Morpholine → 5,7-difluoro-N-(6'-methoxymorpholino-2,3'-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

HRID 1431548Notes

Reaction equation

HRID 1431548 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:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[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:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)=[N:6][CH:7]=[CH:2][C:3]=1[N:104]1[CH2:109][CH2:108][O:107][CH2:106][CH2:105]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 59631310N-(5-bromo-6'-methoxy-2,3'-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-amineHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

Product 1

HCID 1317324045,7-difluoro-N-(6'-methoxymorpholino-2,3'-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of N-(5-bromo-6′-methoxy-2,3′-bipyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (142.1 mg, 0.27 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (25.8 mg, 0.054 mmol), tris(dibenzylideneacetone)dipalladium (0) (25.1 mg, 0.027 mmol), morpholine (0.05 mL, 0.57 mmol), and sodium tert-butoxide (74.9 mg, 0.78 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 that was further purified with SFC chromatography to afford a yellow solid as 5,7-difluoro-N-(6′-methoxymorpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (2H, m), 8.10 (2H, m), 7.95 (2H, m), 7.61 (1H, d, J=9.6 Hz), 7.39 (1H, ddd, J=6.7, 4.8, 2.0 Hz), 7.01 (3H, m), 6.53 (1H, d, J=2.3 Hz), 4.07 (3H, m), 3.91 (4H, m), 3.24 (4H, m), 2.23 (3H, s). Mass Spectrum (pos.) m/e: 541.2 (M+1).

Workup

  1. customwas degassed by nitrogen
  2. temperaturethe reaction was cooled to rt
  3. additionthen treated 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 that
  9. customwas further purified with SFC chromatography

Sources & evidence

ORD record
ord-7043b382cee04df59dbba93a271fdc83
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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