Biphenyl → 4-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

HRID 222941

Reaction equation

HRID 222941 reaction equation
I[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.C1(C2C=CC=CC=2)C=CC=CC=1.[B]1OC(C)(C)C(C)(C)O1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl[C:50]1[C:51]2[CH:61]=[CH:60][C:59](=[O:62])[N:58]([C:63]3[C:68]([F:69])=[CH:67][CH:66]=[CH:65][C:64]=3[F:70])[C:52]=2[N:53]=[C:54]([S:56][CH3:57])[N:55]=1>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([C:50]2[C:51]3[CH:61]=[CH:60][C:59](=[O:62])[N:58]([C:63]4[C:68]([F:69])=[CH:67][CH:66]=[CH:65][C:64]=4[F:70])[C:52]=3[N:53]=[C:54]([S:56][CH3:57])[N:55]=2)[CH:3]=1

Participants

10

Reactant 6

HCID 7095BiphenylHCID 8471TriethylamineHCID 1188893-Iodo-p-toluidineHCID 6364989PinacolboraneHCID 119515134-Chloro-2-methylsulfanyl-8-(2,6-difluorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-oneHCID 17749109Barium hydroxide, octahydrate

Product 1

HCID 592126794-(5-amino-2-methylphenyl)-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-oneYield 80.3%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 3-iodo-4-methylaniline (110.0 mg, 0.47 mmol) in dioxane (1.0 mL) was added (under argon) triethylamine (0.26 mL, 1.86 mmol), palladium diacetate (5.2 mg, 0.023 mmol), 2-(dicyclophexyl phosphino) biphenyl (33.0 mg, 0.093 mmol), and pinacolborane (0.20 mL, 1.40 mmol). The mixture was stirred at about 80° C. for about 1 hour, cooled to room temperature (rt), and added with water (0.2 mL), barium hydroxide octahydrate (440.0 mg, 1.40 mmol) and 4-chloro-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (180.0 mg, 0.47 mmol). The mixture was heated at about 100° C. under stirring for about 1 hour, cooled to room temperature, filtered through celite, and diluted with brine (5.0 mL). The mixture was then extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. Purification via the CombiFlash system then afforded the title compound (155.0 mg, 75%): LC-MS m/z 411 (M+H)+, 2.60 min (ret. time).

Workup

  1. temperaturecooled to room temperature (rt)
  2. temperatureThe mixture was heated at about 100° C.
  3. stirringunder stirring for about 1 hour
  4. temperaturecooled to room temperature
  5. filtrationfiltered through celite
  6. additiondiluted with brine (5.0 mL)
  7. extractionThe mixture was then extracted with CH2Cl2 (3×10 mL)
  8. dry with materialThe combined organic phases were dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customPurification via the CombiFlash system

Sources & evidence

ORD record
ord-b35000c270a04566af2d6062f5ff9a44
Source dataset
uspto-grants-2012_06
Patent number
US08207176B2

Linked notes

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