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4-Chloro-1,2-diaminobenzene → (5R)-5-benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione

HRID 717318
Notes
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Reaction equation

HRID 717318 reaction equation
[CH2:1]([C:8]1([C:23]([O-])=O)[C:12](=[O:13])[N:11]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:10](=[O:22])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl:27][C:28]1[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@:8]1([C:23]2[NH:35][C:30]3[CH:29]=[C:28]([Cl:27])[CH:33]=[CH:32][C:31]=3[N:34]=2)[NH:9][C:10](=[O:22])[N:11]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:12]1=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 72634-Chloro-1,2-diaminobenzeneHCID 81531DiisopropylethylamineHCID 90386932Lithium 4-benzyl-2,5-dioxo-1-[(1R)-1-phenylethyl]imidazolidine-4-carboxylate

Product 1

HCID 71550675(5R)-5-benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione

Reagents, catalysts & solvents 2

HCID 6228
Dimethylformamide
Solvent
HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To the product from Step D (200 mg, 0.581 mmol), 4-chlorobenzene-1,2-diamine (91 mg, 0.639 mmol) in N,N-dimethylformamide (2.5 ml) was added N,N-diisopropylethylamine (0.152 mL, 0.871 mmol) and O-(7-azabensotriazol-1yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (265 mg, 0.697 mmol) sequentially. The reaction mixture was stirred for 16 h, diluted with ethyl acetate (50 mL), washed with water (2×10 mL), saturated aqueous brine (1×10 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo. LC/MS 463.0 (M+1). The crude residue was dissolved in acetic acid (5 ml) and heated at 80° C. for 1 h. The mixture was cooled and the solvent removed in vacuo. The residue was purified by column chromatography (silica gel 40 g column) eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give a mixture of diastereomers as a brown amorphous solid. The isomers were separated via chiral HPLC (ChiralPak AS-H; 40% 2:1 methanol:acetonitrile/carbon dioxide) to afford the first eluting isomer (5R)-5-benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione (1.9 minutes) and the second eluting isomer (5S)-5-benzyl-5-(6-chloro-1H-benzimidazol-2-yl)-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione (2.97 minutes) as colorless amorphous solids. LC/MS 445.0 (M+1). IC50 value=C rating

Workup

  1. washwashed with water (2×10 mL), saturated aqueous brine (1×10 mL)
  2. dry with materialdried with anhydrous sodium sulfate
  3. filtrationfiltered
  4. customthe solvent removed in vacuo
  5. dissolutionThe crude residue was dissolved in acetic acid (5 ml)
  6. temperatureThe mixture was cooled
  7. customthe solvent removed in vacuo
  8. customThe residue was purified by column chromatography (silica gel 40 g column)
  9. washeluting with ethyl acetate/hexane (gradient from 0% to 100%)
  10. customto give
  11. additiona mixture of diastereomers as a brown amorphous solid
  12. customThe isomers were separated via chiral HPLC (ChiralPak AS-H; 40% 2:1 methanol:acetonitrile/carbon dioxide)

Sources & evidence

ORD record
ord-cee5da80b20f4b85985909f532f472ee
Source dataset
uspto-grants-2015_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09193717B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes