2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-5,7-difluoro-2-(3-fluorobenzyl)-3-methylquinoline

HRID 1618661Notes

Reaction equation

HRID 1618661 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:3]=1[CH3:22].[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[NH:26][CH2:25]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:23][C:24]1([CH3:39])[C:28]2=[N:29][CH:30]=[C:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:32]=[C:27]2[N:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[C:3]=2[CH3:22])[CH2:25]1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 672843674-Chloro-5,7-difluoro-2-(3-fluorobenzyl)-3-methylquinolineHCID 672844994-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-morpholine

Product 1

HCID 509395964-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-5,7-difluoro-2-(3-fluorobenzyl)-3-methylquinoline

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

4-Chloro-5,7-difluoro-2-(3-fluorobenzyl)-3-methylquinoline (41.4 mg, 0.129 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (30 mg, 0.129 mmol), Pd2dba3 (11.8 mg, 0.013 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (12.3 mg, 0.026 mmol), sodium tert-butoxide (37.1 mg, 0.386 mmol), and toluene (1.29 mL) were stirred at 105° C. for 2 h. The reaction mixture was then concentrated and the resulting residue partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and water, then dried (MgSO4) and concentrated. Purification of the crude product by reverse-phase HPLC (0-70% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]-pyridin-1-yl)-5,7-difluoro-2-(3-fluorobenzyl)-3-methylquinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 7.63 (1H, ddd, J=9.4, 2.5, 1.4 Hz), 7.51-7.54 (1H, m), 7.27-7.30 (1H, m), 7.05 (1H, ddd, J=7.9, 1.3, 1.2 Hz), 6.86-7.01 (3H, m), 5.55 (1H, dd, J=2.2, 0.4 Hz), 4.42 (2H, s), 3.79-3.86 (1H, m), 3.68-3.78 (4H, m), 3.57 (1H, d, J=9.2 Hz), 2.86-2.98 (4H, m), 2.19 (3H, s), 1.52 (3H, s), 1.47 (3H, s). Mass Spectrum (ESI) m/e=519.1 (M+1).

Workup

  1. concentrationThe reaction mixture was then concentrated
  2. customthe resulting residue partitioned between EtOAc and saturated aqueous sodium bicarbonate solution
  3. washThe organic layer was washed with brine and water
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. customPurification of the crude product by reverse-phase HPLC (0-70% acetonitrile in water)

Sources & evidence

ORD record
ord-9bf9be4b00c64cf2afa5a2ae8f228a57
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

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