Citric Acid → N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-6-(methyloxy)-1H-indole-2-carboxamide

HRID 1874769Notes

Reaction equation

HRID 1874769 reaction equation
[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]C)=O)[NH:9]2)=[CH:5][CH:4]=1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[NH2:31][CH2:32][C:33]1[CH:34]=[CH:35][C:36]([Cl:49])=[C:37]([O:39][C:40]2[CH:41]=[C:42]([CH:45]=[C:46]([Cl:48])[CH:47]=2)[C:43]#[N:44])[CH:38]=1.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C.O.CO>[Cl:49][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][NH:31][C:12]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)=[O:14])=[CH:38][C:37]=1[O:39][C:40]1[CH:41]=[C:42]([C:43]#[N:44])[CH:45]=[C:46]([Cl:48])[CH:47]=1

Participants

10

Reactant 5

HCID 311Citric AcidHCID 3939Lithium Hydroxide2×HCID 81531DiisopropylethylamineHCID 688173Methyl-6-methoxy-2-indolecarboxylateHCID 594514053-{[5-(Aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile

Product 1

HCID 59451580N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-6-(methyloxy)-1H-indole-2-carboxamideYield 37.8%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

Methyl 6-(methyloxy)-1H-indole-2-carboxylate (0.025 g, 0.13 mmol) was dissolved in THF:methanol:water/1:1:1 (3 mL) and lithium hydroxide (0.01 g, 0.38 mmol) was added. The reaction was stirred for 1 h, at which time another portion of lithium hydroxide (0.01 g, 0.38 mmol) was added. The reaction was stirred for 1 h, acidified with 10% aqueous citric acid to pH 4-5 and extracted with EtOAc (3×5 mL). The organic extracts were combined, dried over Na2SO4, filtered and evaporated. To the crude intermediate was added 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL) and then stirred overnight. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 26%) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.38 (d, 1H), 8.88-8.93 (m, 1H), 7.77 (d, 1H), 7.59 (d, 1H), 7.42-7.48 (m, 2H), 7.35 (d, 1H), 7.26 (dd, 1H), 7.23 (d, 1H), 7.04 (d, 1H), 6.84 (d, 1H), 6.66 (dd, 1H), 4.47 (d, 2H), 3.73 (s, 3H). MS: m/z 466.2 (M+1).

Workup

  1. additionwas added
  2. extractionextracted with EtOAc (3×5 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. customevaporated
  6. stirringstirred overnight
  7. customPurification
  8. extractionextracted with EtOAc
  9. dry with materialThe combined organics were dried over Na2SO4
  10. filtrationfiltered
  11. customevaporated

Sources & evidence

ORD record
ord-2ea3822848a44807bc49d0ac652ea744
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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