Hydrochloric Acid → ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate

Temperature

0 °C

To a mixture of 4-fluoro-phenylamine (9 g, 81 mmol), concentrated hydrochloric acid (20.4 mL), and water (35.1 mL) was added sodium nitrite (6.3 g, 89.1 mmol) dissolved in water (7.8 mL). In a separate flask ethyl 2-ethylacetoacetate (14.4 g, 89.1 mmol) in ethanol (63.6 mL) at 0° C. was treated with potassium hydroxide (5.1 g, 89.1 mmol) in water (7.5 mL) and ice and the above solution added. The pH of the reaction was adjusted to 5-6 and the reaction stirred at 0° C. for 3 hours and then stored in the freezer overnight. The reaction was then extracted with ethyl acetate (100 mL) and the organics washed with saturated brine solution (100 mL), dried with anhydrous magnesium sulfate. Most of the solvent was removed in vacuo before it was added dropwise to a 14.5% ethanolic solution of hydrochloric acid (70 mL) at 78° C. Heating was continued for 2 hours. The solvent was removed in vacuo and the residue treated with dichloromethane (300 mL) and water (100 mL). The organic layer was washed with saturated sodium chloride (200 mL), dried over sodium sulfate and concentrated in vacuo. Purification on a short wash column (silica gel, 25% ethyl acetate/hexane) gave ethyl 5-fluoro-3-methyl-1H-indole-2-carboxylate as a white solid. MS (ES) m/z 220.0

1. additionthe above solution added
2. customstored in the freezer overnight
3. extractionThe reaction was then extracted with ethyl acetate (100 mL)
4. washthe organics washed with saturated brine solution (100 mL)
5. dry with materialdried with anhydrous magnesium sulfate
6. customMost of the solvent was removed in vacuo before it
7. additionwas added dropwise to a 14.5% ethanolic solution of hydrochloric acid (70 mL) at 78° C
8. temperatureHeating
9. waitwas continued for 2 hours
10. customThe solvent was removed in vacuo
11. additionthe residue treated with dichloromethane (300 mL) and water (100 mL)
12. washThe organic layer was washed with saturated sodium chloride (200 mL)
13. dry with materialdried over sodium sulfate
14. concentrationconcentrated in vacuo
15. customPurification on
16. washa short wash column (silica gel, 25% ethyl acetate/hexane)

ORD record

ord-10dbf3cb109a4002bf4801a04a4a66b5

Source dataset

uspto-grants-2009_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07517899B2