Aniline → (S)-1-[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide

HRID 2374790Notes

Reaction equation

HRID 2374790 reaction equation
[C:1]([C:3]1[CH:43]=[CH:42][C:6]([CH2:7][C@@:8]2([CH3:41])[N:12]3[C:13]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([NH:26][C@H:27]([CH3:31])[C:28](O)=O)=[O:25])(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:32]3[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=3)[C:9]2=[O:40])=[CH:5][CH:4]=1)#[N:2].CN(C([O:51]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)[CH:71]([CH3:73])[CH3:72].NC1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl.C1COCC1.Cl.O>[OH:51][C:71]1[CH:73]=[CH:28][C:27]([NH:26][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:19]2[S:16]([C:13]2[N:12]3[C@@:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:43][CH:42]=4)([CH3:41])[C:9](=[O:40])[N:10]([C:32]4[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=4)[C:11]3=[N:15][CH:14]=2)(=[O:18])=[O:17])=[O:25])=[CH:31][CH:72]=1

Participants

10

Reactant 5

HCID 6115AnilineHCID 81531DiisopropylethylamineHCID 2724141Tetrabutylammonium FluorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 12136436(R)-2-({(S)-1-[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carbonyl}-amino)-propionic acid

Product 1

HCID 12136441(S)-1-[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amideYield 62.4%

Reagents, catalysts & solvents 4

HCID 313Hydrochloric AcidCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

(S)-1-[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid (see Example 5) (122 mg, 0.2 mmol) was dissolved in methylene chloride (2 mL) under a nitrogen atmosphere. HATU (121 mg, 0.3 mmol) and DIPEA (111 μL, 0.64 mmol) were added. The t-butyldimethylsilyl-(TBDMS-) protected aniline (71 mg, 0.3 mmol) was added and the reaction was stirred overnight. The solvent was evaporated and the resulting residue chromatographed over silica gel (gradient EtOAc/hexanes) to provide a white solid. The white solid was dissolved in methylene chloride (2 mL) and a 1.0 M solution in THF of tetrabutylammonium fluoride (TBAF) (1 mL) was added and the reaction stirred for 3 h. Water and a few drops of 1 N HCl were added and the layers separated. The organic layer was dried over sodium sulfate, filtered, and evaporated. The resulting residue was chromatographed over silica gel (25% EtOAc in methylene chloride) to provide 83 mg of the title compound as a white solid (M+1, 665.2).

Workup

  1. additionwas added
  2. customThe solvent was evaporated
  3. customthe resulting residue chromatographed over silica gel (gradient EtOAc/hexanes)
  4. customto provide a white solid
  5. stirringthe reaction stirred for 3 h
  6. customthe layers separated
  7. dry with materialThe organic layer was dried over sodium sulfate
  8. filtrationfiltered
  9. customevaporated
  10. customThe resulting residue was chromatographed over silica gel (25% EtOAc in methylene chloride)

Sources & evidence

ORD record
ord-321cb804d7364de0b31df181e12965c2
Source dataset
uspto-grants-2008_12
Patent number
US07462637B2

Reaction notes

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