Triethylamine → 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamide

HRID 383573

Reaktionsgleichung

Reaktionsgleichung von HRID 383573
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]([CH2:18][CH3:19])[C:15](=[O:20])[C:14]([C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=3[CH3:30])[C:24]([OH:26])=O)=[N:13][C:12]=2[CH:11]=[N:10]1.C(Cl)(=O)C(Cl)=O.[NH2:38][C:39]1[CH:43]=[CH:42][O:41][N:40]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[N:16]([CH2:18][CH3:19])[C:15](=[O:20])[C:14]([C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([F:31])[C:29]=3[CH3:30])[C:24]([NH:38][C:39]3[CH:43]=[CH:42][O:41][N:40]=3)=[O:26])=[N:13][C:12]=2[CH:11]=[N:10]1

Komponenten

8

Edukt 5

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 516892Sodium BicarbonateHCID 18102163-IsoxazolamineHCID 671996043-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoic acid

Produkt 1

HCID 671981413-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamide

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideKatalysatorHCID 6344DichloromethaneLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

A solution of 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoic acid (360 mg, 0.84 mmol) in 5.0 mL of DCM was treated with oxalyl chloride (0.84 mL of 2.0 M in DCM solution, 1.68 mmol) followed by two drops of DMF while cooling in an ice bath at 0° C. It was stirred at this temperature for 15 min then allowed to stir at RT for 45 min. The reaction mixture was then concentrated under reduce pressure to remove the excess oxalyl chloride. The residue was dissolved in 5.0 mL of DCM, treated with 3-aminoisoxazole (212 mg, 2.52 mmol) followed by Et3N (0.18 mL, 1.26 mmol) and stirred for 18 h. The reaction mixture was treated with 15 mL saturated NaHCO3 and extracted with DCM (2×15 mL). The combined DCM layers were dried over MgSO4. Purification on the ISCO (12 g column, 20-70% EtOAc in hexanes) afforded 3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamide as a light yellow amorphous solid. MS (ES+): 495.1 (M+H)+.

Aufarbeitung

  1. stirringto stir at RT for 45 min
  2. concentrationThe reaction mixture was then concentrated
  3. customto remove the excess oxalyl chloride
  4. dissolutionThe residue was dissolved in 5.0 mL of DCM
  5. stirringstirred for 18 h
  6. extractionextracted with DCM (2×15 mL)
  7. dry with materialThe combined DCM layers were dried over MgSO4
  8. customPurification on the ISCO (12 g column, 20-70% EtOAc in hexanes)

Quellen und Nachweise

ORD-Eintrag
ord-308e5bef9c7f427f972533c1ae6a1c9d
Quelldatensatz
uspto-grants-2013_02
Patentnummer
US08367671B2

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