Cesium carbonate → 3-({4-[(Dimethylamino)carbonyl]phenyl} amino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylic acid

HRID 2364256Notes

Reaction equation

HRID 2364256 reaction equation
[NH2:1][C:2]1[C:3]([C:16]([O:18]CC)=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].N[C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.ClCCl.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:35][N:34]([CH3:36])[C:32]([C:31]1[CH:37]=[CH:38][C:28]([NH:1][C:2]2[C:3]([C:16]([OH:18])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)[CH:7]=2)=[CH:29][CH:30]=1)=[O:33]

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 2355274-Amino-N,N-dimethylbenzamideHCID 23676156Sodium t-butoxideHCID 42637772Ethyl 3-amino-5-(4-fluorobenzyl)picolinate

Product 1

HCID 694827073-({4-[(Dimethylamino)carbonyl]phenyl} amino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylic acidYield 94%

Reagents, catalysts & solvents 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent2×

Procedure

To a dry 100 mL flask under a nitrogen atmosphere was added ethyl 3-amino-5-(4-fluorobenzyl)pyridine-2-carboxylate (89 mg, 0.325 mmol) described in example 1, Cs2CO3 (148 mg, 0.455 mmol), Pd2dba3 (1.5 mg, 0.0016 mmol), and Xantphos (2.8 mg, 0.0049 mmol). Dioxane (15 mL) and 4-amino-N,N-dimethylbenzamide (1.25 mL of a 0.78 M solution in dioxane, 0.975 mmol) were added and the resulting solution was refluxed for 2 hrs. Sodium tert-butoxide (94 mg, 0.975 mmol) was added and the mixture was stirred for 10 minutes. The mixture was cooled to ambient temperature, diluted with dichloromethane, filtered through Celite and concentrated under reduced pressure. Water was added and the aqueous layer was washed with ethyl acetate and then acidified with 1 N hydrochloric acid to a pH of 4. The resulting yellow precipitate was collected by vacuum filtration to yield 3-({4-[(dimethylamino)carbonyl]phenyl}amino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylic acid (120 mg, 94% yield). 1H NMR (CDCl3) δ 7.82 (s, 1 H), 7.46 (s, 1 H), 7.38 (d, J=8.4 Hz, 2 H), 7.13 (d, J=8.4 Hz, 2 H), 7.09-7.05 (m, 2 H), 6.97-6.93 (m, 2 H), 3.88 (s, 2 H), 3.07 (s, 3 H), 2.99 (s, 3 H); MS m/z 392 (M−1).

Workup

  1. temperaturethe resulting solution was refluxed for 2 hrs
  2. filtrationfiltered through Celite
  3. concentrationconcentrated under reduced pressure
  4. additionWater was added
  5. washthe aqueous layer was washed with ethyl acetate
  6. filtrationThe resulting yellow precipitate was collected by vacuum filtration

Sources & evidence

ORD record
ord-cc4b942df1fb4af5b607bcee6dec5803
Source dataset
uspto-grants-2014_04
Patent number
US08691991B2

Reaction notes

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