Triethylamine → 2-(5-Chloroisoxazole-3-carbonyl)-3-dimethylamino-acrylic acid ethyl ester

Temperature

25 °C

A solution of 5-chloro-isoxazole-3-carboxylic acid (791 mg, 5.43 mmol) (preparation described in WO03093250 A2) in dichloromethane (27.2 mL, 0.2M) cooled to 0° C. was treated with oxalyl chloride (0.71 mL, 8.15 mmol, 98%) followed by a few drops of N,N-dimethylformamide. The reaction was allowed to gradually warm up to 25° C. The reaction was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The resulting residue was dissolved in dichloromethane and re-concentrated twice to remove residual oxalyl chloride. The residue was then dissolved in dichloromethane (16 mL, 0.34M) and treated dropwise with a solution of ethyl-3-(dimethylamino)acrylate (0.79 g, 5.51 mmol) in triethylamine (1.6 mL, 11.47 mmol). The resulting red/orange reaction solution was heated to 60° C. overnight. At this time, the reaction was cooled to 25° C. and then partitioned between water (50 mL) and dichloromethane (100 mL). The organics were then washed with water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Biotage chromatography (40M column, 50-60% ethyl acetate/hexanes) afforded 2-(5-chloroisoxazole-3-carbonyl)-3-dimethylamino-acrylic acid ethyl ester (300.6 mg, 20%) as a red oil.

1. concentrationAt this time, the reaction was concentrated in vacuo
2. dissolutionThe resulting residue was dissolved in dichloromethane
3. concentrationre-concentrated twice
4. customto remove residual oxalyl chloride
5. dissolutionThe residue was then dissolved in dichloromethane (16 mL, 0.34M)
6. temperatureThe resulting red/orange reaction solution was heated to 60° C. overnight
7. temperatureAt this time, the reaction was cooled to 25° C.
8. custompartitioned between water (50 mL) and dichloromethane (100 mL)
9. washThe organics were then washed with water (50 mL)
10. dry with materiala saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate
11. filtrationfiltered
12. concentrationconcentrated in vacuo

ORD record

ord-57972fa04f69402a8ec056a98f60b3e7

Source dataset

uspto-grants-2010_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07728029B2