Citric Acid → 3-chloro-5-({2-chloro-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}oxy)benzonitrile

HRID 1874762Notes

Reaction equation

HRID 1874762 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][C:3]=1[OH:20].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28](F)[CH:29]=1)[C:25]#[N:26].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CN1C(=O)CCC1>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:20][C:3]2[CH:4]=[C:5]([CH2:8][N:9]3[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]3=[O:19])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH:29]=1)[C:25]#[N:26]

Participants

7

Reactant 4

HCID 311Citric Acid2×HCID 11430Potassium CarbonateHCID 27348413-Chloro-5-fluorobenzonitrileHCID 594515952-[(4-chloro-3-hydroxyphenyl)methyl]-1H-isoindole-1,3(2H)-dione

Product 1

HCID 594515253-chloro-5-({2-chloro-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}oxy)benzonitrileYield 81%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

2-[(4-Chloro-3-hydroxyphenyl)methyl]-1H-isoindole-1,3(2H)-dione (0.50 g, 2.3 mmol), 3-chloro-5-fluorobenzonitrile (0.54 g, 3.5 mmol), K2CO3 (1.0 g, 7.0 mmol) and NMP (5.0 mL) were added to a round bottom flask. The reaction mixture was placed in an oil bath at 110° C. and stirred overnight. The reaction mixture was cooled to RT and aqueous 10% citric acid (25 mL) and EtOAc (25 mL) were added. Additional aqueous 10% citric acid was added until pH ˜4-5, the layers were separated and the aqueous layer was extracted with EtOAc (2×25 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. Purification was accomplished by column chromatography (hexane/EtOAc) to afford the title compound (0.47 g, 81%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.81-7.92 (m, 4H), 7.79 (d, 1H), 7.58 (d, 1H), 7.44 (d, 1H), 7.37 (d, 1H), 7.29 (d, 1H), 7.23 (dd, 1H), 4.77 (s, 2H). MS: m/z 444.9 (M+23).

Workup

  1. customThe reaction mixture was placed in an oil bath at 110° C.
  2. customthe layers were separated
  3. extractionthe aqueous layer was extracted with EtOAc (2×25 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. customevaporated
  7. customPurification

Sources & evidence

ORD record
ord-39aa689bc2034003902ea1e56d746a9d
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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