6-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine → Benzyl 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)benzoate

HRID 2365467Notes

Reaction equation

HRID 2365467 reaction equation
Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:52]=[CH:53][CH:54]=2)[C:33]([NH:35][C:36]2[CH:51]=[CH:50][C:39]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[CH:38][CH:37]=2)=[O:34])O1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:52]=[CH:53][CH:54]=3)[C:33]([NH:35][C:36]3[CH:51]=[CH:50][C:39]([C:40]([O:42][CH2:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[O:41])=[CH:38][CH:37]=3)=[O:34])[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]

Participants

7

Reactant 2

HCID 578564216-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amineHCID 57856434Benzyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate

Product 1

HCID 44188904Benzyl 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)benzoateYield 65%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolventHCID 10340Sodium CarbonateSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 6-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (1.82 g, 5.22 mmol) and benzyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)benzoate (3.06 g, 5.22 mmol, 78% by mass) in 1 M aqueous sodium carbonate (8 mL) and 1,4-dioxane (24 mL) was sparged with nitrogen with stirring for 5 min. The resulting mixture was treated with tetrakis(triphenylphosphine)palladium(0) (1.20 g, 1.04 mmol) and stirred at reflux for 2.5 h. After this time, the reaction was cooled to ambient temperature, diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The aqueous layer was extracted with ethyl acetate (100 mL) and the combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:4 ethyl acetate/methylene chloride) to afford benzyl 4-(3-(8-(3,4-dimethoxyphenylamino)imidazo[1,2-a]pyrazin-6-yl)benzamido)benzoate (2.02 g, 65%) as an off-white solid: mp 154-160° C.; 1H NMR (300 MHz, CDCl3) δ 10.72 (s, 1H), 9.57 (s, 1H), 8.74 (s, 1H), 8.57 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.08-7.94 (m, 7H), 7.69-7.60 (m, 3H), 7.50-7.34 (m, 5H), 6.92 (d, J=8.7 Hz, 1H), 5.36 (s, 2H), 3.78 (s, 3H), 3.73 (s, 3H); ESI MS m/z 600 [M+H]+; HPLC, 8.93 min, 95.9% (AUC).

Workup

  1. customwas sparged with nitrogen
  2. stirringstirred
  3. temperatureat reflux for 2.5 h
  4. washwashed with brine (100 mL)
  5. extractionThe aqueous layer was extracted with ethyl acetate (100 mL)
  6. dry with materialthe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. customThe residue obtained
  10. customwas purified by chromatography (silica, methylene chloride to 1:4 ethyl acetate/methylene chloride)

Sources & evidence

ORD record
ord-3e1141b543f94990968a0056620e9416
Source dataset
uspto-grants-2014_04
Patent number
US08697699B2

Reaction notes

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