Ethyl Acetate → 2-Fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)benzenamine

HRID 522720Notes

Reaction equation

HRID 522720 reaction equation
[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][C:3]=1[NH2:4].FC(F)(F)S(O[C:25]1[C:36]([CH3:37])=[N:35][C:28]2[N:29]=[C:30]([S:33][CH3:34])[N:31]=[CH:32][C:27]=2[CH:26]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([C:25]2[C:36]([CH3:37])=[N:35][C:28]3[N:29]=[C:30]([S:33][CH3:34])[N:31]=[CH:32][C:27]=3[CH:26]=2)=[CH:5][C:3]=1[NH2:4]

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 690365482-Fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilineHCID 898092287-Methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate

Product 1

HCID 898136922-Fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)benzenamineYield 81%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
60 °C

Procedure

Combine 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (370 mg, 1.474 mmol), 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl trifluoromethanesulfonate (500 mg, 1.474 mmol) and K2CO3 (611 mg, 4.42 mmol) in dioxane (12 mL) and H2O (3 mL), sparge with argon, treat with Pd(PPh3)4 (85 mg, 0.074 mmol) and heat to 60° C. for 3 h. Cool the mixture to RT, stir overnight, treat with EtOAc and wash with brine. Filter the mixture, wash the organic layer again with brine, dry over Na2SO4, concentrate to dryness and purify via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). Combine fractions, remove the organics under reduced pressure and neutralize the aqueous residue with saturated. NaHCO3. Extract the mixture with EtOAc (2×), wash the combined organics with brine, dry over Na2SO4 and concentrate to dryness to afford the title compound as an amorphous solid (373 mg, 81%). MS (m/z): 315.1 (M+1).

Workup

  1. temperatureCool the mixture to RT
  2. washwash with brine
  3. filtrationFilter the mixture
  4. washwash the organic layer again with brine
  5. dry with materialdry over Na2SO4
  6. concentrationconcentrate to dryness
  7. custompurify via reverse-phase chromatography (MeCN/H2O with 0.1% TFA)
  8. customCombine fractions, remove the organics under reduced pressure
  9. extractionExtract the mixture with EtOAc (2×)
  10. washwash the combined organics with brine
  11. dry with materialdry over Na2SO4
  12. concentrationconcentrate to dryness

Sources & evidence

ORD record
ord-c12656869b09431db596b9911fed26cd
Source dataset
uspto-grants-2016_05
Patent number
US09334267B2

Reaction notes

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