1,3-Benzodioxole-5-carboxylic acid → 1-(Benzo[1,3]dioxol-5-yl)-3-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)urea

HRID 412345Notes

Reaction equation

HRID 412345 reaction equation
C(O)(=O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:20])C=CC=CC=1.C([N:32]([CH2:35]C)CC)C.Cl.Cl.[NH2:39][C:40]1[CH:41]=[C:42]([CH:70]=[CH:71][CH:72]=1)[O:43][C:44]1[CH:45]=[CH:46][C:47]2[N:51]=[C:50]([CH2:52][O:53][C:54]3[CH:67]=[CH:66][C:57]([CH2:58][CH:59]4[S:63][C:62](=[O:64])[NH:61][C:60]4=[O:65])=[CH:56][CH:55]=3)[N:49]([CH3:68])[C:48]=2[CH:69]=1>CN(C)C=O.C1(C)C=CC=CC=1>[O:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:32][C:35]([NH:39][C:40]3[CH:72]=[CH:71][CH:70]=[C:42]([O:43][C:44]4[CH:45]=[CH:46][C:47]5[N:51]=[C:50]([CH2:52][O:53][C:54]6[CH:67]=[CH:66][C:57]([CH2:58][CH:59]7[S:63][C:62](=[O:64])[NH:61][C:60]7=[O:65])=[CH:56][CH:55]=6)[N:49]([CH3:68])[C:48]=5[CH:69]=4)[CH:41]=3)=[O:20])=[CH:3][C:4]=2[O:5][CH2:6]1

Participants

7

Reactant 4

HCID 71961,3-Benzodioxole-5-carboxylic acidHCID 8471TriethylamineHCID 199401P,P-Diphenylphosphinic azideHCID 865877725-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride

Product 1

HCID 185376241-(Benzo[1,3]dioxol-5-yl)-3-(3-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)ureaYield 5.6%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of piperonylic acid (133 mg), diphenylphosphoryl azide (217 mg), triethylamine (314 mg) and anhydrous toluene (8 ml) was stirred at 80° C. for 1 hour. To the reaction mixture was added 5-[4-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) and anhydrous N,N-dimethylformamide (4 ml) at room temperature and the mixture was stirred at the same temperature for 1 hour and then allowed to stand overnight. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1→1:0 as the eluant. The product insoluble in a mixture of methanol and diisopropyl ether (5:1) was isolated by filtration and was further purified by preparative reverse phase high performance liquid chromatography using acetonitrile/water=50:50 as the eluant to afford the title compound (26 mg, mp 179.2-182.4° C.).

Workup

  1. stirringthe mixture was stirred at the same temperature for 1 hour
  2. waitto stand overnight
  3. concentrationThe reaction mixture was concentrated
  4. custompartitioned between ethyl acetate and water
  5. washThe extract was washed with saturated aqueous sodium chloride solution
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationconcentrated
  8. customThe residue was chromatographed on a silica gel column
  9. additionThe product insoluble in a mixture of methanol
  10. customdiisopropyl ether (5:1) was isolated by filtration
  11. customwas further purified by preparative reverse phase high performance liquid chromatography

Sources & evidence

ORD record
ord-b0c11f8d08bc412984da50e755ff0134
Source dataset
uspto-grants-2003_05
Patent number
US06562849B1

Reaction notes

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