2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → N-(2,5-di-4-morpholinylphenyl)-3-methyl-2-(2-pyridinyl)-1,7-naphthyridin-4-amine

HRID 1431456Notes

Reaction equation

HRID 1431456 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]=1[CH3:18].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[C:27]3[NH:33]C[C:31]4([CH2:38]COCC4)[C:28]3=[N:29][CH:30]=2)[CH2:21][CH2:20]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C([CH:70]([CH3:72])C)C=1)C.C[C:74](C)([O-:76])C.[Na+]>C1(C)C=CC=CC=1>[N:29]1([C:28]2[CH:31]=[CH:38][C:25]([N:22]3[CH2:21][CH2:20][O:19][CH2:24][CH2:23]3)=[CH:26][C:27]=2[NH:33][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:3]=2[CH3:18])[CH2:30][CH2:74][O:76][CH2:70][CH2:72]1

Participants

6

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596313804-Chloro-3-methyl-2-(pyridin-2-yl)-1,7-naphthyridineHCID 672847056'-Morpholino-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]

Product 1

HCID 59631045N-(2,5-di-4-morpholinylphenyl)-3-methyl-2-(2-pyridinyl)-1,7-naphthyridin-4-amine

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a stirred solution of 4-chloro-3-methyl-2-(pyridin-2-yl)-1,7-naphthyridine (70 mg, 0.27 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (75 mg, 0.27 mmol) and XPhos™ precatalyst (20 mg, 0.03 mmol) in toluene (3 mL) was added sodium tert-butoxide (53 mg, 0.55 mmol) and the reaction was heated at reflux for 2 h. After this time the reaction was allowed to cool to rt and partitioned between EtOAc (60 mL) and water (20 mL). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave N-(2,5-di-4-morpholinylphenyl)-3-methyl-2-(2-pyridinyl)-1,7-naphthyridin-4-amine. H NMR (400 MHz, chloroform-d) δ ppm 9.54 (1H, d, J=1.0 Hz), 8.73-8.78 (1H, m), 8.51 (1H, d, J=5.7 Hz), 7.91-7.99 (2H, m), 7.64 (1H, dd, J=5.8, 1.1 Hz), 7.41 (1H, td, J=4.9, 3.6 Hz), 7.22 (1H, s), 7.12 (1H, d, J=8.6 Hz), 6.48 (1H, dd, J=8.6, 2.7 Hz), 6.03 (1H, d, J=2.7 Hz), 3.89 (4H, t, J=4.6 Hz), 3.69-3.77 (4H, m), 3.01-3.12 (4H, m), 2.88-2.95 (4H, m), 2.45 (3H, s). Mass Spectrum (ESI) m/e=483.2 (M+1).

Workup

  1. temperaturethe reaction was heated
  2. temperatureat reflux for 2 h
  3. custompartitioned between EtOAc (60 mL) and water (20 mL)
  4. dry with materialThe separated organic layer was dried over MgSO4
  5. filtrationfiltered
  6. customevaporated in vacuo
  7. customPurification by reverse phase HPLC (10 to 60% acetonitrile in water)

Sources & evidence

ORD record
ord-b1a8d55f8eff473b94745e5eb136848f
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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