Sodium Carbonate → 5-(8-(Cyclohexylamino)imidazo[1,2-a]pyrazin-5-yl)isoindolin-1-one

HRID 1095463

Reaction equation

HRID 1095463 reaction equation
Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[NH:30][CH2:29]3)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd].[Pd].[Pd].C(OCC)C.C1(C)C=CC=CC=1>[CH:12]1([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[C:31](=[O:35])[NH:30][CH2:29]4)=[CH:3][N:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 219557955-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-oneHCID 576994875-bromo-N-cyclohexylimidazo[1,2-a]pyrazin-8-amine

Product 1

HCID 251153785-(8-(Cyclohexylamino)imidazo[1,2-a]pyrazin-5-yl)isoindolin-1-oneYield 37%

Reagents, catalysts & solvents 3

HCID 86600928Tetrakis palladium triphenylphosphineCatalystHCID 1140TolueneSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
90 °C

Procedure

The product of Step 1 (70 mg, 0.24 mmol), Intermediate 4 (5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one, 77 mg, 0.3 mmol), tetrakis palladium triphenylphosphine (69 mg, 0.06 mmol), sodium carbonate solution (1.5 M, 1.28 mL, 1.92 mmol) and dioxane (3.8 mL) are combined in a flask. The mixture is degassed with nitrogen for 10 min then sealed and heated at 90° C. for 16 h. Brine is added and the mixture is washed with dichloromethane followed by ethyl acetate. The combined organic layers are dried over MgSO4 and evaporated in vacuo to afford a brown oil. The crude material is purified by column chromatography, eluting with 5% methanolic ammonia (7 N) in dichloromethane to give a brown solid. Trituration with 1:1 toluene:diethyl ether yielded the title compound as an off-white solid (30 mg, 37%). 1H-NMR (400 MHz, d6-DMSO) =1.22-1.29 (m, 1H), 1.32-1.49 (m, 4H), 1.64 (d, 1H, J=15.2 Hz), 1.77 (d, 2H, J=12.8 Hz), 1.92 (d, 2H, J=15.2 Hz), 3.97-4.01 (1H, m), 7.33 (d, 1H, J=8.4 Hz), 7.48 (s, 1H), 7.63 (s, 1H), 7.92 (s, 1H). LCMS: Rt 2.24 min (99.6%), m/z (APCI) 348 (M+H)+.

Workup

  1. customThe mixture is degassed with nitrogen for 10 min
  2. customthen sealed
  3. additionBrine is added
  4. washthe mixture is washed with dichloromethane
  5. dry with materialThe combined organic layers are dried over MgSO4
  6. customevaporated in vacuo
  7. customto afford a brown oil
  8. customThe crude material is purified by column chromatography
  9. washeluting with 5% methanolic ammonia (7 N) in dichloromethane
  10. customto give a brown solid

Sources & evidence

ORD record
ord-f1293bd210e44f8e96d80f06326790f4
Source dataset
uspto-grants-2012_03
Patent number
US08138193B2

Linked notes

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