1,2-Dichloroethane → (3R)-3-(4-bromobenzyl)-N-{(1S)-2-[(3R)-3-cyanopiperidin-1-yl]-1-methyl-2-oxoethyl}-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamide

HRID 1040538Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1040538
[Br:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@@:7]2([CH3:32])[N:11]3[C:12]([C:15]([NH:17][C@@H:18]([CH3:22])[C:19]([OH:21])=[O:20])=[O:16])=[CH:13][N:14]=[C:10]3[N:9]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)[C:8]2=[O:31])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH:42]1[CH2:47][CH2:46][CH2:45][C@@H:44]([C:48]#[N:49])[CH2:43]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCN(CC)CC.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@@:7]2([CH3:32])[N:11]3[C:12]([C:15]([NH:17][C@H:18]([CH3:22])[C:19]([N:42]4[CH2:47][CH2:46][CH2:45][C@@H:44]([C:48]#[N:49])[CH2:43]4)=[O:21])=[O:16])=[CH:13][N:14]=[C:10]3[N:9]([C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)[C:8]2=[O:31])=[CH:4][CH:3]=1.[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]2([CH3:32])[N:11]3[C:12]([C:15]([NH:17][C@@H:18]([CH3:22])[C:19]([N:42]4[CH2:47][CH2:46][CH2:45][C@@H:44]([C:48]#[N:49])[CH2:43]4)=[O:20])=[O:16])=[CH:13][N:14]=[C:10]3[N:9]([C:23]3[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=3)[C:8]2=[O:31])=[CH:33][CH:34]=1

Komponenten

10

Edukt 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 58431145(S)-2-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acidHCID 67390990(R)-piperidine-3-carbonitrile trifluoroacetic acid

Produkt 2

HCID 58431118(3R)-3-(4-bromobenzyl)-N-{(1S)-2-[(3R)-3-cyanopiperidin-1-yl]-1-methyl-2-oxoethyl}-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamideHCID 67389892(3R)-3-(4-bromobenzyl)-N-{(1R)-2-[(3R)-3-cyanopiperidin-1-yl]-1-methyl-2-oxoethyl}-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamide

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 142844-(Dimethylamino)pyridineKatalysatorHCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 8471TriethylamineLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

To a solution of (S)-2-{[(R)-5-(4-bromo-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid (2.7 g, 4.8 mmol) in DMF (5 mL) and Et3N (2 mL) was added (R)-piperidine-3-carbonitrile trifluoroacetic acid (1.1 g, 4.8 mmol), HOBt (0.64 g, 4.8 mmol), EDC (0.91 g, 4.8 mmol) and DMAP (0.010 g, 0.082 mmol). The reaction was heated at 80° C. for 5 h. The mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with EtOAc (3×100 mL) and the combined extracts were washed with water, brine (2×100 mL) and dried with MgSO4. The mixture was filtered, concentrated in vacuo and purified by flash chromatography on silica gel. The resulting residue (200 mg) was dissolved in MeOH and purified by reverse phase HPLC to give 12 mg of (3R)-3-(4-bromobenzyl) —N-{(1R)-2-[(3R)-3-cyanopiperidin-1-yl]-1-methyl-2-oxoethyl}-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamide (eluted first), m/z 659.3 [M+1]+ and 15 mg of (3R)-3-(4-bromobenzyl)-N-{(1S)-2-[(3R)-3-cyanopiperidin-1-yl]-1-methyl-2-oxoethyl}-1-(3,5-dichlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[1,2-a]imidazole-5-carboxamide m/z 659.3 [M+1]+.

Aufarbeitung

  1. temperatureThe mixture was cooled to room temperature
  2. extractionThe mixture was extracted with EtOAc (3×100 mL)
  3. washthe combined extracts were washed with water, brine (2×100 mL)
  4. dry with materialdried with MgSO4
  5. filtrationThe mixture was filtered
  6. concentrationconcentrated in vacuo
  7. custompurified by flash chromatography on silica gel
  8. dissolutionThe resulting residue (200 mg) was dissolved in MeOH
  9. custompurified by reverse phase HPLC

Quellen und Nachweise

ORD-Eintrag
ord-e48b36731fe84a56ab34f86c23c86c7f
Quelldatensatz
uspto-grants-2013_10
Patentnummer
US08552205B2

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