Preparation and application of ethyl 3-nitrophenyl acetate_Industrial additives

Background and overview^[1]

Ethyl 3-nitrophenylacetate can be used as a pharmaceutical synthesis intermediate. It can be prepared by the esterification reaction of 3-nitrophenylacetic acid and ethanol. It can be used as a raw material to prepare 2-[3-(3- Methyl-but-2-enoylamino)-phenyl]-heptanoic acid ethyl ester.

Preparation^[1]

A solution of 3-nitrophenylacetic acid (12.755g, 70.4mmole) in 150mL ethanol was treated with 3.83mL concentrated sulfuric acid. The reaction mixture was heated to reflux for 20 hours, concentrated under vacuum to 1/3 of the initial volume, and diluted with 250 mL of ethyl acetate. Wash continuously with two portions of 100 mL water, two portions of 100 mL saturated aqueous sodium bicarbonate solution, 100 mL water and 100 mL saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum to give 14.69 g of ethyl 3-nitrophenylacetate as a pale yellow oil.

Apply^[1]

A solution of ethyl 3-nitrophenylacetate (4.0 g, 19.1 mmole) in 80 mL DMF was treated with 12.46 g cesium carbonate and 2.55 mL amyl iodide. The reaction mixture was stirred at room temperature for 15 hours, diluted with 200 mL of water, and extracted with three 150 mL portions of diethyl ether. The combined organic extracts were washed with 200 mL of water and 200 mL of saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO₂, 5% ethyl acetate/hexane) to give 4.451 g of ethyl 2-(3-nitro-phenyl)-heptanoate as a light yellow oil . A solution of 1.69 g of 10% palladium on carbon in ethyl 2-(3-nitro-phenyl)-heptanoate (4.451 g, 15.9 mmole) in 150 mL of ethyl acetate was subjected to atmospheric pressure of hydrogen for 15 hours. The mixture was filtered through a pad of Celite/SiO₂ and volatiles were removed under vacuum to afford 3.866 g of ethyl 2-(3-amino-phenyl)-heptanoate as a pale yellow oil. A solution of ethyl 2-(3-amino-phenyl)-heptanoate (3.866 g, 15.5 mmole) in 40 mL of chloroform was treated with 1.73 mL of 3,3-dimethacryloyl chloride. The mixture was heated to reflux for 4 hours, quenched by adding 100 mL of water, and extracted with three 50 mL portions of chloroform. The combined organic extracts were extracted with 100 mL of saturated aqueous sodium bicarbonate solution, 100 mL of water and 100 mL of saturated aqueous sodium chloride solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO₂, 15% ethyl acetate/hexane) to afford 3.822 g of 2-[3-(3-methyl-but-2-enoylamino)-phenyl ]-Ethyl heptanoate, which is a light yellow oil.

Main reference materials

[1] CN1578776 – Heterocyclic retinoid compounds