Water → N-((5-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydro-2H-pyran-4-carboxamide

HRID 626557Notes

Reaction equation

HRID 626557 reaction equation
[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.C(Cl)(=O)[C:11](Cl)=[O:12].[NH2:16][C:17]1[N:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:25]=2)=[CH:19][CH:18]=1.O>ClCCCl.C1COCC1>[CH:33]1([C:31]([NH:30][C:26]2[CH:25]=[C:24]([O:23][C:20]3[CH:19]=[CH:18][C:17]([NH:16][C:11]([NH:9][C:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[O:8])=[O:12])=[N:22][CH:21]=3)[CH:29]=[CH:28][N:27]=2)=[O:32])[CH2:34][CH2:35]1

Participants

7

Reactant 4

HCID 962WaterHCID 65578Oxalyl chlorideHCID 13197203Oxane-4-carboxamideHCID 90409531N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide

Product 1

HCID 86273467N-((5-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydro-2H-pyran-4-carboxamideYield 39%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of Example B5 (0.096 g, 0.740 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.081 mL, 0.925 mmol), stirred at RT for 0.5 h, then heated at 75° C. for 3 h. The mixture was cooled to RT, treated with a solution of Example A7 (0.1 g, 0.370 mmol) and TEA (0.155 mL, 1.110 mmol) in THF (5 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc). The material was suspended in 30% MeCN/water (4 mL), sonicated and the resulting solid collected via filtration and dried to afford N-((5-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)tetrahydro-2H-pyran-4-carboxamide (61 mg, 39%). 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 10.88 (s, 1H), 10.86 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.19 (d, J=5.7 Hz, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 6.72 (dd, J=5.7, 2.4 Hz, 1H), 3.88 (m, 2H), 3.31-3.29 (m, 2H), 2.68-2.66 (m, 1H), 1.96-1.95 (m, 1H), 1.73-1.72 (m, 2H), 1.62-1.60 (m, 2H), 0.75 (d, J=6.2 Hz, 4H); MS (ESI) m/z: 426.2 (M+H+).

Workup

  1. temperatureheated at 75° C. for 3 h
  2. temperatureThe mixture was cooled to RT
  3. stirringstirred at RT for 1 h
  4. extractionextracted with EtOAc (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/EtOAc)
  9. customsonicated
  10. filtrationthe resulting solid collected via filtration
  11. customdried

Sources & evidence

ORD record
ord-2688c3cb5d6340c9a94adc3de300132b
Source dataset
uspto-grants-2016_04
Patent number
US09309224B2

Reaction notes

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