Isobutyryl chloride → HCID 86269487, compound

HRID 1049346Notes

Reaction equation

HRID 1049346 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[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:36])=[N:30][C:31]=3[C:32]([F:35])([F:34])[F:33])[CH:22]=[CH:21][N:20]=2)[CH:16]=[N:15]1.CCN(C(C)C)C(C)C.C(Cl)(=O)C(C)C>ClCCCl.O1CCOCC1.C(Cl)Cl.[Ag]OC#N.CCOC(C)=O>[CH3:13][N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH:36][C:8]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[O:9])=[N:30][C:31]=3[C:32]([F:35])([F:34])[F:33])[CH:22]=[CH:21][N:20]=2)[CH:16]=[N:15]1

Participants

11

Reactant 5

HCID 62325Isobutyryl chlorideHCID 65578Oxalyl chloride2×HCID 68424Isobutyramide2×HCID 81531DiisopropylethylamineHCID 90403125HCID 90403125, compound

Product 1

HCID 86269487HCID 86269487, compoundYield 45%

Reagents, catalysts & solvents 5

HCID 178513473HCID 178513473, compoundCatalystHCID 111,2-DichloroethaneSolvent3×HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A suspension of Example B7 (0.021 g, 0.246 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.022 mL, 0.246 mmol), stirred at RT for 5 min, then heated at 80° C. for 1 h. The mixture was cooled to RT, added drop-wise to a solution of 5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-(trifluoromethyl)pyridin-2-amine (0.055 g, 0.164 mmol) and DIEA (0.172 mL, 0.984 mmol) in dioxane (3 mL) and stirred at RT overnight. A solution of silver cyanate (0.246 g, 1.640 mmol) in DCM (3 mL) was treated with isobutyryl chloride (0.035 g, 0.328 mmol), stirred at RT for 2 h, then added to the DCE mixture and stirred at RT for 2 h. A second suspension of Example B7 (140 mg) in DCE (4 mL) was treated with oxalyl chloride (0.15 mL), heated at 80° C. for 2 h, cooled to RT, added to the original reaction mixture and stirred at RT overnight. The mixture was treated with EtOAc and the solids removed via filtration through diatomaceous earth. The filtrate was washed with satd. NaHCO3 (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford N-((5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-(trifluoromethyl)pyridin-2-yl)carbamoyl)isobutyramide (33 mg, 45%) as a light brown solid. 1H NMR (400 MHz, DMSO-d6): δ 11.28 (s, 1H), 10.97 (s, 1H), 8.40 (d, J=5.7 Hz, 1H), 8.34 (d, J=9.1 Hz, 1H), 8.28 (s, 1H), 7.98-7.97 (m, 2H), 7.29 (d, J=2.5 Hz, 1H), 6.78 (dd, J=5.7, 2.5 Hz, 1H), 3.84 (s, 3H), 2.72-2.63 (m, 1H), 1.10 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 449.2 (M+H+).

Workup

  1. temperatureheated at 80° C. for 1 h
  2. temperatureThe mixture was cooled to RT
  3. stirringstirred at RT overnight
  4. stirringstirred at RT for 2 h
  5. stirringstirred at RT for 2 h
  6. temperatureheated at 80° C. for 2 h
  7. temperaturecooled to RT
  8. additionadded to the original reaction mixture
  9. stirringstirred at RT overnight
  10. customthe solids removed via filtration through diatomaceous earth
  11. washThe filtrate was washed with satd
  12. dry with materialNaHCO3 (2×) and the combined organics were dried over Na2SO4
  13. concentrationconcentrated to dryness
  14. custompurified via silica gel chromatography (MeOH/EtOAc)

Sources & evidence

ORD record
ord-0c712016d6a2414a8babe304b5f4f733
Source dataset
uspto-grants-2016_07
Patent number
US09382228B2

Reaction notes

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