Cesium carbonate → Tert-butyl cis-2-(6-(5-methylpyridin-3-ylamino)-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate

HRID 340506

Reaction equation

HRID 340506 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].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[C:58]1[N:63]=[C:62]([NH:64][C@H:65]2[CH2:70][CH2:69][CH2:68][CH2:67][C@H:66]2[NH:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[C:61]([F:79])=[CH:60][C:59]=1[C:80]#[N:81]>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].C(OCC)(=O)C.O.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:58]2[N:63]=[C:62]([NH:64][C@H:65]3[CH2:70][CH2:69][CH2:68][CH2:67][C@H:66]3[NH:71][C:72](=[O:78])[O:73][C:74]([CH3:76])([CH3:77])[CH3:75])[C:61]([F:79])=[CH:60][C:59]=2[C:80]#[N:81])[CH:5]=[N:6][CH:7]=1

Participants

9

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27628943-Amino-5-methylpyridineHCID 86683848Tert-butyl cis-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate

Product 1

HCID 86683885Tert-butyl cis-2-(6-(5-methylpyridin-3-ylamino)-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamateYield 87.6%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

5-methyl-3-pyridineamine (191 mg), cesium carbonate (1.10 g), Pd2(dba)3 (186 mg), and Xantphos (235 mg) were added to a 1,4-dioxane (14 ml) solution containing tert-butyl cis-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (500 mg), followed by stirring at 100° C. for 2 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. Insoluble matter was removed by filtration, the filter cake was washed with water and ethyl acetate, the organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 to 1:4), diisopropylether was added, solid matter was collected by filtration, and a light yellow solid of tert-butyl cis-2-(6-(5-methylpyridin-3-ylamino)-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (523 mg) was thus obtained.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. customInsoluble matter was removed by filtration
  3. washthe filter cake was washed with water and ethyl acetate
  4. customthe organic layer was collected
  5. washwashed with saturated saline
  6. dry with materialdried over anhydrous magnesium sulfate
  7. distillationthe solvent was distilled away under reduced pressure
  8. customThe obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 to 1:4), diisopropylether
  9. additionwas added
  10. filtrationsolid matter was collected by filtration

Sources & evidence

ORD record
ord-983d100231444fbfb0191e96303b33e1
Source dataset
uspto-grants-2014_11
Patent number
US08895585B2

Linked notes

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