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

HRID 225444Notes

Reaction equation

HRID 225444 reaction equation
[CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:16]([F:17])=[C:15]([F:18])[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:10]=2[CH:11]=[O:12])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O.[Br:38][C:39]1[CH:44]=[N:43][C:42](I)=[CH:41][N:40]=1>CCOC(C)=O.O>[Br:38][C:39]1[N:40]=[CH:41][C:42]([C:14]2[C:15]([F:18])=[C:16]([F:17])[C:9]([N:4]3[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]3)=[C:10]([CH:13]=2)[CH:11]=[O:12])=[N:43][CH:44]=1

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 18373917Acetonitrile--water (1/1)HCID 219312002-Bromo-5-iodopyrazineHCID 760452232-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde

Product 1

HCID 866145025-(5-Bromo-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehydeYield 64.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
55 °C

Procedure

To a suspension of 2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (Example 22, step 2) (1.5 g, 3.9 mmol) and sodium carbonate (1.1 g, 11 mmol) in previously degassed acetonitrile/water (1/1) mixture (4 mL) was added 2-bromo-5-iodo-pyrazine (1.0 g, 3.5 mmol) under nitrogen. Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.099 g, 0.14 mmol) was added at room temperature and the reaction was heated overnight at 55° 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 (5-40%) to obtain 931 mgs of product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H), 3.02 (m, 2H), 3.40 (m, 2H), 4.19 (m, 2H), 8.28 (dd, J=8.2, 2.1 Hz, 1H), 8.74 (d, J=1.4 Hz, 1H), 8.78 (m, 1H), 10.29 (s, 1H) ; MS(APCl+) m/z 412, 414 (MH+).

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. customThe phases were separated
  3. extractionthe aqueous phase was re-extracted with EtOAc (×2)
  4. dry with materialThe combined organic layers were dried over MgSO4
  5. concentrationconcentrated
  6. customPurified by column chromatography
  7. washeluting with ethyl acetate in hexanes (5-40%)

Sources & evidence

ORD record
ord-a5ea8dbef0424d469dea3ae24c379745
Source dataset
uspto-grants-2009_07
Patent number
US07557100B2

Reaction notes

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