Hydrochloric Acid → 5-(3-Amino-2-methylphenyl)-3-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-one

HRID 888433

Reaction equation

HRID 888433 reaction equation
Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19][N:18]3[CH3:25])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:26][C:27]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:42].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.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.C(OCC)(=O)C.O1CCOCC1>[NH2:42][C:28]1[C:27]([CH3:26])=[C:32]([C:2]2[N:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[C:22](=[O:23])[N:21]([CH3:24])[CH2:20][CH2:19][N:18]4[CH3:25])=[CH:13][CH:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH:31]=[CH:30][CH:29]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 467380052-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilineHCID 576251295-Bromo-3-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-one

Product 1

HCID 576251475-(3-Amino-2-methylphenyl)-3-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin-2(1H)-oneYield 86%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A 250-mL three-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 14 (2.50 g, 6.16 mmol), 7 (1.79 g, 7.70 mmol), 1,4-dioxane (70 mL) and a solution of sodium carbonate (1.96 g, 18.5 mmol) in water (14 mL). After bubbling nitrogen through the resulting mixture for 30 min, tetrakis(triphenylphosphine)palladium (711 mg, 0.62 mmol) was added and the reaction mixture then heated at reflux for 11 h. After this time the reaction was cooled to room temperature and 2N hydrochloric acid (70 mL) followed by ethyl acetate (70 mL) was added. The mixture was stirred for 0.5 h and then filtered through a pad of Celite 521. The organic layer of the filtrate was separated and extracted with 2N hydrochloric acid (2×30 mL). The acidic extracts were combined and washed with ethyl acetate (4×50 mL). The aqueous solution was then stirred vigorously with ethyl acetate (100 mL) while solid potassium carbonate was added portionwise until a pH of 12 was reached. The aqueous layer was separated and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (70 mL) and dried over magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure and dried in a 49° C. vacuum oven for 24 h to afford 15 in 86% yield (2.32 g) as an amber foam: mp 133-134° C.; 1H NMR (500 MHz, CDCl3) 8.29 (s, 1H), 7.80 (d, 1H, J=8.5 Hz), 7.29 (d, 2H, J=8.5 Hz), 7.05 (t, 1H, J=8.0 Hz), 6.79 (d, 1H, J=7.5 Hz), 6.73 (d, 1H, J=7.5 Hz), 6.68 (s, 1H), 3.72 (s, 3H), 3.64 (m, 1H), 3.20 (m, 1H), 3.01 (m, 1H), 2.99 (s, 3H), 2.66 (m, 1H), 2.24 (s, 3H), 2.17 (s, 3H); MS (ESI+) m/z 433.3 (M+H).

Workup

  1. customA 250-mL three-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser and nitrogen inlet
  3. customAfter bubbling nitrogen through the resulting mixture for 30 min
  4. temperaturethe reaction mixture then heated
  5. temperatureat reflux for 11 h
  6. additionwas added
  7. filtrationfiltered through a pad of Celite 521
  8. customThe organic layer of the filtrate was separated
  9. extractionextracted with 2N hydrochloric acid (2×30 mL)
  10. washwashed with ethyl acetate (4×50 mL)
  11. stirringThe aqueous solution was then stirred vigorously with ethyl acetate (100 mL) while solid potassium carbonate
  12. additionwas added portionwise until a pH of 12
  13. customThe aqueous layer was separated
  14. extractionextracted with ethyl acetate (2×100 mL)
  15. washThe combined organic layers were washed with brine (70 mL)
  16. dry with materialdried over magnesium sulfate
  17. customThe drying agent was removed by filtration
  18. concentrationthe filtrate was concentrated under reduced pressure
  19. customdried in a 49° C. vacuum oven for 24 h

Sources & evidence

ORD record
ord-49ff326a4eeb47f488dc641ae1b7242f
Source dataset
uspto-grants-2012_08
Patent number
US08247550B2

Linked notes

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