(2,4-Difluoro-phenyl)-hydrazine → 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene

HRID 1848990Notes

Reaction equation

HRID 1848990 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]([NH2:17])=O)[S:8][C:7]=3[C:6]=2[N:18]=1.[CH3:19]C(N(C)C)=O.CN(C=O)C.[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[NH:38][NH2:39]>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:38]([C:32]5[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:31]=5[F:30])[N:39]=[CH:19][N:17]=4)[S:8][C:7]=3[C:6]=2[N:18]=1

Participants

6

Reactant 3

HCID 588958(2,4-Difluoro-phenyl)-hydrazineHCID 22628260N,N-dimethylformamide N,N-dimethylacetamide2×HCID 582039499-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylic acid amide

Product 1

HCID 579003099-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azuleneYield 67%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

To a suspension of 9-Chloro-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene-2-carboxylic acid amide (22 g, 76.8 mmol) in dry toluene (250 mL) was added DMA-DMF (56.1 g, 471.4 mmol). The resulting mixture was heated to 90° C. for 2 h. After removal of the solvent and excess of DMA-DMF, the residue (13.6 g, 94.3 mmol) was dissolved in acetic acid (250 mL) and (2,4-difluorophenyl)hydrazine (16.6 g, 115.2 mmol) was added into the mixture. The mixture was stirred at 90° C. for 2 hours. After removal of the solvents, the residue was treated with EtOAc-water (500 mL, 5:1 (v/v)). The mixture was neutralized with sodium bicarbonate aqueous solution until pH=7. The suspension was filtered and the solid was washed with EtOAc (500 mL). The combined organic layers were washed with saturate sodium bicarbonate aqueous solution (300 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to the crude product, which was purified by flash column (EtOAc/Hexanes=1:3) to give 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (21.4 g, yield: 67%) 1H NMR (DMSO, 400 MHz): δ8.35 (s, 1H), 7.98-7.48 (m, 4H), 7.39 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 4.38 (t, J=4.4 Hz, 2H), 3.2 (t, J=4.4 Hz, 2H). LC-MS (ESI): m/z=417 [M+H]+

Workup

  1. customAfter removal of the solvent
  2. customAfter removal of the solvents
  3. additionthe residue was treated with EtOAc-water (500 mL, 5:1 (v/v))
  4. filtrationThe suspension was filtered
  5. washthe solid was washed with EtOAc (500 mL)
  6. washThe combined organic layers were washed with saturate sodium bicarbonate aqueous solution (300 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated to the crude product, which
  10. customwas purified by flash column (EtOAc/Hexanes=1:3)

Sources & evidence

ORD record
ord-8580426c3fbe42248101167c00e811c7
Source dataset
uspto-grants-2015_02
Patent number
US08952043B2

Reaction notes

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