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

HRID 1618653Notes

Reaction equation

HRID 1618653 reaction equation
[CH2:1]([C:8]1[C:17]([CH3:18])=[C:16](Cl)[C:15]2[C:10](=[CH:11][C:12]([F:21])=[CH:13][C:14]=2[F:20])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[NH:25][CH2:24]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>[CH2:1]([C:8]1[C:17]([CH3:18])=[C:16]([N:25]2[C:26]3[C:27](=[N:28][CH:29]=[C:30]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH:31]=3)[C:23]([CH3:38])([CH3:22])[CH2:24]2)[C:15]2[C:10](=[CH:11][C:12]([F:21])=[CH:13][C:14]=2[F:20])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596314902-Benzyl-4-chloro-5,7-difluoro-3-methylquinolineHCID 672844994-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-morpholine

Product 1

HCID 509397332-benzyl-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methylquinoline

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
95 °C

Procedure

A screw cap vial was charged with 2-benzyl-4-chloro-5,7-difluoro-3-methylquinoline (37 mg, 0.122 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (36.9 mg, 0.158 mmol), Pd2dba3 (16.7 mg, 0.018 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (17.4 mg, 0.037 mmol), sodium tert-butoxide (35.1 mg, 0.365 mmol), and toluene (1.22 mL). The mixture was heated to 95° C. under N2 for 18 h. The reaction was concentrated and diluted with EtOAc, then washed with saturated aqueous sodium bicarbonate solution, water, brine, and 1M NaOH. The organic layer was dried (MgSO4) and concentrated. The crude product was purified by preparative HPLC (10-70% acetonitrile in water) to give 2-benzyl-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methylquinoline as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.60-7.68 (1H, m), 7.50 (1H, d, J=2.3 Hz), 7.27-7.31 (2H, m), 7.22-7.25 (3H, m), 6.96 (1H, ddd, J=11.9, 9.0, 2.5 Hz), 5.52 (1H, d, J=2.3 Hz), 4.42 (2H, s), 3.79-3.85 (1H, m), 3.68-3.77 (4H, m), 3.56 (1H, d, J=9.0 Hz), 2.89-2.96 (4H, m), 2.19 (3H, s), 1.51 (3H, s), 1.45 (3H, s). Mass Spectrum (ESI) m/e=512.0 (M+1).

Workup

  1. customA screw cap vial
  2. concentrationThe reaction was concentrated
  3. additiondiluted with EtOAc
  4. washwashed with saturated aqueous sodium bicarbonate solution, water, brine, and 1M NaOH
  5. dry with materialThe organic layer was dried (MgSO4)
  6. concentrationconcentrated
  7. customThe crude product was purified by preparative HPLC (10-70% acetonitrile in water)

Sources & evidence

ORD record
ord-6e6198e2543a47cfb3a99301ebf67e4b
Source dataset
uspto-grants-2014_07
Patent number
US08765940B2

Reaction notes

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