Potassium Phosphate, Tribasic → 2-(2-Fluoro-4-methylsulfanyl-phenylamino)-6-formylaminomethyl-nicotinic acid methyl ester

HRID 1500688Notes

Reaction equation

HRID 1500688 reaction equation
[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:24][C:25]1[CH:30]=[C:29]([S:31][CH3:32])[CH:28]=[CH:27][C:26]=1[NH2:33].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>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]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[NH:33][C:26]1[CH:27]=[CH:28][C:29]([S:31][CH3:32])=[CH:30][C:25]=1[F:24]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 220256172-Fluoro-4-(methylsulfanyl)anilineHCID 583245442-Chloro-6-formylaminomethylnicotinic acid methyl ester

Product 1

HCID 591401592-(2-Fluoro-4-methylsulfanyl-phenylamino)-6-formylaminomethyl-nicotinic acid methyl esterYield 23%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2-chloro-6-formylaminomethyl-nicotinic acid methyl ester (123 mg, 0.54 mmol) in toluene (1.6 mL) was added potassium phosphate (119 mg, 0.76 mmol), 2-fluoro-4-methylsulfanyl-phenylamine (102 mg, 0.65 mmol), tris(dibenzylideneacetone)dipalladium (12.8 mg, 0.014 mmol) and dicyclohexyl-(2′,6′-diisopropoxy-biphenyl-2-yl)-phosphane (25 mg, 0.054 mmol). The reaction mixture was degassed with argon then heated at 100° C. After 25 hours, the reaction mixture was cooled, diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride, water then brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated with ethyl acetate to afford the title compound as a bright yellow solid (43 mg, 23%). LCMS (method B): RT=3.53 min, [M+H]+=350.

Workup

  1. customThe reaction mixture was degassed with argon
  2. temperaturethe reaction mixture was cooled
  3. additiondiluted with ethyl acetate
  4. washwashed with a saturated aqueous solution of ammonium chloride, water
  5. customThe organic phase was isolated
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was triturated with ethyl acetate

Sources & evidence

ORD record
ord-1904aa0acf034389856372ef460fb092
Source dataset
uspto-grants-2015_12
Patent number
US09206174B2

Reaction notes

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