Sodium Carbonate → 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-pyrazin-2-yl)-benzaldehyde

HRID 225445Notes

Reaction equation

HRID 225445 reaction equation
Br[C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:25])=[C:10]([F:24])[C:11]([N:16]3[CH2:21][CH:20]([CH3:22])[O:19][CH:18]([CH3:23])[CH2:17]3)=[C:12]([CH:15]=2)[CH:13]=[O:14])=[N:6][CH:7]=1.[C:26](=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.CB(O)O>CCOC(C)=O.O>[CH3:23][CH:18]1[O:19][CH:20]([CH3:22])[CH2:21][N:16]([C:11]2[C:10]([F:24])=[C:9]([F:25])[C:8]([C:5]3[CH:4]=[N:3][C:2]([CH3:26])=[CH:7][N:6]=3)=[CH:15][C:12]=2[CH:13]=[O:14])[CH2:17]1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 139377Methylboronic Acid2×HCID 18373917Acetonitrile--water (1/1)HCID 866145025-(5-Bromo-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde

Product 1

HCID 866145032-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-pyrazin-2-yl)-benzaldehydeYield 41.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
85 °C

Procedure

To a suspension of 5-(5-Bromo-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde (0.375 g, 0.91 mmol) and sodium carbonate (0.29 g, 2.7 mmol) in previously degassed acetonitrile/water (1/1) mixture (4 mL) was added methyl boronic acid (0.11 g, 1.8 mmol) under nitrogen. Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.026 g, 0.036 mmol) was added at room temperature and the reaction was heated for 5 hours at 85° C. Analysis indicated that starting material had not fully been consumed so an additional 1 equivalent of methyl boronic acid was added to the reaction and stirred overnight at 85° C. The mixture was cooled to room temperature, diluted with EtOAc and water then neutralized. The phases were separated and the aqueous phase was re-extracted with EtOAc (×2). The combined organic layers were dried over MgSO4 and concentrated. Purified by column chromatography eluting with ethyl acetate in hexanes (5-35%) to obtain 132 mgs of product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H), 2.61 (s, 3H), 3.00 (m, 2H), 3.38 (m, 2 H), 4.19 (m, 2H), 8.26 (dd, J=8.2, 2.1 Hz, 1H), 8.54 (d, J=1.2 Hz, 1H), 8.89 (dd, J=2.3, 1.6 Hz, 1H), 10.33 (s, 1H); MS(APCl+) m/z 348 (MH+).

Workup

  1. additionwas added to the reaction
  2. temperatureThe mixture was cooled to room temperature
  3. customThe phases were separated
  4. extractionthe aqueous phase was re-extracted with EtOAc (×2)
  5. dry with materialThe combined organic layers were dried over MgSO4
  6. concentrationconcentrated
  7. customPurified by column chromatography
  8. washeluting with ethyl acetate in hexanes (5-35%)

Sources & evidence

ORD record
ord-373e784c43594897a262f6608d5638a2
Source dataset
uspto-grants-2009_07
Patent number
US07557100B2

Reaction notes

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