Triethylamine → 5-(3-(Cyclopropylamino)-6-methylbenzo[d]isoxazol-7-yl)-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

HRID 910253Notes

Reaction equation

HRID 910253 reaction equation
[CH:1]1([NH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[C:13](I)[C:8]=3[O:7][N:6]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CC1(C)C(C)(C)OBO1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.Br[C:59]1[C:64](=[O:65])[N:63]([CH3:66])[C:62]2[N:67]([C:70]3[C:75]([F:76])=[CH:74][CH:73]=[CH:72][C:71]=3[F:77])[N:68]=[CH:69][C:61]=2[CH:60]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[CH:1]1([NH:4][C:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[C:13]([C:59]4[C:64](=[O:65])[N:63]([CH3:66])[C:62]5[N:67]([C:70]6[C:75]([F:76])=[CH:74][CH:73]=[CH:72][C:71]=6[F:77])[N:68]=[CH:69][C:61]=5[CH:60]=4)[C:8]=3[O:7][N:6]=2)[CH2:3][CH2:2]1

Participants

11

Reactant 7

HCID 8471TriethylamineHCID 10340Sodium CarbonateHCID 14798Sodium HydroxideHCID 27347684,4,5,5-Tetramethyl[1,3,2]dioxaborolaneHCID 27349382-(Dicyclohexylphosphino)-2'-methylbiphenylHCID 46197691HCID 46197691, compoundHCID 58702151N-cyclopropyl-7-iodo-6-methylbenzo[d]isoxazol-3-amine

Product 1

HCID 250526715-(3-(Cyclopropylamino)-6-methylbenzo[d]isoxazol-7-yl)-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of N-cyclopropyl-7-iodo-6-methylbenzo[d]isoxazol-3-amine (0.100 g, 0.32 mmol), triethylamine (0.17 ml, 1.25 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.95 ml of 1.0 M in THF solution, 0.95 mmol), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (0.023 g, 0.065 mmol) and palladium acetate (0.0036 g, 0.016 mmol) in 2.0 mL of dioxane in a sealed glass tube was heated in a microwave at 100° C. for 20 min. After cooling to RT, the reaction mixture was transferred to a 50 mL round-bottom flask and treated with 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (0.089 g, 0.26 mmol) and sodium carbonate (1.0 mL of 2.0 M aqueous solution). Tetakis(triphenylphosphine)palladium (0) (9 mg) was added, and the reaction mixture was heated at 110° C. in an oil bath for 5 h. It was cooled to RT, treated with 5 mL of 1 N NaOH and 60 mL of EtOAc. The organic phase was separated, washed with brine, separated from the aqueous layer, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on SiO2(EtOAc/hexane=80/20) to give the title compound as a yellow crystalline solid. MS (ESI, pos.ion) m/z: 448.1 (M+1).

Workup

  1. temperatureAfter cooling to RT
  2. customthe reaction mixture was transferred to a 50 mL round-bottom flask
  3. temperaturethe reaction mixture was heated at 110° C. in an oil bath for 5 h
  4. temperatureIt was cooled to RT
  5. customThe organic phase was separated
  6. washwashed with brine
  7. customseparated from the aqueous layer
  8. dry with materialdried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe crude material was purified by flash chromatography on SiO2(EtOAc/hexane=80/20)

Sources & evidence

ORD record
ord-45268a6d6fca45f887b9cbf043ac9261
Source dataset
uspto-grants-2011_09
Patent number
US08022085B2

Reaction notes

Loading…