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 1040538Notes

Reaction equation

HRID 1040538 reaction equation
[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

Participants

10

Reactant 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

Product 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

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
80 °C

Procedure

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]+.

Workup

  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

Sources & evidence

ORD record
ord-e48b36731fe84a56ab34f86c23c86c7f
Source dataset
uspto-grants-2013_10
Patent number
US08552205B2

Reaction notes

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