Triphenylphosphine → 5-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl ester

HRID 391240Notes

Reaction equation

HRID 391240 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27](Br)[C:26]([O:30][CH3:31])=[CH:25][C:24]=1[F:32].[Br-].[Cl:35][C:36]1[C:37]([F:44])=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39][Zn+].[Cl-].[NH4+]>CN1CCCC1=O.O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:20][O:21][C:22](=[O:33])[C:23]1[CH:28]=[C:27]([CH2:39][C:38]2[CH:41]=[CH:42][CH:43]=[C:36]([Cl:35])[C:37]=2[F:44])[C:26]([O:30][CH3:31])=[CH:25][C:24]=1[F:32]

Participants

9

Reactant 4

HCID 11776TriphenylphosphineHCID 25517Ammonium ChlorideHCID 57572850Methyl 5-bromo-2-fluoro-4-methoxybenzoateHCID 178505940HCID 178505940, compound

Product 1

HCID 575728695-(3-Chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl esterYield 79.4%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolventHCID 13387N-methyl-2-pyrrolidoneSolvent2×

Procedure

Under a nitrogen atmosphere, tris(dibenzylideneacetone)dipalladium(0) (6.63 g) and triphenylphosphine (5.98 g) were successively added to 1-methyl-2-pyrrolidinone (350 ml) with stirring at room temperature, and the mixture was stirred for 1 hr. A solution of 5-bromo-2-fluoro-4-methoxybenzoic acid methyl ester prepared in Example 2, Step II, in 1-methyl-2-pyrrolidinone and a solution of 3-chloro-2-fluorobenzylzinc bromide prepared in Example 2, Step I, in tetrahydrofuran were successively added dropwise. After the dropwise addition, the mixture was stirred at 85° C. for 2 hr and cooled. To the reaction mixture were added toluene (560 ml) and 12.5% aqueous ammonium chloride solution (980 ml) and the mixture was stirred. The organic layer was washed successively with 25% aqueous ammonium chloride solution (490 ml), 2% aqueous ethylenediamine solution (490 ml, twice) and 10% brine (490 ml, twice). After the washing, the solvent was concentrated under reduced pressure. Ethyl acetate (105 ml) and heptane (420 ml) were added to the residue to allow recrystallization to give 5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoic acid methyl ester (106.8 g, yield 79.4%).

Workup

  1. stirringthe mixture was stirred for 1 hr
  2. additionAfter the dropwise addition
  3. stirringthe mixture was stirred at 85° C. for 2 hr
  4. temperaturecooled
  5. stirringthe mixture was stirred
  6. washThe organic layer was washed successively with 25% aqueous ammonium chloride solution (490 ml), 2% aqueous ethylenediamine solution (490 ml
  7. concentrationAfter the washing, the solvent was concentrated under reduced pressure
  8. additionEthyl acetate (105 ml) and heptane (420 ml) were added to the residue
  9. customrecrystallization

Sources & evidence

ORD record
ord-b154335656e341f38434d1db68b0bb90
Source dataset
uspto-grants-2013_02
Patent number
US08383819B2

Reaction notes

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