4-Aminobenzoic Acid → 4-(4-Cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid

HRID 1410506Notes

Reaction equation

HRID 1410506 reaction equation
CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[O:48][C:47]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])=[N:46][C:45]=1[C:57]#[N:58].[NH2:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([OH:66])=[O:65])=[CH:62][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)CCC.O1CCOCC1.CCOC(C)=O.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]>[C:57]([C:45]1[N:46]=[C:47]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:50]=2[F:56])[O:48][C:44]=1[NH:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([OH:66])=[O:65])=[CH:62][CH:61]=1)#[N:58]

Participants

8

Reactant 4

HCID 9784-Aminobenzoic AcidHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 595875125-Bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile

Product 1

HCID 595874924-(4-Cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acidYield 14%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 67780350nBuOH dioxaneSolvent

Conditions

Temperature
140 °C

Procedure

A solution of tris(dibenzylideneacetone)dipalladium(0) (0.337 g, 0.368 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.213 g, 0.368 mmol) in n-butanol:dioxane (1:1) (5 mL) was stirred at room temperature for 3 minutes. Then 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (1.50 g, 5.262 mmol), 4-aminobenzoic acid (2.165 g, 15.787 mmol) and cesium carbonate (3.429 g, 10.525 mmol) were added and the mixture heated in the microwave for 3 minutes at 140° C. The reaction was diluted with EtOAc and washed with water. The organic phase was passed through an MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by column chromatography using a 20-45% EtOAc:hexane gradient then further purified by trituration of the solid in DCM:hexane (1:1) to afford 4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.251 g, 0.735 mmol, 14%) as a light yellow solid. 1H NMR (DMSO) δ 7.34 (2H, t), 7.40 (2H, d), 7.66 (1H, m), 7.92 (2H, d), 11.16 (1H, br s), 12.76 (1H, br s). LCMS (3) Rt: 1.53 min; m/z (ES+) 342.

Workup

  1. washwashed with water
  2. dry with materialdried over MgSO4
  3. customthe solvent removed in vacuo
  4. customThe residue was purified by column chromatography
  5. customhexane gradient then further purified by trituration of the solid in DCM:hexane (1:1)

Sources & evidence

ORD record
ord-ad25dc05930e4049a6cfb059cc8b7317
Source dataset
uspto-grants-2014_12
Patent number
US08921544B2

Reaction notes

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