5-Aminopyrazine-2-carbonitrile → Tert-butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate

HRID 556816Notes

Reaction equation

HRID 556816 reaction equation
[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].Br[C:17]1[CH:22]=[C:21]([NH:23][CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)[C:20]([N+:38]([O-:40])=[O:39])=[CH:19][N:18]=1>CN(C=O)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:26]3)[C:20]([N+:38]([O-:40])=[O:39])=[CH:19][N:18]=2)=[N:3][CH:4]=1)#[N:9]

Participants

6

Reactant 3

HCID 139252945-Aminopyrazine-2-carbonitrileHCID 23676156Sodium t-butoxideHCID 59613413Tert-butyl 3-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate

Product 1

HCID 66745665Tert-butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 21735183Dimethylformamide tolueneSolvent

Conditions

Temperature
150 °C

Procedure

Palladium (II) acetate (39 mg, 0.17 mmol) was added to (±)-2,2″-bis(diphenylphosphino)-1,1″-binaphthalene (321 mg, 0.51 mmol) in DMF/toluene (1/1 15 mL) and the resulting mixture was degassed under a stream of nitrogen gas for 10 min. 2-Amino-5-cyanopyrazine (210 mg, 1.7 mmol), sodium tert-butoxide (250 mg, 2.6 mmol) and tert-butyl 3-((2-bromo-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate (713 mg, 1.7 mmol) were added and the mixture was degassed for a further 5 minutes then heated at 150° C. for 30 min using microwave irradiation. The mixture was concentrated in vacuo and water and ethyl acetate were added. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography on silica, eluting with a gradient of ethyl acetate in hexane, 10-100% over 50 min. The fractions containing the product contaminated with 2-amino-5-cyanopyrazine were combined, evaporated and repurified by silica column chromatography, eluting with a gradient of ethyl acetate in hexane, 10-50% over 45 min. Tert-butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-nitropyridin-4-ylamino)methyl)piperidine-1-carboxylate was obtained as a yellow solid (265 mg, 34%).

Workup

  1. customthe resulting mixture was degassed under a stream of nitrogen gas for 10 min
  2. customthe mixture was degassed for a further 5 minutes
  3. custommicrowave irradiation
  4. concentrationThe mixture was concentrated in vacuo and water and ethyl acetate
  5. additionwere added
  6. extractionThe aqueous phase was extracted three times with ethyl acetate
  7. dry with materialThe combined organic phases were dried (Na2SO4)
  8. concentrationconcentrated
  9. customThe residue was purified by flash column chromatography on silica
  10. washeluting with a gradient of ethyl acetate in hexane, 10-100% over 50 min
  11. additionThe fractions containing the product
  12. customevaporated
  13. customrepurified by silica column chromatography
  14. washeluting with a gradient of ethyl acetate in hexane, 10-50% over 45 min

Sources & evidence

ORD record
ord-0aacf18b88394ba5be1673cf5baef928
Source dataset
uspto-grants-2011_11
Patent number
US08058045B2

Reaction notes

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