Cesium carbonate → 5-(5-Amino-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde

HRID 225443Notes

Reaction equation

HRID 225443 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-].[Cs+].[Cs+].C1(C)C=CC=CC=1.CC(O)C.O.Br[C:47]1[N:48]=[CH:49][C:50]([NH2:53])=[N:51][CH:52]=1>CCOC(C)=O.O>[NH2:53][C:50]1[N:51]=[CH:52][C:47]([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:48][CH:49]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 5995392-Amino-5-bromopyrazineHCID 66631872toluene IPA waterHCID 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 866145015-(5-Amino-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehydeYield 35.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
85 °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 (0.500 g, 1.3 mmol) and cesium carbonate (1.2 g, 3.6 mmol) in previously degassed toluene/IPA/water (4/4/1) mixture (2.5 mL) was added 5-bromo-pyrazin-2-ylamine (Maybridge, 0.208 g, 1.2 mmol) under nitrogen. Tetrakis(triphenylphosphine)palladium-(0) (0.055 g, 0.05 mmol) was added at room temperature and the reaction was heated at 85° C. for 3.5 hrs. 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 (10-60%) to obtain 150 mgs of product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H), 2.97 (m, 2H), 3.34 (m, 2H), 4.18 (m, 2H), 4.78 (s, 2H), 8.08 (d, J=1.6 Hz, 1H), 8.19 (dd, J=8.4, 2.1 Hz, 1H), 8.44 (m, 1H), 10.37 (s, 1H); MS(APCl+) m/z 349 (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 (10-60%)

Sources & evidence

ORD record
ord-d1399685032946078dbe748a4f467f04
Source dataset
uspto-grants-2009_07
Patent number
US07557100B2

Reaction notes

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