Stannanecarbonitrile, tributyl- → (2,5-Dimorpholinopyridin-3-ylamino)-3-methyl-2-(pyridin-2-yl)quinoline-8-carbonitrile

HRID 1431537Notes

Reaction equation

HRID 1431537 reaction equation
Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:8]([CH3:18])=[C:7]2[NH:19][C:20]1[C:21]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:22][CH:23]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn]([C:85]#[N:86])(CCCC)CCCC)CCC>CN1CCCC1=O.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[Pd+2]>[O:35]1[CH2:34][CH2:33][N:32]([C:21]2[C:20]([NH:19][C:7]3[C:6]4[C:11](=[C:2]([C:85]#[N:86])[CH:3]=[CH:4][CH:5]=4)[N:10]=[C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[C:8]=3[CH3:18])=[CH:25][C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:23][N:22]=2)[CH2:37][CH2:36]1

Participants

6

Reactant 3

HCID 200512Stannanecarbonitrile, tributyl-HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl2×HCID 596314868-chloro-N-(2,5-dimorpholinopyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

Product 1

HCID 59631330(2,5-Dimorpholinopyridin-3-ylamino)-3-methyl-2-(pyridin-2-yl)quinoline-8-carbonitrile

Reagents, catalysts & solvents 2

HCID 2733347Palladium(II) trifluoroacetateCatalyst2×HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
160 °C

Procedure

To a stirred solution of 8-chloro-N-(2,5-dimorpholinopyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.180 g, 0.35 mmol) in 1-methylpyrrolidin-2-one (3.46 mL) was added palladium bis(trifluoroacetate) (0.017 g, 0.052 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-biphenyl (0.050 g, 0.11 mmol) followed by tri-n-butyltin cyanide (0.109 g, 0.35 mmol). The reaction was heated to 160° C. for 36 h. A further 0.3 eq of palladium bis(trifluoroacetate) and 0.6 eq of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine was added. The reaction was further heated at 160° C. for 3 h. After which, the reaction was cooled to 23° C. The crude product was filtered through a plug of alumina eluting with EtOAc. The organic layer was washed with water, dried over MgSO4 and filtered and evaporated in vacuo. The crude product was purified by column chromatography on alumina (0 to 50% EtOAc/hexane)) to give the desired product 4-((2,5-dimorpholinopyridin-3-ylamino)-3-methyl-2-(pyridin-2-yl)quinoline-8-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (1H, ddd, J=4.8, 1.8, 1.0 Hz), 8.29 (1H, dd, J=7.1, 1.3 Hz), 8.19 (1H, dd, J=8.5, 1.3 Hz), 8.03-8.08 (2H, m), 7.96 (1H, dt, J=7.9, 1.1 Hz), 7.61-7.65 (2H, m), 7.53 (1H, ddd, J=7.6, 4.8, 1.3 Hz), 6.55 (1H, d, J=2.7 Hz), 3.65 (4H, m), 3.39 (4H, m), 2.95 (4H, m), 2.88 (4H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=508.3 (M+1).

Workup

  1. temperatureThe reaction was further heated at 160° C. for 3 h
  2. temperatureAfter which, the reaction was cooled to 23° C
  3. filtrationThe crude product was filtered through a plug of alumina eluting with EtOAc
  4. washThe organic layer was washed with water
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customevaporated in vacuo
  8. customThe crude product was purified by column chromatography on alumina (0 to 50% EtOAc/hexane))

Sources & evidence

ORD record
ord-50c97e3a8c554dfcaa08cc446da7a903
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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