Binap, (A+-)- → N-[(1S,2S)-2-{[5-(Difluoromethoxy)pyridin-2-yl]amino}-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide

HRID 1750715Notes

Reaction equation

HRID 1750715 reaction equation
[NH2:1][C@H:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]1[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[CH:26][N:25]=1.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.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:32][CH:31]([F:33])[O:30][C:27]1[CH:28]=[CH:29][C:24]([NH:1][C@H:2]2[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]2[NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[N:25][CH:26]=1

Participants

7

Reactant 4

HCID 634876Binap, (A+-)-HCID 231205792-Bromo-5-(difluoromethoxy)pyridineHCID 23676156Sodium t-butoxideHCID 118308058N-[(1S,2S)-2-Amino-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide2×

Product 1

HCID 118308214N-[(1S,2S)-2-{[5-(Difluoromethoxy)pyridin-2-yl]amino}-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 46; 100 mg, 0.33 mmol) in dry toluene (3 ml) was added 2-bromo-5-(difluoromethoxy)pyridine (CAS number 845827-14-7; 89 mg, 0.33 mmol), BINAP (20 mg, 0.033 mmol), tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.016 mmol) and sodium tert-butoxide (44 mg, 0.46 mmol). The reaction was placed under an atmosphere of nitrogen, sealed and heated at 110° C. for 2.5 hours then filtered through a thiol cartridge, eluting with ethyl acetate and water. The filtrate was diluted with further ethyl acetate and water and then partitioned. The organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) then triturated with heptane and diethyl ether to afford the title compound.

Workup

  1. customsealed
  2. filtrationthen filtered through a thiol cartridge
  3. washeluting with ethyl acetate and water
  4. additionThe filtrate was diluted with further ethyl acetate and water
  5. custompartitioned
  6. washThe organics were washed with water
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe crude material was purified by column chromatography (silica, 0-100% ethyl acetate/petrol)
  11. customthen triturated with heptane and diethyl ether

Sources & evidence

ORD record
ord-17aa0d43086241e9a9765063d9d0f20d
Source dataset
uspto-grants-2015_10
Patent number
US09156829B2

Reaction notes

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