Diisopropylethylamine → (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid{1-[(R)-1-(6-bromo-pyridin-3-yl)-ethylcarbamoyl]-cyclopropyl}-amide

HRID 2038752Notes

Reaction equation

HRID 2038752 reaction equation
Cl.[Br:2][C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH2:11])[CH3:10])=[CH:5][CH:4]=1.[C:12]([C:14]1[CH:48]=[CH:47][C:17]([CH2:18][C@@:19]2([CH3:46])[N:23]3[C:24]([C:27]([NH:29][C:30]4([C:33](O)=[O:34])[CH2:32][CH2:31]4)=[O:28])=[CH:25][N:26]=[C:22]3[N:21]([C:36]3[CH:41]=[C:40]([Cl:42])[C:39]([F:43])=[C:38]([Cl:44])[CH:37]=3)[C:20]2=[O:45])=[CH:16][CH:15]=1)#[N:13].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Br:2][C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:11][C:33]([C:30]2([NH:29][C:27]([C:24]3[N:23]4[C@@:19]([CH2:18][C:17]5[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:48][CH:47]=5)([CH3:46])[C:20](=[O:45])[N:21]([C:36]5[CH:41]=[C:40]([Cl:42])[C:39]([F:43])=[C:38]([Cl:44])[CH:37]=5)[C:22]4=[N:26][CH:25]=3)=[O:28])[CH2:32][CH2:31]2)=[O:34])[CH3:10])=[CH:5][CH:4]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 53487712(R)-1-(6-bromo-pyridin-3-yl)-ethylamine HCl saltHCID 673908991-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid

Product 1

HCID 88959123(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid{1-[(R)-1-(6-bromo-pyridin-3-yl)-ethylcarbamoyl]-cyclopropyl}-amideYield 108%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of the above (R)-1-(6-bromo-pyridin-3-yl)-ethylamine HCl salt (500 mg, 1.82 mmol) in DMF (10 mL) was added 1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid (900 mg, 1.66 mmol) and diisopropylethylamine (1.45 mL, 8.30 mmol). The mixture was stirred at room temperature for 5 min. HATU (694 mg, 1.83 mmol) was added to the mixture and the clear yellow mixture was stirred for 17 h. The mixture was diluted with ethyl acetate (35 mL) and washed with water (8 mL). The organic phase was washed with 5% aqueous NaCl solution (2×10 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to pale yellow oil. The crude oil was purified via flash chromatography on silica gel, eluting with 1-6% MeOH/CH2Cl2, to afford 1.3 g of the title compound as a yellow foam.

Workup

  1. stirringthe clear yellow mixture was stirred for 17 h
  2. washwashed with water (8 mL)
  3. washThe organic phase was washed with 5% aqueous NaCl solution (2×10 mL) and brine (20 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated to pale yellow oil
  7. customThe crude oil was purified via flash chromatography on silica gel
  8. washeluting with 1-6% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-da362cfc7e34475f951cf7bb9389d5e8
Source dataset
uspto-grants-2013_11
Patent number
US08575360B2

Reaction notes

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