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

HRID 449163Notes

Reaction equation

HRID 449163 reaction equation
[C:1]([C:3]1[CH:37]=[CH:36][C:6]([CH2:7][C@@:8]2([CH3:35])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([OH:24])=O)[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[C:28](F)=[C:27]([Cl:33])[CH:26]=3)[C:9]2=[O:34])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[I:71][C:72]1[CH:73]=[CH:74][C:75]([C:78]2([NH2:81])[CH2:80][CH2:79]2)=[N:76][CH:77]=1>CN(C=O)C.CCOC(C)=O>[I:71][C:72]1[CH:73]=[CH:74][C:75]([C:78]2([NH:81][C:22]([C:19]3([NH:18][C:16]([C:13]4[N:12]5[C@@:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:37][CH:36]=6)([CH3:35])[C:9](=[O:34])[N:10]([C:25]6[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:33])[CH:26]=6)[C:11]5=[N:15][CH:14]=4)=[O:17])[CH2:20][CH2:21]3)=[O:24])[CH2:79][CH2:80]2)=[N:76][CH:77]=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 584311461-(5-Iodo-pyridin-2-yl)-cyclopropylamineHCID 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 67390272(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid {1-[1-(5-iodo-pyridin-2-yl)-cyclopropyl-carbamoyl]-cyclopropyl}-amideYield 90%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1-{[(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}-cyclopropane-carboxylic acid (1.21 g, 2.32 mmol), HATU (970 mg, 2.55 mmol) and diisopropyl-ethylamine (808 μL, 4.64 mmol) in DMF (4 mL) was added 1-(5-iodo-pyridin-2-yl)-cyclopropylamine (724 mg, 2.78 mmol). The mixture was stirred for 1.5 h and then diluted with EtOAc (30 mL). The layers were separated and the organic layer was washed with water (3×30 mL) and brine (1×25 mL), dried with MgSO4, filtered, and concentrated to afford a crude solid. The crude material was purified by flash chromatography on silica gel, eluting with 50% hexanes in ethyl acetate (and increasing polarity to 75% ethyl acetate) to afford 1.60 g of the title compound:

Workup

  1. customThe layers were separated
  2. washthe organic layer was washed with water (3×30 mL) and brine (1×25 mL)
  3. dry with materialdried with MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto afford a crude solid
  7. customThe crude material was purified by flash chromatography on silica gel
  8. washeluting with 50% hexanes in ethyl acetate (and increasing polarity to 75% ethyl acetate)

Sources & evidence

ORD record
ord-2ce62d0018184b879a544367c2a1f756
Source dataset
uspto-grants-2013_07
Patent number
US08481750B2

Reaction notes

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