Pyridine → N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide

HRID 2279001Notes

Reaction equation

HRID 2279001 reaction equation
[C:1](Cl)(Cl)=[O:2].[O:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:7][CH2:6]1.N1C=CC=CC=1.[CH2:23]([C:25]1[N:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:26]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]2[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=2)[CH:34]=1)[CH3:24]>C(Cl)Cl.CCOC(C)=O.O>[CH2:23]([C:25]1[N:30]=[C:29]([NH:31][C:1]([N:13]2[CH2:14][CH2:15][N:11]([CH:8]3[CH2:7][CH2:6][O:5][CH2:10][CH2:9]3)[C:12]2=[O:16])=[O:2])[CH:28]=[CH:27][C:26]=1[O:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]2[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=2)[CH:34]=1)[CH3:24]

Participants

8

Reactant 4

HCID 1049PyridineHCID 6371PhosgeneHCID 904038036-Ethyl-5-[[2-(1-methyl-1h-pyrazol-4-yl)-4-pyridinyl]oxy]-2-pyridinamineHCID 904259751-(Oxan-4-yl)imidazolidin-2-one

Product 1

HCID 86268413N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamideYield 60.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of phosgene (15% in toluene, 1.440 g, 2.184 mmol) under Ar, was treated with a solution of Example B1 (0.149 g, 0.874 mmol) and pyridine (0.104 g, 1.310 mmol) in DCM (4 mL), stirred for 15 min, then concentrated to dryness. The residue was treated with a solution of Example A9 (0.129 g, 0.437 mmol) and TEA (0.221 g, 2.184 mmol) in DCM (4 mL), stirred for 0.5 h, then treated with water and EtOAc. The layers were separated, the aqueous layer extracted with additional EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure and the aqueous residue was neutralized with satd. NaHCO3 and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (130 mg, 60%). 1H NMR (400 MHz, DMSO-d6): δ 10.91 (s, 1 H), 8.33 (d, J=5.7 Hz, 1 H), 8.24 (s, 1 H), 7.94 (d, J=0.7 Hz, 1 H), 7.89 (d, J=8.8 Hz, 1 H), 7.59 (d, J=8.8 Hz, 1 H), 7.17 (d, J=2.4 Hz, 1 H), 6.58 (dd, J=5.7, 2.4 Hz, 1 H), 3.90-3.87 (m, 3 H), 3.83 (s, 3 H), 3.81-3.79 (m, 2 H), 3.45 (t, J=8.3 Hz, 2 H), 3.37 (dd, J=12.4, 10.5 Hz, 2 H), 2.56 (q, J=7.5 Hz, 2 H), 1.71 (qd, J=12.2, 4.5 Hz, 2 H), 1.62-1.58 (m, 2 H), 1.10 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 492.3 (M+H+).

Workup

  1. concentrationconcentrated to dryness
  2. stirringstirred for 0.5 h
  3. customThe layers were separated
  4. extractionthe aqueous layer extracted with additional EtOAc (1×)
  5. washthe combined organics were washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated to dryness
  8. custompurified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA)
  9. customThe organics were removed under reduced pressure
  10. extractionNaHCO3 and extracted with EtOAc (2×)
  11. washThe combined organics were washed with brine
  12. dry with materialdried over Na2SO4
  13. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-518ecaaafa364f33ac9d4ed8d8fd7f6d
Source dataset
uspto-grants-2015_09
Patent number
US09133183B2

Reaction notes

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