Acetic Acid → 2-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione

HRID 561936Notes

Reaction equation

HRID 561936 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]1)[C:5]2=[O:24].[CH3:25]C(O)=O.[NH2:29][CH2:30][C@@H:31]([OH:42])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[CH3:41].C[CH2:44][N:45](CC)CC.[CH2:50]1[CH2:54][O:53][CH2:52][CH2:51]1>O.C1CC=CCC=1.CO.[Ni]>[CH3:41][C:35]1[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=1[O:33][CH2:32][C@H:31]([OH:42])[CH2:30][NH:29][C:51]1[CH:52]=[CH:44][NH:45][C:54](=[O:53])[C:50]=1[C:25]1[NH:1][C:2]2[C:10]([N:11]=1)=[CH:9][C:8]1[C:7](=[O:14])[N:6]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]3)[C:5](=[O:24])[C:4]=1[CH:3]=2

Participants

10

Reactant 5

HCID 176Acetic AcidHCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 2133977(2R)-1-amino-3-(2,4-dimethylphenoxy)propan-2-olHCID 597619885-Amino-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6-nitro-isoindole-1,3-dione

Product 1

HCID 1362003262-{4-[(R)-3-(2,4-Dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-1H-1,3,6-triaza-s-indacene-5,7-dione

Reagents, catalysts & solvents 4

HCID 935NickelCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 123431,4-CyclohexadieneSolvent

Procedure

To a solution of 5-amino-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-6-nitro-isoindole-1,3-dione (40 mg, 0.12 mmol) in THF (6 mL) was added Raney Ni in H2O (1 mL) and cyclohexa-1,4-diene (800 μL). After it was stirred at the room temperature for 30 min, the reaction mixture was loaded directly on the top of a column and washed with CH2Cl2/MeOH/28% aqueous NH4OH (90:10:1). The residue obtained from evaporation of the wash was mixed with 4-iodo-2-methoxynicotinicaldehyde (34 mg, 0.13 mmol) and AcOH (0.5 mL) in MeOH (10 mL). The mixture was stirred at the room temperature for 64 h, concentrated under reduced pressure, mixed with 4 M HCl/dioxane (8 mL) and H2O (0.6 mL), heated at 50° C. for 1.5 h, and concentrated under reduced pressure to give a crude, which was subjected to HPLC purification to furnish a fluorescent product in TFA salt form. (R)-1-Amino-3-(2,4-dimethyl-phenoxy)-propan-2-ol (45 mg, 0.24 mmol) and Et3N (70 μL, 0.5 mmol) were added into the solution of this fluorescent product and the mixture was evaporated after 17.5 h of heating at 80° C. The residual crude was subjected to HPLC to afford the title compound in TFA salt form (7.86 mg, 9.2%). 1H NMR (DMSO-d6) δ 2.13 (s, 3H, CH3), 2.19 (s, 3H, CH3), 3.02-4.05 (16H), 4.15 (m, 1H), 5.35 (br s, 1H, OH), 5.53 (br s, 1H, OH), 6.23 (d, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H), 6.92 (d, J=7 Hz, 1H), 6.98 (s, 1H), 7.39 (d, J=7 Hz, 1H), 7.65 (s, 1H), 8.11 (s, 1H), 9.78 (br s, 1H, NH), 10.94 (br s, 1H, NH), 11.30 (br s, 1H, NH); ESI-MS m/z 602.5 (MH+).

Workup

  1. washwashed with CH2Cl2/MeOH/28% aqueous NH4OH (90:10:1)
  2. customThe residue obtained from evaporation of the wash
  3. stirringThe mixture was stirred at the room temperature for 64 h
  4. concentrationconcentrated under reduced pressure
  5. additionmixed with 4 M HCl/dioxane (8 mL) and H2O (0.6 mL)
  6. temperatureheated at 50° C. for 1.5 h
  7. concentrationconcentrated under reduced pressure
  8. customto give a crude, which
  9. customwas subjected to HPLC purification
  10. customto furnish a fluorescent product in TFA salt form
  11. customthe mixture was evaporated after 17.5 h
  12. temperatureof heating at 80° C

Sources & evidence

ORD record
ord-19e41fe57f9e4ad78f1ab05f50f47644
Source dataset
uspto-grants-2011_11
Patent number
US08063225B2

Reaction notes

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