Triethylamine → HCID 25117148, compound

HRID 2088638Notes

Reaction equation

HRID 2088638 reaction equation
I[C:2]1[C:10]2[O:9][N:8]=[C:7]([NH:11][CH3:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:13].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.CC1(C)C(C)(C)OBO1.CCN(CC)CC.Br[C:57]1[C:58](=[O:75])[N:59]([CH3:74])[C:60]2[N:65]([C:66]3[CH:71]=[CH:70][C:69]([F:72])=[CH:68][C:67]=3[F:73])[N:64]=[CH:63][C:61]=2[N:62]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].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.O>[F:73][C:67]1[CH:68]=[C:69]([F:72])[CH:70]=[CH:71][C:66]=1[N:65]1[C:60]2[N:59]([CH3:74])[C:58](=[O:75])[C:57]([C:2]3[C:10]4[O:9][N:8]=[C:7]([NH:11][CH3:12])[C:6]=4[CH:5]=[CH:4][C:3]=3[CH3:13])=[N:62][C:61]=2[CH:63]=[N:64]1

Participants

11

Reactant 6

HCID 8471TriethylamineHCID 10340Sodium CarbonateHCID 27347684,4,5,5-Tetramethyl[1,3,2]dioxaborolaneHCID 27349382-(Dicyclohexylphosphino)-2'-methylbiphenylHCID 58245884HCID 58245884, compoundHCID 58702150HCID 58702150, compound2×

Product 1

HCID 25117148HCID 25117148, compound

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

The preparation of 7-iodo-N,6-dimethylbenzo[d]isoxazol-3-amine was disclosed in PCT Int. Appl. WO 2006094187 A2. A mixture of 7-iodo-N,6-dimethylbenzo[d]isoxazol-3-amine (250 mg, 0.87 mmol) followed by 2-(dicyclohexylphosphino)-2′-methylbiphenyl (63 mg, 0.17 mmol), Pd(OAc)2 (10 mg, 0.043 mmol) in 2.0 mL dioxane in a glass tube was treated with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.6 mL of 1.0 M in THF solution, 2.6 mmol) and Et3N (0.48 mL, 3.47 mmol) under argon. The glass tube was sealed and the reaction mixture was then heated in a microwave at 100° C. for 20 min. The reaction mixture was cooled to RT and transferred to a 20 mL of RBF, rinsing with 2 mL of THF. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (11.2 mg, 9.67 μmol), 5-bromo-1-(2,4-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (110 mg, 0.32 mmol; made in a manner similar to the method described in Example 1, Steps 1-3). It was cooled to 0° C. with an ice bath, and sodium carbonate (1.1 mL of 1.0 N solution) was added drop wise. The reaction mixture was stirred at RT for 5 min, and heated in an oil bath at 70° C. for 5 h. The reaction mixture was treated with water and extracted with EtOAc (2×20 mL). The combine EtOAc layers were washed with brine and dried over MgSO4, filtered and concentrated. Purification on the ISCO (12 g column, 25-90% EtOAc in hexanes) afforded 1-(2,4-difluorophenyl)-7-methyl-5-(6-methyl-3-(methylamino)benzo[d]isoxazol-7-yl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one as a light yellow amorphous solid. MS (ES+): 423.1 (M+H)+.

Workup

  1. customThe glass tube was sealed
  2. temperatureThe reaction mixture was cooled to RT
  3. washrinsing with 2 mL of THF
  4. temperatureIt was cooled to 0° C. with an ice bath
  5. temperatureheated in an oil bath at 70° C. for 5 h
  6. extractionextracted with EtOAc (2×20 mL)
  7. washThe combine EtOAc layers were washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customPurification on the ISCO (12 g column, 25-90% EtOAc in hexanes)

Sources & evidence

ORD record
ord-4b2d12ae3cfc428ead6b014fca6c5e14
Source dataset
uspto-grants-2013_05
Patent number
US08435987B2

Reaction notes

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