Acetamidine monohydrochloride → 8-Chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene

HRID 1530643Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1530643
[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10](I)[N:11]=1)[CH2:7][CH2:6][O:5]2.Cl.[C:18]([NH2:21])(=[NH:20])[CH3:19].[C:22]1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Cl.[F:65][C:66]([F:71])([F:70])[CH2:67][NH:68]N>CN(C=O)C.C(O)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].CCN(CC)CC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][N:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:22]3[N:68]([CH2:67][C:66]([F:71])([F:70])[F:65])[N:21]=[C:18]([CH3:19])[N:20]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2

Komponenten

9

Edukt 4

HCID 67170Acetamidine monohydrochlorideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 21934076(2,2,2-Trifluoroethyl)hydrazine hydrochlorideHCID 582047809-Chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepine

Produkt 1

HCID 866523128-Chloro-2-[5-methyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azuleneAusbeute 76 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 167845palladium(II) acetateKatalysatorHCID 176Acetic AcidLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 8471TriethylamineLösungsmittel

Reaktionsbedingungen

Temperatur
40 °C

Versuchsvorschrift

A mixture of 12-chloro-4-iodo-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene (1.60 g, 4.60 mmol) and acetamidine hydrochloride (481 g, 5.06 mmol), Et3N (4.00 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 532 mg, 0.920 mmol), and Pd(OAc)2 (103 mg, 0.460 mmol) in DMF (20.0 mL) was heated under carbon monoxide atmosphere at 40° C. for 3 h. After cooling to room temperature, a solution of (2,2,2-trifluoroethyl)hydrazine hydrochloride (800 mg, 5.32 mmol) in acetic acid (15.0 mL) was added. The resultant mixture was further heated at 65° C. for 3 h. After concentratin, the residue was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.5% NH4HCO3 to give 12-chloro-4-[3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (1.35 mg, 76% yield) as pale yellow solid. LCMS (ESI) m/z: 385.1 [M+H+].

Aufarbeitung

  1. temperatureAfter cooling to room temperature
  2. extractionthe residue was extracted with ethyl acetate
  3. washwashed with brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customevaporated
  7. customThe crude product was purified by reverse phase Combiflash
  8. washeluting with a 0-40% gradient of CH3CN in 0.5% NH4HCO3

Quellen und Nachweise

ORD-Eintrag
ord-8426f00e3ba3486ba40bcda2936cdaac
Quelldatensatz
uspto-grants-2015_07
Patentnummer
US09090628B2

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