Application of 5-Nitrobenzofuran-2-carboxylic acid_Kain Industrial Additive

Background and overview^[1][2]

5-Nitrobenzofuran-2-carboxylic acid and manganese pentacarbonyl bromide can be used as pharmaceutical and chemical synthesis intermediates.

Apply^[1-2]

5-Nitrobenzofuran 2-carboxylic acid is an important intermediate for the treatment of major depression drugs and an important intermediate in the synthesis of luminescent materials. Examples of its applications are as follows: the synthetic antidepressant vilazodone. Vilazodone, the English name is vilazodone, is a benzofuran derivative with the chemical name 5 [4 [4 (3 butyl 5 cyano) indole] 1 piperazine] benzene and furan 2 carboxamide. Vilazodone was originally developed by Merck KGaA. It is a 5 HT dual-action antidepressant. It not only selectively inhibits the reuptake of 5 HT, but also partially activates the 5 HT1A receptor. , is also the first new antidepressant of the indole alkylamine class.

Vilazodone has a unique mechanism of action, rapid and clear clinical efficacy, and fewer sexual side effects. It has better prospects than traditional SSRI antidepressants. The steps are as follows:

(1) Using 5 nitrosalicylic aldehyde as raw material and ethyl bromoacetate under the action of potassium carbonate, the compound 5 nitrobenzofuran 2 formic acid is obtained by heating and hydrolysis; 5 nitrobenzene Preparation of furan-2-carboxylic acid, using 5-nitrosalicylicaldehyde as raw material, solvent as N,N dimethylformamide (DMF), heating and reaction with ethyl bromoacetate under the action of potassium carbonate and hydrolysis Compound 5 nitrobenzofuran 2 carboxylic acid is obtained, the reaction temperature is 90°C to 130°C, and the molar ratio of 5 nitrosalicylicaldehyde: potassium carbonate: ethyl bromoacetate is 1:1 to 1.1:2.

(2) After the reaction between 5 nitrobenzofuran 2 formic acid and isobutyl chloroformate, ammonia water is added to obtain 5 nitrobenzofuran 2 carboxamide; 5 nitrobenzofuran 2 carboxamide is obtained 2 Dissolve formic acid in methylene chloride, react with triethylamine and isobutyl chloroformate in an ice-water bath, add ammonia water after the reaction, remove the organic solvent under reduced pressure, dissolve the solid with ethyl acetate and tetrahydrofuran, and purify to obtain 5 Nitrobenzofuran 2 Carboxamide.

(3) 5 Nitrobenzofuran 2 formamide is reduced with insurance powder to obtain the intermediate 5 aminobenzofuran 2 formamide; 5 Nitrobenzofuran 2 formamide and The reducing agent insurance powder reacts in the solvent water and ethanol. After the reaction, the organic solvent is removed, the pH is adjusted to 2.0 with acid, the product is extracted, and the product is dried. After removing the organic solvent, the intermediate 5 aminobenzofuran 2 carboxamide is obtained, 5 The molar ratio of nitrobenzofuran 2 carboxamide to insurance powder is 1:3~6.

(4)5 Aminobenzofuran 2 carboxamide and bis(2 chloroethyl)amine are ring closed under the action of alkali to obtain 5 piperazine benzofuran 2 carboxamide; 5 piperazine Preparation of oxazinebenzofuran 2 carboxamide: 5 aminobenzofuran 2 carboxamide, bis(2 chloroethyl)amine and sodium bicarbonate, n-butanol react under nitrogen protection, after the reaction is completed Add water, adjust the pH to 9.0 with alkali, extract, wash with water, wash with alkali, dry and remove the solvent, the crude product is separated and purified by chromatography to obtain 5 piperazine benzofuran 2 carboxamide, the alkali is potassium carbonate Or sodium bicarbonate or triethylamine or sodium carbonate or sodium hydroxide; the molar ratio of 5 aminobenzofuran 2 carboxamide and bis(2 chloroethyl)amine is 1:0.5~2, aminobenzofuran The molar ratio of furan 2 carboxamide to base is 1:0.5~2. (5) 5 piperazine benzofuran 2 carboxamide was substituted with 3 (4 chlorobutyl) 5 cyanoindole to obtain vilazodone.

5 piperazine benzofuran 2 formamide, 3 (4 chlorobutyl) 5 cyanoindole, sodium bicarbonate and potassium iodide, N, N dimethylformamide ( DMF) was dissolved, and the temperature was raised to 100°C for reaction. After the reaction was completed, it was cooled to room temperature and purified to obtain vilazodone.

Preparation ^[1,3]

Method 1: Use 5-nitrobenzofuran 2 formic acid R ester as the starting material, add an appropriate amount of alkaline solution, and then stir and react at a certain temperature for 2 to 3 hours to obtain the hydrolyzate. The post-treatment method is simple. After adjusting the pH and filtering, the target product with higher purity can be obtained. The solvents used refer to alcohols (methanol, ethanol, isopropyl alcohol), acetone, tetrahydrofuran, water, N, N dimethylformamide or their mixed solvents. Among them, water is preferred. The reaction temperature that needs to be controlled is room temperature to 100°C, preferably room temperature.

The specific steps are as follows: Add 20.0g (80.3mmol) of 5-nitrobenzofuran 2-propyl formate into a 500mL three-necked flask, add 161mL of 2.5mol/L K2CO3 (401.6mmol) acetone solution, and stir at 45°C. After 2 to 3 hours, the thin layer chromatography monitoring (TLC) reaction was completed, and then the pH was adjusted to 4.5 with 2mol/L hydrochloric acid aqueous solution, suction filtration, and the filter cake was washed with water to obtain a light yellow solid, which was detected by TLC. The solid is a single point, which is 5-nitrobenzofuran 2-carboxylic acid. It is dried under vacuum at 45°C for 24 hours, and 17.9 g is weighed to obtain 5-nitrobenzofuran 2-carboxylic acid, with a yield of 89.5%. m.p.270 274°C.

Method 2: Step 1) Add activated potassium carbonate (16.55g, 120mmol) to the stirred solution of salicylaldehyde (1) (60mmol) in anhydrous DMF (15mL). A solution of ethyl bromoacetate (10.0 g, 60 mmol) in anhydrous DMF (20 mL) was then added to the above mixture, and the reaction mixture was stirred at 130°C for 6 hours. The solvent was then evaporated to approximately 1/3 of its volume, yielding a brown slurry. The crude product was extracted with CHCl (200 mL) and water (3 x 100 mL).

The organic layer was dried (MgSO 4), filtered and concentrated in vacuo, and the resulting residue was purified by flash column chromatography (petroleum ether/ethyl acetate 100:0 v/v, increased to 95:5 v/v) to obtain a yellow color solid. Yield: 22%, Rf 0.60 (petroleum ether/EtOAc 4:1v/v), melting point 139-141°C. Step 2) A solution of benzo[b]furan-2-carboxylic acid ethyl ester (2) (32 mmol) was treated with 2M aqueous sodium. Methanol (100 mL) was added to hydroxide (50 mL) and warmed gently on a steam bath. After hydrolysis is complete (approximately 30 min), the reaction solution is cooled and acidified to pH 1 by adding concentrated HCl dropwise. The solution was then extracted with diethyl ether (3 x 150 mL), and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo to give a crude yellow solid. The crude yellow solid was washed with water, collected and dried under vacuum with phosphorus pentoxide to obtain 5 nitrobenzofuran 2 carboxylic acid. Yield: 95%, Rf 0.0 (petroleum ether/EtOAc 1:1v/v), melting point 268-270°C.

（R1=-NO2）

Main reference materials

[1] CN201210069650.2 A new preparation method of 5-nitrobenzofuran-2-carboxylic acid

[2] CN201110416975.9 Synthesis method of antidepressant vilazodone

[3] Aboraia, Ahmed S.; Yee, Sook Wah; Gomaa, Mohamed Sayed; Shah, Nikhil; Robotham, Anna C.; Makowski, Bart; Prosser, David; Brancale, Andrea; Jones, Glenville; Simons, Claire Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 14 p. 4939 – 4946