2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 2-(2,4-bis(trifluoromethyl)phenyl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine

HRID 1431490Notes

Reaction equation

HRID 1431490 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.[F:54][C:55]([F:81])([F:80])[C:56]1[CH:61]=[C:60]([C:62]([F:65])([F:64])[F:63])[CH:59]=[CH:58][C:57]=1[C:66]1[C:75]([CH3:76])=[C:74](Cl)[C:73]2[C:68](=[CH:69][C:70]([F:79])=[CH:71][C:72]=2[F:78])[N:67]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:81][C:55]([F:54])([F:80])[C:56]1[CH:61]=[C:60]([C:62]([F:64])([F:65])[F:63])[CH:59]=[CH:58][C:57]=1[C:66]1[C:75]([CH3:76])=[C:74]([NH:47][C:46]2[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)=[N:42][CH:43]=[C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[CH:45]=2)[C:73]2[C:68](=[CH:69][C:70]([F:79])=[CH:71][C:72]=2[F:78])[N:67]=1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596310462,5-Dimorpholinopyridin-3-amineHCID 596311972-(2,4-Bis(trifluoromethyl)phenyl)-4-chloro-5,7-difluoro-3-methylquinoline

Product 1

HCID 596314182-(2,4-bis(trifluoromethyl)phenyl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.016 g, 0.034 mmol), 2,5-dimorpholinopyridin-3-amine (0.067 g, 0.25 mmol), 2-(2,4-bis(trifluoromethyl)phenyl)-4-chloro-5,7-difluoro-3-methylquinoline (0.090 g, 0.21 mmol), Pd2dba3 (7.74 mg, 8.46 μmol) and sodium tert-butoxide (0.051 g, 0.53 mmol) in toluene (2.1 mL) at 120° C. for 75 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 2-(2,4-bis(trifluoromethyl)phenyl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (1H, s), 7.98 (1H, d, J=8.0 Hz), 7.81 (1H, br. s), 7.62 (1H, J=2.4 Hz), 7.59-7.54 (2H, m), 7.10 (1H, ddd, J=13.3, 8.4, 2.5 Hz), 6.24 (1H, br. s.), 3.93 (4H, m), 3.79 (4H, app t, J=4.7 Hz), 3.40 (4H, br. s.), 3.01 (4H, app t, J=4.9 Hz), 1.92 (3H, s). Mass Spectrum (ESI) m/e=654.3 (M+1).

Workup

  1. customwas prepared
  2. customat 120° C.
  3. customfor 75 h
  4. customThe crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc)

Sources & evidence

ORD record
ord-ddbd0704f7a04f0291f7049a23c79f42
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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