O-Phenylenediamine → 2-[3-(2-Amino-phenylcarbamoylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide

HRID 343195Notes

Reaction equation

HRID 343195 reaction equation
[CH:1]([C:4](C1C=CC=CC=1)(C(=O)N)[N:5]1[C:11](=[O:12])[C:10]([CH2:14][C:15]([OH:17])=O)([CH3:13])[C:9](=[O:18])[N:8](C2C=CC=CC=2)[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]1=2)([CH3:3])C.C(OC(C[C:49]1(CC(O)=O)[C:55](=[O:56])[N:54]([C:57]([CH:69](C)C)([C:61]2C=CC(OC)=CC=2)C(=O)N)[C:53]2[CH:72]=[CH:73][CH:74]=[CH:75][C:52]=2N(C2C=CC=CC=2)C1=O)=O)C1C=CC=CC=1.[C:87]1([NH2:94])[CH:92]=[CH:91][CH:90]=[CH:89][C:88]=1[NH2:93].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1C[CH2:107][CH2:106][CH2:105]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:93][C:88]1[CH:89]=[CH:90][CH:91]=[CH:92][C:87]=1[NH:94][C:15]([CH2:14][C:10]1([CH3:13])[C:9](=[O:18])[N:8]([CH2:49][C:55]([N:54]([CH:57]([CH3:61])[CH3:69])[C:53]2[CH:52]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[O:56])[C:7]2[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=2[N:5]([C:4]2[CH:107]=[CH:106][CH:105]=[CH:3][CH:1]=2)[C:11]1=[O:12])=[O:17]

Participants

7

Reactant 5

HCID 7243O-PhenylenediamineHCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 67696769[1-(isopropyl-phenyl-carbamoylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]acetic acidHCID 86753587{3-(Benzyloxycarbonyl-methyl)-1-[isopropyl-(4-methoxy-phenyl)-carbamoylmethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl}acetic acid

Product 1

HCID 676972962-[3-(2-Amino-phenylcarbamoylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

A stirring solution of 100 mg (0.20 mmol) of [1-(Isopropyl-phenyl-carbamoylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-acetic acid, prepared as in Intermediate 7, 32 mg (0.30 mmol, 1.5 equiv) of 1,2-phenylene diamine, 187 mg (0.40 mmol, 2.0 equiv) of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), and 80 mg (0.60 mmol, 3.0 equiv) of diisopropylethylamine in 2 mL of DMF is heated at 50° C. for 48 h. The DMF is removed in vacuo and the residue is dissolved in 20 mL of EtOAc and extracted with 20 mL 1N HCl. The organic layer is dried (MgSO4) and the solvent removed in vacuo. The resulting oil is purified by silica gel flash column chromatography using dichloromethane/MeOH 20/1 as eluent followed by further purification via reverse phase MPLC using a C-18 column and 60% acetonitrile/40% H2O with 0.1% TFA as eluent followed by lyophilization to afford 30 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ9.38 (s, 0.7H), 9.17 (s, 0.3H), 7.53-7.04 (m, 17H), 6.81 (d, 1H, J=4.7), 4.97 (m, 1H), 4.57 (d, 0.5H, J=16.6), 4.27 (s, br, 2H), 3.87 (d, 0.5H, J=16.6), 3.36 (d, 1H, J=15.6), 3.13 (d, 1H, J=15.6), 2.60 (d, 0.5H, J=15.3), 2.42 (d, 0.5H, J=15.3), 1.61 (s, 1H), 1.22 (s, 2H), 1.09 (m, 6H); low resolution MS (FAB)m/e 590 (MH+), 482.

Workup

  1. customThe DMF is removed in vacuo
  2. dissolutionthe residue is dissolved in 20 mL of EtOAc
  3. extractionextracted with 20 mL 1N HCl
  4. dry with materialThe organic layer is dried (MgSO4)
  5. customthe solvent removed in vacuo
  6. customThe resulting oil is purified by silica gel flash column chromatography
  7. customfollowed by further purification via reverse phase MPLC

Sources & evidence

ORD record
ord-a22dfe043c31444e85885ce42874c5b0
Source dataset
uspto-grants-1999_01
Patent number
US05859007

Reaction notes

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