Hydrochloric Acid → {4-[3-(4-Cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-phenyl}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone

HRID 220871Notes

Reaction equation

HRID 220871 reaction equation
CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.O1CCOCC1.[CH:32]1([N:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][O:44][C:45]3[CH:53]=[CH:52][C:48]([C:49]([OH:51])=O)=[CH:47][C:46]=3[F:54])[CH2:37][CH2:36]2)[CH2:34][CH2:33]1.[CH3:55][N:56]1[C:65]2[NH:64][C:63]3[CH:66]=[CH:67][CH:68]=[CH:69][C:62]=3[NH:61][CH2:60][C:59]=2[CH:58]=[N:57]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:32]1([N:35]2[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][CH2:43][O:44][C:45]3[CH:53]=[CH:52][C:48]([C:49]([N:61]4[CH2:60][C:59]5[CH:58]=[N:57][N:56]([CH3:55])[C:65]=5[NH:64][C:63]5[CH:66]=[CH:67][CH:68]=[CH:69][C:62]4=5)=[O:51])=[CH:47][C:46]=3[F:54])[CH2:39][CH2:40]2)[CH2:33][CH2:34]1

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 575552724-[3-(4-Cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-benzoic AcidHCID 1357419771-Methyl-1,4,5,10-tetrahydrobenzo[b]pyrazolo[3,4-e][1,4]diazepine

Product 1

HCID 135736005{4-[3-(4-Cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-phenyl}-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanoneYield 15%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

HBTU (325 mg, 0.9 mmol) and 4M HCl in dioxan (0.45 ml, 1.8 mmol) were added to a solution of 4-[3-(4-cyclopropyl-piperazin-1-yl)-propoxy]-3-fluoro-benzoic acid from Example E48.3 (230 mg, 0.7 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 30 min. 3-Methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E65 (186 mg, 0.9 mmol) and DIEA (pH=9) were added and the mixture was stirred at room temperature for 18 h. The mixture was heated at 60° C. for 3 h then HBTU (300 mg, 0.8 mmol) was added. The mixture was heated at 60° C. for 2 days then solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in EtOAc, washed with saturated Na—HCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a brown solid identified as the title compound (55 mg, 15%).

Workup

  1. stirringthe mixture was stirred at room temperature for 18 h
  2. temperatureThe mixture was heated at 60° C. for 3 h
  3. temperatureThe mixture was heated at 60° C. for 2 days
  4. customsolvents were removed in vacuo
  5. customazeotroped with toluene
  6. dissolutionThe residue was redissolved in EtOAc
  7. washwashed with saturated Na—HCO3
  8. dry with materialbrine, dried
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane)
  11. customto give a brown solid

Sources & evidence

ORD record
ord-444eeef82eeb4035bd75bf767c579d0c
Source dataset
uspto-grants-2012_06
Patent number
US08202858B2

Reaction notes

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