Acetamide → N-(5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide

HRID 2279054Notes

Reaction equation

HRID 2279054 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:30]([NH2:33])(=[O:32])[CH3:31].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>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]>[C:30]([NH:33][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([N:18]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)[C:19]3=[O:29])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)(=[O:32])[CH3:31]

Participants

7

Reactant 4

HCID 178AcetamideHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 90426999N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide

Product 1

HCID 90425714N-(5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamideYield 90.8%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
93 °C

Procedure

A mixture of Example C1 (0.300 g, 0.718 mmol), acetamide (0.127 g, 2.154 mmol), Cs2CO3 (0.468 g, 1.436 mmol) and Xantphos (0.046 g, 0.079 mmol) in dioxane (7 mL) was sparged with Ar under sonication. Pd2(dba)3 0.053 g, 0.057 mmol) was added, and the mixture was sparged again with Ar and heated at 93° C. overnight. The mixture was cooled to RT, and partitioned with EtOAc and brine. The aqueous layer was extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/DCM). The material was suspended in 4:1 MeCN/water, frozen and lyophilized overnight, and further dried in a drying oven to afford N-(5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (0.287 g, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.98 (s, 1 H), 10.57 (s, 1 H), 8.23 (dd, J=2.9, 0.5 Hz, 1 H), 8.19 (d, J=5.7 Hz, 1 H), 8.08 (dd, J=9.0, 0.5 Hz, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.66 (d, J=2.3 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1 H), 3.94-3.79 (m, 5 H), 3.49-3.37 (m, 4 H), 2.04 (s, 3 H), 1.78-1.67 (m, 2 H), 1.64-1.58 (m, 2H); MS (ESI) m/z: 441.2 (M+H+).

Workup

  1. customthe mixture was sparged again with Ar
  2. temperatureThe mixture was cooled to RT
  3. custompartitioned with EtOAc and brine
  4. extractionThe aqueous layer was extracted with EtOAc (3×)
  5. dry with materialthe combined organics were dried over Na2SO4
  6. concentrationconcentrated to dryness
  7. custompurified by silica gel chromatography (MeOH/DCM)
  8. temperaturefrozen
  9. customfurther dried in a drying oven

Sources & evidence

ORD record
ord-7faf26bf18d74e538d8ad2f25586bece
Source dataset
uspto-grants-2015_09
Patent number
US09133183B2

Reaction notes

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