Pyridine → US9133183, Example 1

HRID 2278973Notes

Reaction equation

HRID 2278973 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.N1C=CC=CC=1.[O:27]=[C:28]1[N:32]([CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:31][CH2:30][N:29]1[C:39](Cl)=[O:40]>C(Cl)Cl.O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:39]([N:29]4[CH2:30][CH2:31][N:32]([CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[C:28]4=[O:27])=[O:40])=[N:18][CH:19]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1

Participants

6

Reactant 3

HCID 1049PyridineHCID 593227775-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)pyridin-2-amineHCID 904274552-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carbonyl chloride

Product 1

HCID 86270030US9133183, Example 1Yield 80.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A 0° C. solution of Example A2 (6.4 g, 23.94 mmol) and pyridine (6 mL, 74.2 mmol) in DCM (150 mL) was treated with a solution of Example B2 (8.36 g, 35.9 mmol) in DCM (10 mL), stirred at 0° C. for 5 min, warmed to RT and stirred for 1.5 h. The mixture was diluted with water, stirred for 15 min, and the layers separated. The organic layer was washed with water and the combined aqueous layers were extracted with DCM (4×). The combined organics were dried over Na2SO4, concentrated to dryness, treated with MeOH and concentrated again to dryness. The residue was dissolved in DCM, sonicated, treated with MTBE, sonicated and the resulting solid collected via filtration. The solid was treated with Et2O, sonicated and again collected via filtration to afford N-(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 (8.93 g, 80%). 1H NMR (400 MHz, DMSO-d6): δ 10.96 (s, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.25 (s, 1 H), 8.23 (d, J=2.9 Hz, 1 H), 8.07 (dd, J=9.0, 0.7 Hz, 1 H), 7.96 (d, J=0.7 Hz, 1 H), 7.72 (dd, J=9.0, 2.9 Hz, 1 H), 7.22 (d, J=2.4 Hz, 1 H), 6.69 (dd, J=5.7, 2.5 Hz, 1 H), 3.93-3.87 (m, 3 H), 3.84 (s, 3 H), 3.83-3.77 (m, 2 H), 3.49-3.43 (m, 2 H) 3.42-3.34 (m, 2 H), 1.78-1.64 (m, 2 H), 1.59 (m, 2 H); MS (ESI) m/z: 464.2 (M+H+).

Workup

  1. temperaturewarmed to RT
  2. stirringstirred for 1.5 h
  3. stirringstirred for 15 min
  4. customthe layers separated
  5. washThe organic layer was washed with water
  6. extractionthe combined aqueous layers were extracted with DCM (4×)
  7. dry with materialThe combined organics were dried over Na2SO4
  8. concentrationconcentrated to dryness
  9. additiontreated with MeOH
  10. concentrationconcentrated again to dryness
  11. dissolutionThe residue was dissolved in DCM
  12. customsonicated
  13. additiontreated with MTBE
  14. customsonicated
  15. filtrationthe resulting solid collected via filtration
  16. additionThe solid was treated with Et2O
  17. customsonicated
  18. filtrationagain collected via filtration

Sources & evidence

ORD record
ord-c608c8584d8640c687c0c152c52a997d
Source dataset
uspto-grants-2015_09
Patent number
US09133183B2

Reaction notes

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