Hydrochloric Acid → Ethyl 3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropionate

Temperature

75 °C

Under a nitrogen atmosphere, to a suspension of anhydrous magnesium chloride (36.5 g) and ethyl acetate (200 mL) was slowly added dropwise tetrahydrofuran (55.2 g). After completion of the dropwise addition, the mixture was stirred at 75° C. for 2 hr to dissolve anhydrous magnesium chloride. The solution was added dropwise to an ice-cold suspension of potassium ethylmalonate (52.1 g) and triethylamine (46.5 g) in ethyl acetate (200 mL). After the dropwise addition, the suspension was warmed to 70° C. To the suspension was slowly added dropwise at 70° C. a suspension of 5-bromo-2,4-dimethoxybenzoic acid chloride obtained in Step 2 of Example 1 in tetrahydrofuran. After completion of the dropwise addition, the mixture was stirred at 70° C. for 0.5 hr, and the completion of the reaction was confirmed by HPLC. 2N Hydrochloric acid (240 mL) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The organic layer was separated, and washed successively with water (200 mL), twice with 5% sodium hydrogencarbonate (200 mL), and water (200 mL). After washing, the solvent was evaporated under reduced pressure, toluene (200 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. The obtained ethyl 3-(5-bromo-2,4-dimethoxyphenyl)-3-oxopropionate (52.8 g) as a white solid was directly used in the next step.

1. additionAfter completion of the dropwise addition
2. additionAfter the dropwise addition
3. temperaturethe suspension was warmed to 70° C
4. additionTo the suspension was slowly added dropwise at 70° C.
5. additionAfter completion of the dropwise addition
6. stirringthe mixture was stirred at 70° C. for 0.5 hr
7. temperaturecooling
8. stirringthe mixture was stirred at room temperature for 1 hr
9. customThe organic layer was separated
10. washwashed successively with water (200 mL), twice with 5% sodium hydrogencarbonate (200 mL), and water (200 mL)
11. washAfter washing
12. customthe solvent was evaporated under reduced pressure, toluene (200 mL)
13. additionwas added to the concentrated residue
14. concentrationthe mixture was concentrated again under reduced pressure

ORD record

ord-b3fa477cfd874c6d89480a640bf3f05e

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08420821B2