4-Aminobenzonitrile → 4-(5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile

HRID 1042271

Reaction equation

HRID 1042271 reaction equation
[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N:10]1[C:15]2[NH:16][CH:17]=[CH:18][C:14]=2[C:13]([C:19]2[C:20]([NH:25][C:26]3[C:27]4[CH:28]=[CH:29][N:30]=[C:31](Cl)[C:32]=4[CH:33]=[CH:34][C:35]=3[CH3:36])=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:12][CH:11]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:10]1[C:15]2[NH:16][CH:17]=[CH:18][C:14]=2[C:13]([C:19]2[C:20]([NH:25][C:26]3[C:35]([CH3:36])=[CH:34][CH:33]=[C:32]4[C:27]=3[CH:28]=[CH:29][N:30]=[C:31]4[NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:12][CH:11]=1

Participants

7

Reactant 4

HCID 133964-AminobenzonitrileHCID 2733832Lithium HexamethyldisilazideHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 59627376N-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-yl)-1-chloro-6-methylisoquinolin-5-amine

Product 1

HCID 251326674-(5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 4-aminobenzonitrile (35 mg, 299 mmol), N-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-yl)-1-chloro-6-methylisoquinolin-5-amine (110 mg, 284 μmol), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 11 μmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (9 mg, 23 μmol) were suspended in THF (1 mL) and sealed. The mixture was sonicated until homogeneously mixed. Lithium bis(trimethylsilyl)amide (1.28 mL, 1280 mmol) was then added through a syringe, then mixed well with sonication. The reaction tube was heated via microwave to 120° C. for 15 min. The reaction mixture was cooled to room temperature, then partitioned between EtOAc (3×50 mL) and NaHCO3 (aq., sat). The organic layer was washed with brine, and extracted with HCl (aq., 1 N, 3×50 mL). The aqueous layers were combined and filtered through a layer of celite. The filter cake was rinsed with 1 N HCl. The filtrate was then cooled in ice and neutralized with NH4OH (aq., conc.) to pH 8, then extracted with EtOAc (4×50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and then concentrated to give a brown solid which was then triturated with MeOH to give a light brown solid upon filtration. The filter cake was air dried over the weekend to give 4-(5-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-ylamino)-6-methylisoquinolin-1-ylamino)benzonitrile. MS (ESI, pos. ion) m/z: 469.2

Workup

  1. customsealed
  2. customThe mixture was sonicated
  3. additionuntil homogeneously mixed
  4. additionmixed well with sonication
  5. temperatureThe reaction mixture was cooled to room temperature
  6. custompartitioned between EtOAc (3×50 mL) and NaHCO3 (aq., sat)
  7. washThe organic layer was washed with brine
  8. extractionextracted with HCl (aq., 1 N, 3×50 mL)
  9. filtrationfiltered through a layer of celite
  10. washThe filter cake was rinsed with 1 N HCl
  11. temperatureThe filtrate was then cooled in ice and neutralized with NH4OH (aq., conc.) to pH 8
  12. extractionextracted with EtOAc (4×50 mL)
  13. washwashed with brine
  14. dry with materialdried over Na2SO4
  15. concentrationconcentrated
  16. customto give a brown solid which
  17. customwas then triturated with MeOH
  18. customto give a light brown solid
  19. filtrationupon filtration
  20. customdried over the weekend

Sources & evidence

ORD record
ord-83496dde42b748eaa605099e5d576c5b
Source dataset
uspto-grants-2013_10
Patent number
US08557830B2

Linked notes

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