Hydrochloric Acid → Ethyl 3-(5-bromo-2-fluoro-4-methoxyphenyl)-3-oxopropionate

Temperature

60 °C

Under a nitrogen atmosphere, potassium ethylmalonate (13.7 g) and triethylamine (12.2 g) were suspended in THF (100 mL). Furthermore, anhydrous magnesium chloride (9.56 g) was added by portions while paying attention to heat generation. The suspension was stirred at 60° C. for 1.5 hr, and to the suspension was slowly added dropwise at 60° C. a suspension of acid chloride obtained in the above-mentioned Step 2 in toluene. After completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hr. The completion of the reaction was confirmed by HPLC, and the mixture was cooled to room temperature. Toluene (50 mL) was added to the reaction mixture, and 2N hydrochloric acid (60 mL) was added. After dropwise addition, the mixture was stirred at room temperature for 1 hr. The organic layer was separated, and washed successively with water (50 mL), twice with 5% sodium hydrogencarbonate (50 mL), and water (50 mL). After washing, the solvent was evaporated under reduced pressure, toluene (50 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. To the concentrated residue was added toluene (50 mL), and a solution of the obtained ethyl 3-(5-bromo-2-fluoro-4-methoxyphenyl)-3-oxopropionate in toluene was directly used in the next step.

1. temperatureto heat generation
2. additionto the suspension was slowly added dropwise at 60° C.
3. additionAfter completion of the dropwise addition
4. stirringthe mixture was stirred at 60° C. for 2 hr
5. temperaturethe mixture was cooled to room temperature
6. additionwas added
7. additionAfter dropwise addition
8. stirringthe mixture was stirred at room temperature for 1 hr
9. customThe organic layer was separated
10. washwashed successively with water (50 mL), twice with 5% sodium hydrogencarbonate (50 mL), and water (50 mL)
11. washAfter washing
12. customthe solvent was evaporated under reduced pressure, toluene (50 mL)
13. additionwas added to the concentrated residue
14. concentrationthe mixture was concentrated again under reduced pressure
15. additionTo the concentrated residue was added toluene (50 mL)

ORD record

ord-938ca0e92da94be6b13e6f84dac3e527

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08420821B2