N-Isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino)-acetamide → 2-[3-(1H-indol-2-ylmethyl)-3-methoxy-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl) acetamide

HRID 343203Notes

Reaction equation

HRID 343203 reaction equation
[CH:1]([N:4]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:5](=[O:21])[CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:3])[CH3:2].C(OC([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1[CH2:46][C:47]([O:54][CH3:55])([C:51](Cl)=[O:52])[C:48](Cl)=[O:49])=O)(C)(C)C>C1COCC1>[NH:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[C:38]1[CH2:46][C:47]1([O:54][CH3:55])[C:48](=[O:49])[N:7]([CH2:6][C:5]([N:4]([CH:1]([CH3:3])[CH3:2])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:51]1=[O:52]

Participants

4

Reactant 2

HCID 10644060N-Isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino)-acetamideHCID 541779232-(N-tert-butoxycarbonyl-1H-indol-2-ylmethyl)-2-methoxy-malonyl dichloride

Product 1

HCID 676964312-[3-(1H-indol-2-ylmethyl)-3-methoxy-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl) acetamideYield 12.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 0.76 g (2.0 mmol) of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Intermediate 43, in 10 mL of THF is added dropwise to a solution of 1.0 g (2.4 mmol) of 2-(N-tert-butoxycarbonyl-1H-indol-2-ylmethyl)-2-methoxy-malonyl dichloride in 35 mL of THF. The brown solution is heated at reflux for 1 d. After removal of THF in vacuo the residue is diluted with 100 mL of 1N HCl and extracted with EtOAc (×2). the organic extract is washed with 1N HCl, brine, sat. NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to a brown foam. Purification by silica gel flash chromatography (30-50% EtOAc/petroleum ether) followed by reverse phase C-18 MPLC (70-80% methanol/H2O) gave 0.15 g of the title compound as a white powder: 1H NMR (d6 -DMSO 300 MHz) δ10.78 (s,1H), 7.57 (d, 1H, J=6), 7.5-6.9 (m, 16H), 6.69 (d, 1H, J=8), 4.82 (m, 1H), 4.26 (m, 2H), 3.79 (s, 3H), 3.56 (q, 2H, J=16), 0.99 (t, 6H, J=7); low resolution MS (FAB) m/e 617 (MH+).

Workup

  1. temperatureThe brown solution is heated
  2. temperatureat reflux for 1 d
  3. customAfter removal of THF in vacuo the residue
  4. additionis diluted with 100 mL of 1N HCl
  5. extractionextracted with EtOAc (×2)
  6. extractionthe organic extract
  7. washis washed with 1N HCl, brine, sat. NaHCO3 and brine
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated in vacuo to a brown foam
  10. customPurification by silica gel flash chromatography (30-50% EtOAc/petroleum ether)

Sources & evidence

ORD record
ord-797fb04cb4284bef8429b7dff1239fd1
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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