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 1530643Notes

Reaction equation

HRID 1530643 reaction equation
[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

Participants

9

Reactant 4

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

Product 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]azuleneYield 76%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 176Acetic AcidSolventHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
40 °C

Procedure

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+].

Workup

  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

Sources & evidence

ORD record
ord-8426f00e3ba3486ba40bcda2936cdaac
Source dataset
uspto-grants-2015_07
Patent number
US09090628B2

Reaction notes

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