2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → N-(2,5-Dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(5-(methylsulfonyl)pyridin-3-yl)quinolin-4-amine

HRID 1431599Notes

Reaction equation

HRID 1431599 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]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:19]=2)[C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([NH2:37])=[CH:35][C:34]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.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>[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([NH:37][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:15]=[N:16][CH:17]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:19]=4)[C:3]=3[CH3:24])=[CH:35][C:34]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596310462,5-Dimorpholinopyridin-3-amineHCID 672857114-Chloro-5,7-difluoro-3-methyl-2-(5-(methylsulfonyl)pyridin-3-yl)quinoline

Product 1

HCID 50907186N-(2,5-Dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(5-(methylsulfonyl)pyridin-3-yl)quinolin-4-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

A screw-cap vial was charged with 4-chloro-5,7-difluoro-3-methyl-2-(5-(methylsulfonyl)pyridin-3-yl)quinoline (40 mg, 0.11 mmol), 2,5-dimorpholinopyridin-3-amine (28.7 mg, 0.11 mmol), tris(dibenzylideneacetone)dipalladium (0) (10.0 mg, 11.0 μmol), X-Phos (10.3 mg, 0.022 mmol), sodium tert-butoxide (31.3 mg, 0.33 mmol), and toluene (1.1 mL). The reaction was stirred at 105° C. for 30 min, then cond. The resulting residue was partitioned between DCM and water, and extracted twice with DCM. The combined organic layer was dried over magnesium sulfate and cond, and the crude product was purified by flash chromatography (basic alumina, 0-60% EtOAc in hexanes). This afforded N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(5-(methylsulfonyl)pyridin-3-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=597.0 (M+1). 1H NMR (500 MHz, CDCl3) δ ppm 9.26 (1H, d, J=2.2 Hz), 9.16 (1H, s), 8.56 (1H, s), 7.89 (1H, s), 7.72 (1H, s), 7.63 (1H, s), 7.09 (1H, s), 6.43 (1H, s), 3.88-4.08 (4H, m), 3.85 (4H, br. s.), 3.23 (4H, br. s.), 3.08 (4H, br. s.), 2.18 (3H, s), 1.57 (3H, s).

Workup

  1. customThe resulting residue was partitioned between DCM and water
  2. extractionextracted twice with DCM
  3. dry with materialThe combined organic layer was dried over magnesium sulfate and cond
  4. customthe crude product was purified by flash chromatography (basic alumina, 0-60% EtOAc in hexanes)

Sources & evidence

ORD record
ord-e8d00e180beb4b3cb9d1013e48f6e0ec
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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