Acetamidine monohydrochloride → 10-Bromo-9-fluoro-3-[5-methyl-2-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide

HRID 575098Notes

Reaction equation

HRID 575098 reaction equation
[NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[Br:6][C:7]1[C:8]([F:25])=[CH:9][C:10]2[O:16][CH2:15][CH2:14]N3C(I)=[C:18]([C:20]([NH2:22])=[O:21])[N:19]=[C:12]3[C:11]=2[CH:24]=1.Cl.[C:27]([NH2:30])(=N)[CH3:28].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[F:73][C:74]([F:79])([F:78])[CH2:75]NN>CN(C=O)C.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C.C(N(CC)CC)C>[Br:6][C:7]1[C:8]([F:25])=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:3]3[C:4]([C:5]4[N:1]([CH2:75][C:74]([F:79])([F:78])[F:73])[N:2]=[C:27]([CH3:28])[N:30]=4)=[C:18]([C:20]([NH2:22])=[O:21])[N:19]=[C:12]3[C:11]=2[CH:24]=1

Participants

11

Reactant 5

HCID 67170Acetamidine monohydrochlorideHCID 787402,2,2-TrifluoroethylhydrazineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 8669305210-Bromo-9-fluoro-3-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamideHCID 178418936HCID 178418936, compound

Product 1

HCID 8669312810-Bromo-9-fluoro-3-[5-methyl-2-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide

Reagents, catalysts & solvents 5

HCID 167845palladium(II) acetateCatalystHCID 176Acetic AcidSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
80 °C

Procedure

Title compound was prepared following the carbonylative triazole synthesis procedure (referred herein as Procedure I as described in: Staben, S. T.; Blaquiere, N Angew. Chem. Int. Ed. 2010, 49, p. 325. To a solution of 10-bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (300 mg, 0.66 mmol) and acetamidine hydrochloride (1.50 equiv., 99.1 mg, 0.99 mmol) in DMF (3.3 mL, 0.2M) was added triethylamine (0.66 mL, 1.0 mL/mmol). The solution was purged with nitrogen gas. Palladium (II) acetate (0.05 equiv., 7.4 mg) and xantphos (0.05 equiv., 19.8 mg) were added and the flask was purged with a carbon monoxide balloon. The reaction was heated to 80° C. for 2 hours. The CO balloon was removed and the reaction mixture was cooled to room temperature. 2,2,2-trifluoroethylhydrazine (70% in H2O, 3.0 equiv., 0.25 mL) and acetic acid (2.6 mL, 4 mL/mmol) were added and the mixture was heated to 80° C. for 1 hour. The reaction was cooled to room temperature, diluted with methylene chloride and filtered over celite. 1N NaOH was added and the solution was extracted with methylene chloride 3×. The organic layers were combined, dried with Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to give a yellow solid (282 mg).

Workup

  1. customThe solution was purged with nitrogen gas
  2. customthe flask was purged with a carbon monoxide balloon
  3. customThe CO balloon was removed
  4. temperaturethe reaction mixture was cooled to room temperature
  5. temperaturethe mixture was heated to 80° C. for 1 hour
  6. temperatureThe reaction was cooled to room temperature
  7. filtrationfiltered over celite
  8. addition1N NaOH was added
  9. extractionthe solution was extracted with methylene chloride 3×
  10. dry with materialdried with Na2SO4
  11. concentrationconcentrated
  12. customThe crude residue was purified by flash column chromatography (10-100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-b95aeed105a74fa58e49abb2a6e03cea
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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