Cesium carbonate → tert-butyl (3S,5R)-1-(3-(2-(2,6-difluorophenyl)-quinazolin-8-ylamino)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate

HRID 408477Notes

Reaction equation

HRID 408477 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1.FC(F)(F)S(O[C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N:37]=[C:36]([C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1[F:46])[N:35]=[CH:34]2)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:45][C:44]1[CH:43]=[CH:42][CH:41]=[C:40]([F:46])[C:39]=1[C:36]1[N:35]=[CH:34][C:33]2[C:38](=[C:29]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[N:8]3[CH2:13][C@H:12]([CH3:14])[CH2:11][C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]3)[CH:30]=[CH:31][CH:32]=2)[N:37]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 58386794HCID 58386794, compoundHCID 866564422-(2,6-Difluorophenyl)quinazolin-8-yl trifluoromethanesulfonate

Product 1

HCID 86656443tert-butyl (3S,5R)-1-(3-(2-(2,6-difluorophenyl)-quinazolin-8-ylamino)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamateYield 79%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of the tert-butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (1.0 eq) in 1,4-dioxane (0.067M) was added 2-(2,6-difluorophenyl)quinazolin-8-yl trifluoromethanesulfonate (1.0 eq), palladium acetate (0.2 eq), BINAP (1.5 eq), and cesium carbonate (3.0 eq). The reaction mixture was stirred at 120° C. for 10 min in microwave. The residue was dissolved in ethyl acetate (120 mL), and washed with water, brine, then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by column (ethyl acetate:hexanes=1:1 with 10% methanol) to yield tert-butyl (3S,5R)-1-(3-(2-(2,6-difluorophenyl)-quinazolin-8-ylamino)pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate (79%). LC/MS (m/z): 547.1 (MH+), Rt=0.87

Workup

  1. washwashed with water, brine
  2. dry with materialdried over MgSO4
  3. filtrationfiltered
  4. customevaporated under reduced pressure
  5. customto give crude product, which
  6. customwas purified by column (ethyl acetate:hexanes=1:1 with 10% methanol)

Sources & evidence

ORD record
ord-2d09762c81874f7a8fbe5b5eaf01c4d4
Source dataset
uspto-grants-2014_06
Patent number
US08759338B2

Reaction notes

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