Oxalyl chloride → N-((5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide

HRID 1049341Notes

Reaction equation

HRID 1049341 reaction equation
[C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)[C:8](Cl)=[O:9].[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[C:30]([O:32][C:33]4[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=4)[CH:29]=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.[OH-].[Na+].[Cl-].[Na+].O>ClCCCl.C1COCC1>[CH3:13][N:14]1[CH2:15][CH2:16][CH:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[C:30]([O:32][C:33]4[CH:34]=[CH:35][C:36]([NH:39][C:8]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[O:9])=[N:37][CH:38]=4)[CH:29]=[CH:28][N:27]=3)=[CH:24][CH:25]=2)[CH2:18][CH2:19]1

Participants

8

Reactant 5

HCID 65578Oxalyl chlorideHCID 68424IsobutyramideHCID 81531DiisopropylethylamineHCID 904033245-((2-(4-(1-Methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amineHCID 131715167NaOH brine

Product 1

HCID 86269489N-((5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramideYield 14%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of Example B7 (0.045 g, 0.520 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.046 mL, 0.520 mmol), stirred at RT for 5 min, then warmed to 80° C. for 0.5 h. The mixture was cooled to RT, added drop wise to a solution of 5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (0.125 g, 0.347 mmol) and DIEA (0.363 mL, 2.081 mmol) in THF (3 mL) and stirred at RT overnight. The mixture was treated with 1:1 1 N NaOH/brine, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via reverse-phase silica gel chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure. The remaining aqueous layer was neutralized with 1N NaOH, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness. The material was suspended in 1:1 MeCN/H2O, frozen and lyophilized to afford N-((5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide (23 mg, 14%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 10.85 (s, 1H), 8.51 (d, J=5.7 Hz, 1H), 8.28 (d, J=2.9 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.46 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 6.84 (dd, J=5.6, 2.4 Hz, 1H), 2.84 (m, 2H), 2.66 (m, 1H), 2.17 (s, 3H), 1.94 (m, 2H), 1.75-1.59 (m, 5H), 1.08 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 474.3 (M+H+).

Workup

  1. temperaturewarmed to 80° C. for 0.5 h
  2. temperatureThe mixture was cooled to RT
  3. stirringstirred at RT overnight
  4. extractionextracted with EtOAc (3×)
  5. dry with materialthe combined organics were dried over Na2SO4
  6. concentrationconcentrated to dryness
  7. custompurified via reverse-phase silica gel chromatography (MeCN/H2O with 0.1% TFA)
  8. customThe organics were removed under reduced pressure
  9. extractionextracted with EtOAc (3×)
  10. dry with materialthe combined organics were dried over Na2SO4
  11. concentrationconcentrated to dryness
  12. temperaturefrozen

Sources & evidence

ORD record
ord-75451dbe2db84a2084d8be922710d356
Source dataset
uspto-grants-2016_07
Patent number
US09382228B2

Reaction notes

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