Cesium carbonate → 4-cyclopropyl-5-fluoro-N-[3-fluoro-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine

HRID 410570Notes

Reaction equation

HRID 410570 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:8]=1)[NH2:5].Cl[C:15]1[N:20]=[C:19]([CH:21]2[CH2:23][CH2:22]2)[C:18]([F:24])=[CH:17][N:16]=1.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.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]1([C:19]2[C:18]([F:24])=[CH:17][N:16]=[C:15]([NH:5][C:4]3[CH:6]=[C:7]([C:9]4[S:13][CH:12]=[N:11][CH:10]=4)[CH:8]=[C:2]([F:1])[CH:3]=3)[N:20]=2)[CH2:23][CH2:22]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 672565063-Fluoro-5-(1,3-thiazol-5-yl)anilineHCID 772310692-chloro-4-cyclopropyl-5-fluoroPyrimidine

Product 1

HCID 672579164-cyclopropyl-5-fluoro-N-[3-fluoro-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amineYield 78%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

3-Fluoro-5-(1,3-thiazol-5-yl)aniline (0.91 g, 4.69 mmol), 2-chloro-4-cyclopropyl-5-fluoropyrimidine (0.809 g, 4.69 mmol), palladium(II) acetate (0.105 g, 0.469 mmol), Xantphos (0.407 g, 0.703 mmol), and cesium carbonate (3.05 g, 9.37 mmol) were added to a dry flask. Degassed with argon, and then added dioxane (20 mL). The reaction mixture was degassed with argon for five minutes, and then heated to 90° C. After 2 hours, the reaction mixture was cooled, diluted with ethyl acetate, filtered through celite, and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate and hexanes to afford solids. The solids were dissolved in hot ethyl acetate (25 mL) and then triturated with hexanes (50 mL) while cooling. After 2 hours, the mixture was filtered to afford 4-cyclopropyl-5-fluoro-N-[3-fluoro-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (1.2 g, 3.6 mmol, 78%). MS ESI: [M+H]+ m/z 331.1.

Workup

  1. customDegassed with argon
  2. customThe reaction mixture was degassed with argon for five minutes
  3. temperaturethe reaction mixture was cooled
  4. additiondiluted with ethyl acetate
  5. filtrationfiltered through celite
  6. concentrationconcentrated
  7. customThe residue was purified by column chromatography on silica gel
  8. washeluting with ethyl acetate and hexanes
  9. customto afford solids
  10. customtriturated with hexanes (50 mL)
  11. temperaturewhile cooling
  12. waitAfter 2 hours
  13. filtrationthe mixture was filtered

Sources & evidence

ORD record
ord-5077a111fae34b0bbda32895f3e7fe9f
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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