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

HRID 1616462Notes

Reaction equation

HRID 1616462 reaction equation
Br[C:2]1[C:3]([F:31])=[C:4]([C:18]([CH3:30])=[C:19]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:20]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6].CC1(C)C(C)(C)OB([C:40]2[CH:52]=[CH:51][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:42][CH:41]=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>[CH3:15][C:14]1[CH:13]=[C:12]([CH3:16])[NH:11][C:10](=[O:17])[C:9]=1[CH2:8][NH:7][C:5]([C:4]1[C:3]([F:31])=[C:2]([C:40]2[CH:41]=[CH:42][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:51][CH:52]=2)[CH:20]=[C:19]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:18]=1[CH3:30])=[O:6]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27955024-((Morpholino)methyl)phenylboronic acid pinacol esterHCID 866726653-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzamide

Product 1

HCID 71465120N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-fluoro-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamideYield 52%

Reagents, catalysts & solvents 3

HCID 15220664Palladium--triphenylphosphane (1/1)CatalystHCID 962WaterSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 3-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzamide (112 mg, 0.23 mmol) in 1,4-Dioxane (2 ml) and Water (1 ml) was added 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (103 mg, 0.34 mmol) followed by Na2CO3 (84.04 mg, 0.79 mmol). The solution was purged with nitrogen for 5 minutes before the addition of palladium-triphenylphosphine (1:4) (26 mg, 0.02 mmol). The yellow mixture was then purged with nitrogen for 5 minutes before being heated to 100° C. After 4 hours LCMS indicated no unreacted starting material was present. The darken reaction mixture was diluted with deionized water (5 ml) and extracted with 10% MeOH in DCM (5×5 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 99:1 DCM:MeOH to 95:5 DCM:MeOH) to give 69 mg (52%) of the title compound as an off-white solid. LC-MS 97%, 2.70 min (7 minute LC-MS method), m/z=591.2, 1H NMR (500 MHz, Chloroform-d) δ ppm 12.10 (br s, 1H), 7.53-7.30 (m, 4H), 7.13 (d, J=7.4 Hz, 1H), 7.07 (br s, 1H), 5.88 (s, 1H), 4.55 (br s, 2H), 3.93 (d, J=11.2 Hz, 2H), 3.73-3.69 (m, 4H), 3.52 (s, 2H), 3.30 (t, J=10.8 Hz, 2H), 3.02 (q, J=6.9 Hz, 2H), 2.92 (ddd, J=14.6, 10.7, 3.7 Hz, 1H), 2.46 (s, 4H), 2.35 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H), 1.79-1.43 (m, 4H), 0.86 (t, J=7.0 Hz, 3H).

Workup

  1. customThe yellow mixture was then purged with nitrogen for 5 minutes
  2. customThe darken reaction mixture
  3. extractionextracted with 10% MeOH in DCM (5×5 ml)
  4. dry with materialThe combined organic extracts were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by FCC (5 g silica, Isolute cartridge, gradient of eluents; 99:1 DCM:MeOH to 95:5 DCM:MeOH)

Sources & evidence

ORD record
ord-67c27f60af914657b48f45e62a535d03
Source dataset
uspto-grants-2014_07
Patent number
US08765732B2

Reaction notes

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