Morpholine → HCID 59631587, compound

HRID 1431545Notes

Reaction equation

HRID 1431545 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[N:21]=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:19]=2[CH3:36])[C:5]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[N:6][CH:7]=1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.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:28][C:26]1[CH:25]=[C:24]([F:29])[CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:4]1[C:5]([C:8]3[C:13]([F:14])=[CH:12][N:11]=[C:10]([O:15][CH3:16])[CH:9]=3)=[N:6][CH:7]=[C:2]([N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:3]=1)=[C:19]([CH3:36])[C:20]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[N:21]2

Participants

7

Reactant 4

HCID 8083MorpholineHCID 23676156Sodium t-butoxideHCID 59631176HCID 59631176, compoundHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

Product 1

HCID 59631587HCID 59631587, compound

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of N-(5-bromo-5′-fluoro-2′-methoxy-2,4′-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (50.2 mg, 0.091 mmol), morpholine (0.03 mL, 0.34 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl (9.1 mg, 0.019 mmol), tris(dibenzylideneacetone)dipalladium (0) (8.5 mg, 9.28 μmol), and sodium tert-butoxide (26.7 mg, 0.28 mmol) in dry Toluene (3 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 21.5 h, the reaction was cooled to rt, then treated with water. After extracting twice with EtOAc, the organic layer was combined and dried over anhydrous magnesium sulfate. After filtration and concentration, the light orange film was purified with HPLC 10-60% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution. The impure fractions were further purified with SFC chromatography to afford a white solid as 5,7-difluoro-N-(5′-fluoro-2′-methoxy-5-morpholino-2,4′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.68 (1H, br. s.), 8.10 (2H, t, J=2.0 Hz), 7.96 (2H, m), 7.66 (1H, m.), 7.38 (1H, m), 7.07 (2H, m), 6.61 (1H, m), 3.96 (3H, s), 3.91 (4H, m), 3.30 (4H, m), 2.17 (3H, s). Mass Spectrum (pos.) m/e: 559.2 (M+1).

Workup

  1. customwas degassed by nitrogen
  2. temperaturethe reaction was cooled to rt
  3. additiontreated with water
  4. extractionAfter extracting twice with EtOAc
  5. dry with materialdried over anhydrous magnesium sulfate
  6. filtrationAfter filtration and concentration
  7. customthe light orange film was purified with HPLC 10-60% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution
  8. customThe impure fractions were further purified with SFC chromatography

Sources & evidence

ORD record
ord-567d6d0d050d460cbab1d8acf32b0e6e
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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