Citric Acid → HCID 67452511, compound

HRID 1816526Notes

Reaction equation

HRID 1816526 reaction equation
CN(C)[C:3](=[O:12])[C@@H:4]([CH3:11])[O:5][CH:6]([O:8][CH2:9][CH3:10])[CH3:7].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Mg]Br.FC1C=C(F)C=CC=1Br.[Mg].[Cl-].[NH4+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH2:9]([O:8][CH:6]([O:5][C@H:4]([CH3:11])[C:3]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][C:19]=1[F:21])=[O:12])[CH3:7])[CH3:10]

Participants

8

Reactant 6

HCID 311Citric AcidHCID 25517Ammonium ChlorideHCID 676741-Bromo-2,4-difluorobenzeneHCID 5462224MagnesiumHCID 11788739HCID 11788739, compoundHCID 178505836HCID 178505836, compound

Product 1

HCID 67452511HCID 67452511, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

N,N-Dimethylamine (405.7 g, 9.0 mol) was blown in a solution of (D)-methyl lactate (469 g, 4.5 mol) in methanol (234 mL) at 0-15° C. and the solution was stirred in a sealed vessel at 60-65° C. for 24 hr. The reaction mixture was concentrated under reduced pressure to give (D)-N,N-dimethyl lactamide (525 g). To the solution of a part (109 g, 0.93 mol) of the obtained (D)-N,N-dimethyl lactamide in THF (97 mL) were successively added dropwise methanesulfonic acid (0.9 g, 9.4 mmol) and ethyl vinyl ether (74 g, 1.03 mol) at 15-20° C. and the mixture was stirred for 5 hr to give a solution of (2R)-N,N-dimethyl-2-O-(1-ethoxyethyl)lactamide in THF. Subsequently, to this amide solution was dropwise added a solution of 2,4-difluorophenylmagnesium bromide, which had been synthesized from 2,4-difluorobromobenzene (180 g, 0.93 mol) and magnesium (23 g, 0.95 mol) by a conventional method, in THF (485 mL) at room temperature. The mixture was stirred overnight. The reaction solution was flown into cooled aqueous ammonium chloride solution, neutralized with aqueous citric acid solution and extracted 3 times with toluene. The organic layer was mixed and the mixture was washed successively with aqueous ammonium chloride solution and water to give a solution of (2R)-2-(1-ethoxyethoxy)-1-(2,4-difluorophenyl)-1-propanone in toluene. Subsequently, methanol (97 mL) and methanesulfonic acid (0.9 g, 9.4 mmol) were added, and the mixture was stirred at 40° C. for 2.5 hr. The reaction mixture was washed successively with 5% brine (once) and water (two times) and the organic layer was concentrated under reduced pressure to give the title compound as a pale-yellow oil (120 g, yield 69%).

Workup

  1. extractionextracted 3 times with toluene
  2. additionThe organic layer was mixed
  3. washthe mixture was washed successively with aqueous ammonium chloride solution and water

Sources & evidence

ORD record
ord-45791f519f3048f48811f490ac5306d6
Source dataset
uspto-grants-2005_04
Patent number
US06884892B2

Reaction notes

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