Ethyl Acetoacetate → 5-Isopropyl-6-methoxy-3-methyl-1H-indole-2-carboxylic acid ethyl ester

Temperature

70 °C

4-Isopropyl-3-methoxy-phenylamine HCl salt (3.1 g, 19 mmol) was cooled to −5 C (Ice/Methanol bath), and a mixture of 8 ml water and 5 ml concentrated. HCl was added dropwise. The reaction mixture was stirred for five minutes, and sodium nitrite (1.42 g, 21 mmol) disolved in 3 ml water was added dropwise over 10 minutes. The reaction mixture was stirred for 45 min, then sodium acetate (1.3 g, 16 mmol) was added. In a separate flask, to a stirring mixture of ethyl alpha-acetoacetate (3.26 g, 21 mmol) in 15 ml absolute ethanol was added KOH (1.2 g, 21 mmol) dissolved in 3 ml water and then added ice (10 g). This mixture was added to the diazonium salt, and the reaction mixture was stirred at zero degrees C for 3.5 hours. The reaction mixture was stored at −10 C for 16 hours, then extracted with EtOAC. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to a liquid residue. In a separate flask, mixed 100 ml EtOH was mixed slowly with 22 ml acetyl chloride, with cooling in an ice bath. The EtOH/acetyl chloride solution was heated to 70 degrees C, and added the residue was added via pipette over 10 min. The reaction mixture was heated to reflux for 2.5 hours, cooled, evaporated under reduced pressure to give a slurry; diluted with water (100 ml) and filtered. The solid was washed with water. The solid was triturated with hexanes to give 5-Isopropyl-6-methoxy-3-methyl-1H-indole-2-carboxylic acid ethyl ester (1.7 g, 34% ) as a solid.

1. concentrationconcentrated
2. additionHCl was added dropwise
3. additionwas added dropwise over 10 minutes
4. stirringThe reaction mixture was stirred for 45 min
5. stirringthe reaction mixture was stirred at zero degrees C for 3.5 hours
6. waitThe reaction mixture was stored at −10 C for 16 hours
7. extractionextracted with EtOAC
8. washThe combined organic layers were washed with brine
9. dry with materialdried over magnesium sulfate
10. concentrationconcentrated under reduced pressure to a liquid residue
11. additionIn a separate flask, mixed 100 ml EtOH
12. additionwas mixed slowly with 22 ml acetyl chloride
13. temperaturewith cooling in an ice bath
14. additionadded the residue
15. additionwas added via pipette over 10 min
16. temperatureThe reaction mixture was heated
17. temperatureto reflux for 2.5 hours
18. temperaturecooled
19. customevaporated under reduced pressure
20. customto give a slurry
21. filtrationfiltered
22. washThe solid was washed with water
23. customThe solid was triturated with hexanes

ORD record

ord-b9829395f2ca447c82ce2c41a2afb9cb

Source dataset

uspto-grants-2010_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07858632B2