Potassium Carbonate → N-((6-methyl-5-((2'-morpholino-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide

HRID 1049356Notes

Reaction equation

HRID 1049356 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)[CH:40]=2)O1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:14]1[N:13]=[C:12]([NH:16][C:17]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)[CH:40]=2)[CH:7]=1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 210816614-(4-(Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholineHCID 90402622N-((5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)isobutyramide

Product 1

HCID 90403581N-((6-methyl-5-((2'-morpholino-[2,4'-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramideYield 28%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of N-((5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)carbamoyl)isobutyramide (0.136 g, 0.390 mmol), K2CO3 (0.108 g, 0.780 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (0.136 g, 0.468 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.045 g, 0.039 mmol), sparged again with Ar and heated at 95° C. overnight. The mixture was cooled to RT, treated with EtOAc and the solids removed via filtration through a pad of diatomaceous earth and Na2SO4. The filtrate was concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was purified twice more via silica gel chromatography (MeOH/EtOAc). The resulting material was treated with Et2O, sonicated and the solid collected via filtration to afford N-((6-methyl-5-((2′-morpholino-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)isobutyramide (52 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.05 (s, 1H), 10.84 (s, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.21 (d, J=5.2 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.44 (s, 1H), 7.30 (dd, J=5.2, 1.3 Hz, 1H), 6.80 (dd, J=5.6, 2.4 Hz, 1H), 3.70 (m, 4H), 3.51 (m, 4H), 2.66 (m, 1H), 2.27 (s, 3H), 1.09 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 477.3 (M+H+).

Workup

  1. customwas sparged with Ar
  2. customsparged again with Ar
  3. temperatureThe mixture was cooled to RT
  4. additiontreated with EtOAc
  5. customthe solids removed via filtration through a pad of diatomaceous earth and Na2SO4
  6. concentrationThe filtrate was concentrated to dryness
  7. custompurified via silica gel chromatography (MeOH/DCM)
  8. customThe material was purified twice more via silica gel chromatography (MeOH/EtOAc)
  9. additionThe resulting material was treated with Et2O
  10. customsonicated
  11. filtrationthe solid collected via filtration

Sources & evidence

ORD record
ord-f252f2d4246c4459989daae36b6c6aae
Source dataset
uspto-grants-2016_07
Patent number
US09382228B2

Reaction notes

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