P-Toluic Acid → 1-(3-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-p-tolylurea

HRID 412343Notes

Reaction equation

HRID 412343 reaction equation
C[C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=O)=[CH:6][CH:7]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:18])C=CC=CC=1.C([N:30]([CH2:33]C)CC)C.Cl.Cl.[NH2:37][C:38]1[CH:39]=[C:40]([CH:68]=[CH:69][CH:70]=1)[O:41][C:42]1[CH:43]=[CH:44][C:45]2[N:49]=[C:48]([CH2:50][O:51][C:52]3[CH:65]=[CH:64][C:55]([CH2:56][CH:57]4[S:61][C:60](=[O:62])[NH:59][C:58]4=[O:63])=[CH:54][CH:53]=3)[N:47]([CH3:66])[C:46]=2[CH:67]=1>CN(C)C=O.C1(C)C=CC=CC=1>[O:62]=[C:60]1[NH:59][C:58](=[O:63])[CH:57]([CH2:56][C:55]2[CH:64]=[CH:65][C:52]([O:51][CH2:50][C:48]3[N:47]([CH3:66])[C:46]4[CH:67]=[C:42]([O:41][C:40]5[CH:39]=[C:38]([NH:37][C:33]([NH:30][C:2]6[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=6)=[O:18])[CH:70]=[CH:69][CH:68]=5)[CH:43]=[CH:44][C:45]=4[N:49]=3)=[CH:53][CH:54]=2)[S:61]1

Participants

7

Reactant 4

HCID 7470P-Toluic 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 185377251-(3-[2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]phenyl)-3-p-tolylureaYield 6.1%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of p-toluic acid (109 mg), diphenylphosphoryl azide (209 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 2.5 hours. 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=3/2→3/1→ethyl acetate as the eluant. The product insoluble in methanol was isolated by filtration and further purified by preparative reverse phase high performance liquid chromatography using acetonitrile:water=50:50→55:45→60:40 as the eluant to afford the title compound (27 mg, mp 173.0-175.2° C.).

Workup

  1. stirringthe mixture was stirred at the same temperature for 2.5 hours
  2. concentrationThe reaction mixture was concentrated
  3. custompartitioned between ethyl acetate and water
  4. washThe extract was washed with saturated aqueous sodium chloride solution
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated
  7. customThe residue was chromatographed on a silica gel column
  8. customThe product insoluble in methanol was isolated by filtration
  9. customfurther purified by preparative reverse phase high performance liquid chromatography

Sources & evidence

ORD record
ord-7c1002bf1f27429088100c5cb9d708e6
Source dataset
uspto-grants-2003_05
Patent number
US06562849B1

Reaction notes

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