Reference of 458-03-7, A common heterocyclic compound, 458-03-7, name is 1-Ethoxy-3-fluorobenzene, molecular formula is C8H9FO, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.
2- (3-Ethoxy-phenyl)-2-methyl-propionitrile was prepared using a procedure adapted from literature (Organic Syntheses, Vol. 79, pp. 209-215). To a solution of 1-ethoxy-3-fluoro benzene (3.0 g, 19.4 mmol) in 25 mL of toluene was added solid potassium bis (trimethylsilyl)amide (5.84g, 29.2 mmol, 1.5 eq) followed by isobutyronitrile (7.08 mL, 77.8 mmol, 4 eq). The reaction mixture was stirred at 100 C for 12 hr. It was diluted with 75 mL of ethyl acetate and 75 mL of IN aqueous hydrochloric acid. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water (1 x 50 mL), brine (1 x 50 mL), and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in 5 mL of methylene chloride and applied to a 40 g silica gel cartridge. The product was eluted using a gradient of ethyl acetate in hexanes to yield 2.96 g (15.6mmol, 80%) of pure 2-(3-ethoxy- phenyl) -2-methyl-propionitrile. LR-MS: 190.12 [(M+H)+] 2- (3-Ethoxy-phenyl)-2-methyl-propionitrile (2.96 grams, 15.65 mmol) was dissolved in a freshly prepared acetic acid solution of iodine monochloride (20 mL of a 1.54 M iodine monochloride solution in acetic acid, 30.8 mmol). The reaction was slightly exothermic. The reaction mixture was allowed to stand at room temperature for 3 d. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with 10% sodium carbonate (1x), brine (1x), and dried (anhydrous magnesium sulfate). The solids were filtered off, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (110 g of silica gel, eluting with a gradient of ethyl acetate in hexanes) to give 2- (3-ethoxy-4-iodo-phenyl)-2-methyl-propionitrile g, 51%). LR-MS: 316.21 [(M+H)+] Nitrogen gas was bubbled through a solution of (3-ethoxy-4-iodo-phenyl)-2-methyl- propionitrile (2.53 grams, 8 mmol) and diisopropylethylamine (2.09 mL, 12 mmol) in methanol (10 mL). Using a balloon filled with carbon monoxide gas (CO) and equipped with a needle, CO was bubbled through the mixture until it was saturated. Palladium (II) acetate (100 mg) was added, and the mixture was stirred under an atmosphere of CO at 60 C for 6 d. The reaction mixture was filtered and concentrated. The residue was partitioned between methylene chloride and 1.0M hydrochloric acid. The organic layer was dried (anhydrous magnesium sulfate), filtered. The residue was purified by flash chromatography (120 g of silica gel, eluting with a gradient of ethyl acetate in hexanes) to give methyl 4-(cyano-dimethylmethyl)-2-ethoxy- benzoate (1.09 g, 55%). LR-MS: 248.19 [(M+H)@]
The basis of chemical reaction formula synthesis, the synthesis route is composed of some specific reactions and combined according to certain logical thinking. We look forward to the emergence of more reaction modes in the future.
Reference:
Patent; F.HOFFMANN-LA ROCHE AG; WO2005/110996; (2005); A1;,
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