N-methyl-2-pyrrolidone → 3-(5,7-Difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzonitrile

HRID 1431747Notes

Reaction equation

HRID 1431747 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:34][N:35]1CCCC1=O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([Sn](C#N)(CCCC)CCCC)CCC>FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.[Pd+2]>[F:25][C:23]1[CH:22]=[C:21]([F:26])[CH:20]=[C:19]2[C:24]=1[C:15]([NH:14][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[CH:5]=1)[C:34]#[N:35])=[C:16]([CH3:33])[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:18]2

Participants

6

Reactant 4

HCID 13387N-methyl-2-pyrrolidoneHCID 200512Stannanecarbonitrile, tributyl-HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl2×HCID 59631163N-(3-chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

Product 1

HCID 574202483-(5,7-Difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzonitrile

Reagents, catalysts & solvents 1

HCID 2733347Palladium(II) trifluoroacetateCatalyst2×

Conditions

Temperature
160 °C

Procedure

To a stirred solution of N-(3-chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (0.059 g, 0.13 mmol) in 1-methylpyrrolidin-2-one (1.26 mL, 0.13 mmol) was added palladium bis(trifluoroacetate) (0.013 g, 0.038 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl (0.036 g, 0.076 mmol) followed by tri-n-butyltin cyanide (0.040 g, 0.13 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 2-(dicyclohexylphosphino)-2′,4′,6′,-triisopropyl-biphenyl were added. Heating continued at 160° C. for a further 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 organics were 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 3-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.62 (1H, s), 8.02 (1H, td, J=7.6, 1.8 Hz), 7.91 (1H, dt, J=7.8, 1.1 Hz), 7.65-7.70 (1H, m), 7.45-7.54 (2H, m), 6.81 (1H, dd, J=2.1, 1.3 Hz), 6.56 (1H, t, J=2.1 Hz), 6.34 (1H, d, J=1.2 Hz), 3.69 (4H, m), 3.09 (4H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=458.2 (M+1).

Workup

  1. temperatureHeating
  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 organics were 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-e8d08ec50c24431b94380b16f6372305
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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