from 0.0181 μM to 0.5677 μM. Specifically, compounds 10c and 10e, with IC50 values of 0.0240 μM and 0.0181 μM, respectively, emerged as the most potent XO inhibitors, and their potencies were comparable to that of febuxostat. Structure-activity relationship analysis revealed that the methyl group at 4-position of pyrimidine ring could damage the potency, and the XO inhibitory potency was maintained when carbonyl group was changed to an imino group. Lineweaver-Burk plot analysis revealed that the representative compound 10c acted as a mixed-type inhibitor. A potassium oxonate induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 10c, and the results showed that compound 10c (5 mg/kg) was able to significantly lower the serum uric acid level. Furthermore, in acute oral toxicity study, no sign of toxicity was observed when the mice were administered with a single 2000 mg/kg oral dose of compound 10c. These results suggested that compound 10c was a potent and promising uric acid-lowing agent for the treatment of hyperuricemia.

PROCESS FOR THE PREPARATION OF 2-[3-CYANO-4-(2-METHYLPROPOXY)PHENYL]-4-METHYLTHIAZOLE-5-CARBOXYLIC ACID AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

The present invention relates to novel and improved processes for the preparation of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 and its pharmaceutically acceptable salts thereof. the present invention also provides the novel process for the preparation of crystalline forms of 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methylthiazole-5-carboxylic acid compound of formula-1 and its intermediates.

NOVEL 1,2,4-TRIAZOLE COMPOUND

A novel 1,2,4-triazole compound which is useful as a therapeutic agent for hyperuricemia and gout due to hyperuricemia is provided. A compound is represented by the following general formula (1): wherein R2 represents an unsubstituted or substituted pyridyl group, R1 represents a similar pyridyl group, a pyridine-N-oxide group corresponding to these pyridyl groups, or a phenyl group, and R3 represents hydrogen or a lower alkyl group substituted with pivaloyloxy group and R3 bonds to a nitrogen atom in the ring. A process for production of a compound by reacting a nitrile and a hydrazide, and a therapeutic agent, particularly a xanthine oxidase inhibitor are also provided.

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.