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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
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 717318
[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
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

6

Edukt 3

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

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228
Dimethylformamide
Lösungsmittel
HCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

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

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-cee5da80b20f4b85985909f532f472ee
Quelldatensatz
uspto-grants-2015_11
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09193717B2

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