2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 8-chloro-N-(2,5-dimorpholinopyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)-quinolin-4-amine

HRID 1431536Notes

Reaction equation

HRID 1431536 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.Cl[C:55]1[C:64]2[C:59](=[C:60]([Cl:65])[CH:61]=[CH:62][CH:63]=2)[N:58]=[C:57]([C:66]2[CH:71]=[C:70]([CH3:72])[CH:69]=[CH:68][N:67]=2)[C:56]=1[CH3:73].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]>[Cl:65][C:60]1[CH:61]=[CH:62][CH:63]=[C:64]2[C:59]=1[N:58]=[C:57]([C:66]1[CH:71]=[C:70]([CH3:72])[CH:69]=[CH:68][N:67]=1)[C:56]([CH3:73])=[C:55]2[NH:47][C:46]1[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[N:42][CH:43]=[C:44]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:45]=1

Participants

7

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 596310462,5-Dimorpholinopyridin-3-amineHCID 596311454,8-Dichloro-3-methyl-2-(4-methylpyridin-2-yl)quinoline

Product 1

HCID 509080448-chloro-N-(2,5-dimorpholinopyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)-quinolin-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 (0.025 g, 0.053 mmol), 2,5-dimorpholinopyridin-3-amine (0.105 g, 0.40 mmol), 4,8-dichloro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (0.1 g, 0.33 mmol) and Pd2dba3 (0.012 g, 0.013 mmol) and sodium tert-butoxide (0.079 g, 0.83 mmol) in toluene (3.3 mL) at 100° C. for 1.6 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1)). The desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concd then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield pure product 8-chloro-N-(2,5-dimorpholinopyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)-quinolin-4-amine. 1H NMR (400 MHz, CD2Cl2) δ ppm 8.57 (1H, d, J=4.9 Hz), 7.82 (3H, m), 7.57 (1H, d, J=2.5 Hz), 7.43 (1H, dd, J=8.4, 7.4 Hz), 7.27 (1H, d, J=4.3 Hz.), 6.89 (1H, br. s.), 6.22 (1H, br. s.), 3.88 (4H, br. s.), 3.68 (4H, m), 3.20 (4H, br. s.), 2.90 (4H, m), 2.51 (3H, m), 2.39 (3H, s). Mass Spectrum (ESI) m/e=531.2 (M+1).

Workup

  1. customwas prepared
  2. customat 100° C.
  3. customfor 1.6 h
  4. customThe crude product was purified by column chromatography on silica gel (0 to 100% DCM/MeOH/ammonium hydroxide (90/9/1))
  5. customThe desired product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions
  6. additionwere concd then diluted with EtOAc
  7. washAfter washing twice with satd aq. sodium bicarbonate solution
  8. customthe solvent was removed under reduced pressure

Sources & evidence

ORD record
ord-65947240c1aa49849ed2c05c3fd489ed
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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