Potassium Phosphate, Tribasic → Ethyl 4-oxo-1-((4'-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylate

HRID 1497696Notes

Reaction equation

HRID 1497696 reaction equation
Br[C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[O:15]=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][N:10]=2)[N:5]([CH2:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=2[C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[CH:6]=[C:7]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 27343894-(Trifluoromethyl)phenylboronic acidHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 86725447Ethyl 1-(2-bromobenzyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate

Product 1

HCID 86725449Ethyl 4-oxo-1-((4'-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylateYield 7.6%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
100 °C

Procedure

To a mixture of ethyl 1-(2-bromobenzyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (136 mg, 0.35 mmol), 4-(trifluoromethyl)phenylboronic acid (133 mg, 0.7 mmol), palladium(II) acetate (15.7 mg, 0.07 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (57.5 mg, 0.140 mmol), and tribasic potassium phosphate (371 mg, 1.75 mmol) in a 20 mL vial were added previously degassed toluene (4.5 mL) and water (1.0 mL) at room temperature under a nitrogen atmosphere. The resulting suspension was heated to 100° C. and stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, the black reaction mixture was cooled to room temperature and poured into a mixture of water and brine solution and the organic compound was extracted into ethyl acetate (2×100 mL). The combined extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave a crude brown oil which was purified using ISCO (40 g) column chromatography, eluting with ethyl acetate in hexanes (0 to 100%) and 10 to 20% methanol in dichloromethane. The desired fractions were combined and the solvent was removed under vacuum to obtain ethyl 4-oxo-1-((4′-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylate (37) (12 mg, 7.6% yield) as a brown solid.

Workup

  1. temperatureThen, the black reaction mixture was cooled to room temperature
  2. extractionthe organic compound was extracted into ethyl acetate (2×100 mL)
  3. washThe combined extracts were washed with brine solution
  4. dry with materialdried over anhydrous MgSO4
  5. filtrationFiltration and concentration
  6. customgave a crude brown oil which
  7. customwas purified
  8. washeluting with ethyl acetate in hexanes (0 to 100%) and 10 to 20% methanol in dichloromethane
  9. customthe solvent was removed under vacuum

Sources & evidence

ORD record
ord-a2a84054423a4225bfcd39f0d87de624
Source dataset
uspto-grants-2015_12
Patent number
US09199987B2

Reaction notes

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