Pyridine → US9133183, Example 15

HRID 2278993Notes

Reaction equation

HRID 2278993 reaction equation
[CH:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20].[CH3:23][N:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[C:33]([O:35][C:36]3[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=3)[CH:32]=[CH:31][N:30]=2)[CH:26]=[N:25]1>C(Cl)Cl.O>[CH:1]1([N:7]2[CH2:11][CH2:10][N:9]([C:19]([NH:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][C:33]4[CH:32]=[CH:31][N:30]=[C:29]([C:27]5[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=5)[CH:34]=4)=[CH:41][N:40]=3)=[O:20])[C:8]2=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

7

Reactant 4

HCID 1049PyridineHCID 6371PhosgeneHCID 5803521-Cyclohexyl-2-imidazolidinoneHCID 593227775-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amine

Product 1

HCID 86270406US9133183, Example 15Yield 64.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

A solution of Example B7 (0.085 g, 0.505 mmol) and pyridine (0.133 g, 1.684 mmol) in DCM (2 mL) was added to phosgene (20% in toluene, 0.833 g, 1.684 mmol), under Ar, stirred for 15 min, then concentrated to dryness. The residue was dissolved in DCM (2 mL), treated with a solution of Example A2 (0.09 g, 0.337 mmol) and TEA (0.102 g, 1.010 mmol) in DCM (2 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with DCM (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 3-cyclohexyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (100 mg, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1 H), 8.37 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (d, J=9.0 Hz, 1 H), 7.96 (s, 1 H), 7.71 (dd, J=9.0, 2.9 Hz, 1 H), 7.23 (d, J=2.4 Hz, 1 H), 6.70 (dd, J=5.7, 2.4 Hz, 1 H), 3.84 (s, 3 H), 3.79 (m, 2 H), 3.61 (m, 1 H), 3.43 (m, 2 H), 1.67 (m, 5 H), 1.35 (m, 4 H), 1.08 (m, 1 H); MS (ESI) m/z: 462.2 (M+H+).

Workup

  1. concentrationconcentrated to dryness
  2. dissolutionThe residue was dissolved in DCM (2 mL)
  3. stirringstirred at RT for 1 h
  4. extractionextracted with DCM (2×)
  5. washthe combined organics were washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated to dryness
  8. custompurified via silica gel chromatography (MeOH/DCM)

Sources & evidence

ORD record
ord-5791e92081214d9485807125696a969e
Source dataset
uspto-grants-2015_09
Patent number
US09133183B2

Reaction notes

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