Carbon Dioxide → 4-[[(1H-indol-4-yl)methylamino]carbonyl]amino-2,6-dimethylbenzoic acid, methyl ester

HRID 1058456Notes

Reaction equation

HRID 1058456 reaction equation
COC(C1C(C)=CC(C(O)=O)=CC=1C)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)=O.[CH3:45][C:46]1[CH:47]=[C:48]([N:57]=[C:58]=[O:59])[CH:49]=[C:50]([CH3:56])[C:51]=1[C:52]([O:54][CH3:55])=[O:53].Cl.[NH:61]1[C:69]2[CH:68]=[CH:67][CH:66]=[C:65]([CH2:70][NH2:71])[C:64]=2[CH:63]=[CH:62]1>C1C=CC=CC=1>[NH:61]1[C:69]2[C:64](=[C:65]([CH2:70][NH:71][C:58]([NH:57][C:48]3[CH:49]=[C:50]([CH3:56])[C:51]([C:52]([O:54][CH3:55])=[O:53])=[C:46]([CH3:45])[CH:47]=3)=[O:59])[CH:66]=[CH:67][CH:68]=2)[CH:63]=[CH:62]1

Participants

8

Reactant 6

HCID 280Carbon DioxideHCID 81531Diisopropylethylamine2×HCID 199401P,P-Diphenylphosphinic azideHCID 158568511-Methyl 2,6-dimethyl-1,4-benzenedicarboxylateHCID 186730533,5-Dimethyl-4-(methoxycarbonyl)phenylisocyanateHCID 226614481H-indole-4-methanamine hydrochloride

Product 1

HCID 865863334-[[(1H-indol-4-yl)methylamino]carbonyl]amino-2,6-dimethylbenzoic acid, methyl ester

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent2×

Conditions

Temperature
75 °C

Procedure

In an inert atmosphere, a solution of 4-(methoxycarbonyl)-3,5-dimethylbenzoic acid (2.08 g, 10 mmol), diphenylphosphoryl azide (2.8 g, 10.17 mmol) and diisopropylethylamine (1.92 mL, 11 mmol) in benzene (25 mL) is stirred at room temperature for 1 h, then the reaction temperature is slowly raised to 75° C. The reaction is held at that temperature until the evolution of gas (CO2) is no longer evident and the reaction solution containing 3,5-dimethyl-4-(methoxycarbonyl)phenylisocyanate is cooled to 40° C. Another portion of diisopropylethylamine (1.92 mL, 11 mmol) is added, followed by 1H-indole-4-methanamine hydrochloride salt (Example 68; 2.95 g, 11 mmol) and the solution is stirred and heated at reflux under argon overnight. The reaction mixture is cooled, diluted with benzene (50 mL) and washed in turn with 1N hydrochloric acid (50 mL) and dilute brine. The aqueous layers are re-extracted with benzene and the combined extracts are dried (MgSO4) and evaporated under reduced pressure. The product is purified if necessary by crystallization or by chromatography over silica gel using increasing concentrations of ethyl acetate in hexane to furnish the urea, 4-[[(1H-indol-4-yl)methylamino]carbonyl]amino-2,6-dimethylbenzoic acid, methyl ester.

Workup

  1. temperatureis cooled to 40° C
  2. temperatureheated
  3. temperatureat reflux under argon overnight
  4. temperatureThe reaction mixture is cooled
  5. washwashed in turn with 1N hydrochloric acid (50 mL) and dilute brine
  6. extractionThe aqueous layers are re-extracted with benzene
  7. dry with materialthe combined extracts are dried (MgSO4)
  8. customevaporated under reduced pressure
  9. customThe product is purified if
  10. customnecessary by crystallization
  11. temperatureby chromatography over silica gel using increasing concentrations of ethyl acetate in hexane

Sources & evidence

ORD record
ord-497752eb64194bc3b6f585ae7320c399
Source dataset
uspto-grants-2003_02
Patent number
US06515124B2

Reaction notes

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