Morpholine → HCID 59631182, compound

HRID 1431552Notes

Reaction equation

HRID 1431552 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:28])=[CH:24][C:25]=3[F:27])[N:20]=[C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:18]=2[CH3:35])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:104]1[CH2:109][CH2:108][O:107][CH2:106][CH2:105]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:27][C:25]1[CH:24]=[C:23]([F:28])[CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:4]1[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:14][CH3:15])=[N:6][CH:7]=[C:2]([N:104]3[CH2:109][CH2:108][O:107][CH2:106][CH2:105]3)[CH:3]=1)=[C:18]([CH3:35])[C:19]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)=[N:20]2

Participants

8

Reactant 5

HCID 8083MorpholineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 59631297HCID 59631297, compoundHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

Product 1

HCID 59631182HCID 59631182, compound

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of N-(5-bromo-2-(2-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (84.1 mg, 0.158 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (16.6 mg, 0.035 mmol), tris(dibenzylideneacetone)dipalladium (0) (15.4 mg, 0.017 mmol), morpholine (0.03 mL, 0.345 mmol), and sodium tert-butoxide (47.8 mg, 0.5 mmol) in dry toluene (5 mL) was degassed by nitrogen. The mixture was heated to 100° C. After 23 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 residue was purified on basic alumina (5-20% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with SFC chromatography to afford 5,7-difluoro-N-(2-(2-methoxyphenyl)-5-morpholinopyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.67 (1H, ddd, J=4.9, 1.8, 1.0 Hz), 8.10 (1H, d, J=2.5 Hz), 7.92 (1H, m), 7.75 (1H, d, J=7.8 Hz), 7.57 (1H, ddd, J=9.7, 2.5, 1.3 Hz), 7.49 (1H, dd, J=7.4, 1.8 Hz), 7.46 (1H, m), 7.34 (1H, ddd, J=7.6, 4.8, 1.3 Hz), 7.13 (1H, td, J=7.4, 1.0 Hz), 7.08 (1H, m), 6.96 (1H, ddd, J=13.4, 8.7, 2.3 Hz), 6.65 (1H, m), 3.95 (3H, s), 3.90 (4H, m), 3.29 (4H, m), 1.94 (3H, br. s.) Mass Spectrum (pos.) m/e: 540.3 (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 residue was purified on basic alumina (5-20% EtOAc in hexanes)
  8. customto afford an impure orange residue
  9. customThe light orange film was further purified with SFC chromatography

Sources & evidence

ORD record
ord-3a6b074b96874b7397b0664546e4f1f5
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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