Potassium Phosphate, Tribasic → HCID 67469548, compound

HRID 1522552Notes

Reaction equation

HRID 1522552 reaction equation
[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[N:19]=1)[C:13]([O:15][CH3:16])=[O:14].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26](B(O)O)[CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.ClCCl.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([F:31])=[C:24]([C:10]2[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:23]=1

Participants

10

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 3718925(5-Chloro-2-fluoro-phenyl)boronic acidHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 40425123Methyl 2-bromo-6-methylpyridine-4-carboxylate

Product 1

HCID 67469548HCID 67469548, compoundYield 30.6%

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent2×HCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 21226138Dichloromethane ethylacetateSolvent

Procedure

Potassium phosphate tribasic (13.84 g, 65.2 mmol), palladium acetate (0.390 g, 1.739 mmol), methyl 2-bromo-6-methylisonicotinate (5 g, 21.73 mmol), 5-chloro-2-fluorophenylboronic acid (5.68 g, 32.6 mmol) and dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (1.521 g, 3.26 mmol) were combined in toluene (70 mL) and water (14 mL) and heated at 110° C. in an oil bath for 1 hour. The reaction was then cooled and diluted with water (30 mL), filtered through Celite® and the layers were separated. The aqueous layer was extracted with ether and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a residue. The residue was dissolved in ethyl acetate/dichloromethane and absorbed onto silica gel before chromatography on silica eluting with 10% ethyl acetate in hexanes to give an off white powder which was dissolved in dichloromethane, dried onto silica gel and further purified by chromatography on silica using a step gradient (0-10% ethyl acetate/hexanes) to give methyl 2-(5-chloro-2-fluorophenyl)-6-methylisonicotinate (1.86 g, 30.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.64-2.68 (3H, m) 3.91-3.95 (3H, m) 7.45 (1H, dd, J=11.12, 8.84 Hz) 7.59 (1H, ddd, J=8.84, 4.29, 2.78 Hz) 7.75-7.81 (1H, m) 8.01 (1H, dd, J=6.57, 2.78 Hz) 8.06 (1H, s). ESI-MS: m/z 280.1 (M+H).

Workup

  1. temperatureThe reaction was then cooled
  2. filtrationfiltered through Celite®
  3. customthe layers were separated
  4. extractionThe aqueous layer was extracted with ether
  5. dry with materialthe combined organic layers were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give a residue
  9. customabsorbed onto silica gel before chromatography on silica eluting with 10% ethyl acetate in hexanes
  10. customto give an off white powder which
  11. customdried onto silica gel
  12. customfurther purified by chromatography on silica using a step gradient (0-10% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-e4d47ec0ee4c442ab820a59b1cdac9e4
Source dataset
uspto-grants-2015_07
Patent number
US09073918B2

Reaction notes

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