Hydrochloric Acid → Ethyl 2-formylthiophene-3-carboxylate

温度

-78 °C

3-Thiophenecarboxylic acid (3.48 g) was dissolved in tetrahydrofuran (50 ml), and N,N,N',N'-tetramethylethylenediamine (10 ml) was added. The mixture was cooled to -78° C., and n-butyllithium (1.6M in hexane, 41.3 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (4.6 ml) was added dropwise. The mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a mixture of 2-formyl-3-thiophenecarboxylic acid and 5-formyl-3-thiophenecarboxylic acid (2.11 g). This mixture was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (0.95 ml) and potassium carbonate (1.66 g) were added. The reaction mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-formyl-3-thiophenecarboxylic acid ethyl ester (1.75 g). 2-Formyl-3-thiophenecarboxylic acid ethyl ester (1.66 g) in methylene chloride (20 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.32 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (1.08 g). 2-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (7.8 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-difluoromethyl-3-thiophenecarboxylic acid (0.88 g) as crystals.

1. temperatureThe mixture was warmed to room temperature
2. stirringstirred for 15 hours
3. extractionextracted with ethyl acetate
4. dry with materialThe extract was dried over anhydrous magnesium sulfate
5. concentrationconcentrated under reduced pressure
6. customThe residue was purified by silica gel column chromatography
7. customto give
8. stirringThe reaction mixture was stirred at room temperature for 15 hours
9. extractionextracted with diethyl ether
10. washThe extract was washed with 5% aqueous potassium hydrogen sulfate
11. dry with materialdried over anhydrous magnesium sulfate
12. concentrationconcentrated under reduced pressure
13. concentrationthe desired fractions were concentrated under reduced pressure

ORDレコード

ord-2025e2d774ec4a5a91148c4827499937

出典データセット

uspto-grants-1998_11

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US05840917