Sodium Carbonate → N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-4'-(morpholinomethyl)-5-((tetrahydro-2H-pyran-4-yl)(2,2,2-trifluoroethyl)amino)-[1,1'-biphenyl]-3-carboxamide

HRID 1959285Notes

Reaction equation

HRID 1959285 reaction equation
Br[C:2]1[CH:3]=[C:4]([N:22]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23][C:24]([F:27])([F:26])[F:25])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:42]2[CH:54]=[CH:53][C:45]([CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[CH:44][CH:43]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:42]2[CH:43]=[CH:44][C:45]([CH2:46][N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[CH:53][CH:54]=2)[CH:3]=[C:4]([N:22]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23][C:24]([F:27])([F:26])[F:25])[C:5]=1[CH3:21])=[O:8]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27955024-((Morpholino)methyl)phenylboronic acid pinacol esterHCID 70872615HCID 70872615, compound

Product 1

HCID 70872641N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-4'-(morpholinomethyl)-5-((tetrahydro-2H-pyran-4-yl)(2,2,2-trifluoroethyl)amino)-[1,1'-biphenyl]-3-carboxamideYield 82%

Reagents, catalysts & solvents 3

HCID 15220664Palladium--triphenylphosphane (1/1)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

In a 2 necked RBF, 5-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzamide (200 mg, 0.38 mmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (126 mg, 0.41 mmol) in 1,4-dioxane (3.0 ml) was treated with a solution containing Na2CO3 (140 mg, 1.3 mmol) in water (1.0 ml). Nitrogen was bubbled through the mixture using a long needle for 5 minutes before the addition of palladium-triphenylphosphane (1:4) (44 mg, 0.04 mmol). Nitrogen was bubbled through the yellow suspension for a further 5 minutes before heating the reaction mixture to 100° C. for 5.5 hours. The reaction mixture was diluted with water (10 ml) and 10% MeOH in CH2Cl2 (10 ml). The layers were separated and the aqueous phase was extracted with 10% MeOH in CH2Cl2 (3×15 ml). The combined organic extracts were washed with brine (40 ml), dried over MgSO4, filtered and concentrated in-vacuo. The crude residue was purified by column chromatography (10 g SNAP cartridge, Isolera, 0-4% MeOH:CH2Cl2) to give the title compound (193 mg, 82%) as an off white powder. LC-MS 100%, 3.34 min (7 minute LC-MS method), m/z=627.5; 1H NMR (500 MHz, Acetone) δ 10.76 (s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.57 (t, J=5.6 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 5.91 (s, 1H), 4.44 (d, J=5.5 Hz, 2H), 3.97 (s, 2H), 3.90 (dd, J=11.4, 4.1 Hz, 2H), 3.61 (t, J=4.6 Hz, 4H), 3.50 (s, 2H), 3.29 (t, J=11.5 Hz, 2H), 3.06 (tt, J=11.4, 3.8 Hz, 1H), 2.39 (d, J=5.0 Hz, 7H), 2.34 (s, 3H), 2.22 (s, 3H), 1.82 (dd, J=12.3, 1.7 Hz, 2H), 1.70-1.56 (m, 2H).

Workup

  1. customNitrogen was bubbled through the mixture
  2. customfor 5 minutes
  3. customNitrogen was bubbled through the yellow suspension for a further 5 minutes
  4. additionThe reaction mixture was diluted with water (10 ml) and 10% MeOH in CH2Cl2 (10 ml)
  5. customThe layers were separated
  6. extractionthe aqueous phase was extracted with 10% MeOH in CH2Cl2 (3×15 ml)
  7. washThe combined organic extracts were washed with brine (40 ml)
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in-vacuo
  11. customThe crude residue was purified by column chromatography (10 g SNAP cartridge, Isolera, 0-4% MeOH:CH2Cl2)

Sources & evidence

ORD record
ord-96b62d95ba4a4be9884447e6a755060c
Source dataset
uspto-grants-2013_04
Patent number
US08410088B2

Reaction notes

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