Cesium carbonate → 3-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile

HRID 1630334Notes

Reaction equation

HRID 1630334 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[Cl:23].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[Cl:23][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:15]=1[NH:14][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1)[C:19]#[N:20]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 5198964-Amino-3-chlorobenzonitrileHCID 210775872-Chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine

Product 1

HCID 715133123-Chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrileYield 45%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (211 mg, 1 mmol), 4-amino-3-chlorobenzonitrile (305 mg, 2 mmol), cesium carbonate (0.65 g, 2 mmol), XantPhos (17 mg, 0.03 mmol) and Pd2(dba)3 (5 mg, 0.02 mmol) in dioxane (3 mL) was sonnicated in an ultrasonic bath for 1 min. The mixture was then degassed under a stream of nitrogen for 5 min. The tube was sealed and the reaction was heated at 100° C. for 18 h. The reaction mixture was cooled and diluted with ethyl acetate (15 mL). The organic layer was washed with water (2×20 mL) and the combined aqueous extracts were further washed with ethyl acetate (2×15 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) gave 3-chloro-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)benzonitrile as a white solid (140 mg, 45%). 1H NMR (400 MHz, CDCl3): δ 8.85 (d, J=8.8, 1H); 8.23 (d, J=1.1, 1H); 7.80 (s, 1H); 7.68 (d, J=1.9, 1H); 7.58-7.53 (m, 1H); 5.32 (s br, 1H); 3.11 (d, J=4.7, 3H).

Workup

  1. customThe mixture was then degassed under a stream of nitrogen for 5 min
  2. customThe tube was sealed
  3. temperatureThe reaction mixture was cooled
  4. additiondiluted with ethyl acetate (15 mL)
  5. washThe organic layer was washed with water (2×20 mL)
  6. washthe combined aqueous extracts were further washed with ethyl acetate (2×15 mL)
  7. customThe combined organics were passed through a phase separation cartridge
  8. customthe solvent removed under reduced pressure
  9. customPurification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane)

Sources & evidence

ORD record
ord-5bee55ddc08d4c47a94515cf5b1c2ba4
Source dataset
uspto-grants-2014_07
Patent number
US08791130B2

Reaction notes

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