Hydrochloric Acid → 3-(5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionic acid ethyl ester

HRID 391243Notes

Reaction equation

HRID 391243 reaction equation
[Cl-].[Mg+2].[Cl-].[C:4]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:5][C:6]([O-:8])=O.[K+].[Cl:14][C:15]1[C:16]([F:34])=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][C:19]1[C:20]([O:29][CH3:30])=[CH:21][C:22]([F:28])=[C:23]([CH:27]=1)C(Cl)=O.Cl>O1CCCC1.C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:11]([O:10][C:4](=[O:9])[CH2:5][C:6]([C:23]1[CH:27]=[C:19]([CH2:18][C:17]2[CH:31]=[CH:32][CH:33]=[C:15]([Cl:14])[C:16]=2[F:34])[C:20]([O:29][CH3:30])=[CH:21][C:22]=1[F:28])=[O:8])[CH3:12]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 3446434Potassium ethyl malonateHCID 5360315Magnesium ChlorideHCID 575728405-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride

Product 1

HCID 575728593-(5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionic acid ethyl ester

Reagents, catalysts & solvents 3

HCID 1140TolueneSolvent2×HCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

Triethylamine (9.71 g) and magnesium chloride (7.61 g) were successively added to a suspension of potassium ethyl malonate (10.8 g) in tetrahydrofuran with stirring at room temperature. After stirring at 60-70° C. for 1.5 hr, a solution of 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl chloride prepared in Step V in toluene was added dropwise, and the mixture was further stirred for 30 min. After cooling, toluene (50 ml) and 2N hydrochloric acid (60 ml) were added to the reaction mixture, and the mixture was stirred for 1 hr. The organic layer was washed successively with water (50 ml), 5% sodium hydrogencarbonate (50 ml, twice), and water (50 ml) again, and the organic layer was concentrated under reduced pressure. Toluene (50 ml) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (50 ml) to give a solution of 3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionic acid ethyl ester in toluene. This was identified as the title compound by HPLC.

Workup

  1. stirringAfter stirring at 60-70° C. for 1.5 hr
  2. stirringthe mixture was further stirred for 30 min
  3. temperatureAfter cooling
  4. stirringthe mixture was stirred for 1 hr
  5. washThe organic layer was washed successively with water (50 ml), 5% sodium hydrogencarbonate (50 ml
  6. concentrationtwice), and water (50 ml) again, and the organic layer was concentrated under reduced pressure
  7. additionToluene (50 ml) was added to the residue
  8. concentrationthe mixture was concentrated under reduced pressure
  9. dissolutionThe residue was dissolved in toluene (50 ml)

Sources & evidence

ORD record
ord-45b765037a4f40bab4824c04ebe83af3
Source dataset
uspto-grants-2013_02
Patent number
US08383819B2

Reaction notes

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