Ethanol → 3-Chloro-5'-fluoro-2'-methoxy[1,1'-biphenyl]-4-carboxylic acid

HRID 1891425Notes

Reaction equation

HRID 1891425 reaction equation
Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17](B(O)O)[CH:18]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.CC(OC)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[C:13]([F:12])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]

Participants

9

Reactant 4

HCID 702EthanolHCID 10340Sodium CarbonateHCID 1088294-Bromo-2-chlorobenzoic acidHCID 27826735-Fluoro-2-methoxyphenylboronic acid

Product 1

HCID 251528833-Chloro-5'-fluoro-2'-methoxy[1,1'-biphenyl]-4-carboxylic acidYield 97%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
75 °C

Procedure

4-Bromo-2-chlorobenzoic acid (205 g) and 5-fluoro-2-methoxyphenylboronic acid (161 g) were dissolved in toluene (2 L) and ethanol (2 L) in a 10 L reactor vessel. Sodium carbonate (2 L of a 2 M aqueous solution) was added followed by tetrakis(triphenylphosphine)palladium(0) (15.39 g). The reaction was heated at 75° C. for 16 h. The reaction was diluted with water (2.5 L) and TBME (2 L) and stirred. Further water (0.5 L) was added and the mixture stirred for a further 5 min to complete dissolution of the solids. The aqueous layer was separated, filtered through a Celite pad and cooled to 15° C. The solution was acidified to pH 1 over 1 h by the addition of conc. HCl (532 mL, final pH1). The solid was filtered off and washed with ice cold water (400 ml) to give a tan solid. This was dried for 72 h in a vacuum oven at 45° C. over CaCl2 to give the sub titled product (237 g).

Workup

  1. stirringthe mixture stirred for a further 5 min
  2. dissolutiondissolution of the solids
  3. customThe aqueous layer was separated
  4. filtrationfiltered through a Celite pad
  5. temperaturecooled to 15° C
  6. additionThe solution was acidified to pH 1 over 1 h by the addition of conc. HCl (532 mL
  7. filtrationThe solid was filtered off
  8. washwashed with ice cold water (400 ml)
  9. customto give a tan solid
  10. dry with materialThis was dried for 72 h in a vacuum oven at 45° C. over CaCl2

Sources & evidence

ORD record
ord-7227ef24696749219724627040d31c6c
Source dataset
uspto-grants-2013_08
Patent number
US08507544B2

Reaction notes

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