2-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl → 7-{[2-(isoquinolin-7-ylamino)-pyridine-3-carbonyl]-amino}-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

HRID 887678Notes

Reaction equation

HRID 887678 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](Cl)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:30][C:31]1[CH:40]=[C:39]2[C:34]([CH:35]=[CH:36][N:37]=[CH:38]2)=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>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].O>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:30][C:31]4[CH:40]=[C:39]5[C:34]([CH:35]=[CH:36][N:37]=[CH:38]5)=[CH:33][CH:32]=4)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

6

Reactant 3

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 14660277Isoquinolin-7-amineHCID 866032387-[(2-Chloro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

Product 1

HCID 687999697-{[2-(isoquinolin-7-ylamino)-pyridine-3-carbonyl]-amino}-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
70 °C

Procedure

To a mixture of 7-[(2-chloro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (20.8 g, 50 mmol, 1.0 eq.), 7-aminoisoquinoline (7.2 g, 50 mmol, 1.0 eq.), Pd2(dba)3 (915 mg, 1 mmol, 0.02 eq), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (CAS#213697-53-1, Strem Chemicals cat no. 15-1145; 785 mg, 2 mmol, 0.04 eq) under N2 in a 250 mL pressure reaction vessel was added 1.0 M LiNTMS2 THF solution (120 mL, 120 mmol, 2.4 eq.). The reaction vessel was sealed with a Teflon screwcap and the mixture was stirred at 70° C. for 17 h. The mixture was then cooled to RT. 100 mL of water was added to the mixture and the mixture was extracted with 500 mL of EtOAc. The organic layer was washed with sat. NH4Cl solution, 1M NaHPO4 solution (4×200 mL) then dried over MgSO4. After filtration and concentration, the crude was purified through a silica gel column chromatography, eluting with CH2Cl2/EtOAc. The desired title compound was obtained as a yellow solid. MS (ES+): 524 (M+H)+. Calc'd for C31H33N5O3—523.26

Workup

  1. customin a 250 mL pressure reaction vessel
  2. temperatureThe mixture was then cooled to RT
  3. extractionthe mixture was extracted with 500 mL of EtOAc
  4. washThe organic layer was washed with sat. NH4Cl solution, 1M NaHPO4 solution (4×200 mL)
  5. dry with materialthen dried over MgSO4
  6. filtrationAfter filtration and concentration
  7. customthe crude was purified through a silica gel column chromatography
  8. washeluting with CH2Cl2/EtOAc

Sources & evidence

ORD record
ord-0c0ad855cf5041d18931fbffaa26a888
Source dataset
uspto-grants-2012_08
Patent number
US08247430B2

Reaction notes

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