1,1'-Carbonyldiimidazole → HCID 68799027, compound

HRID 2405852Notes

Reaction equation

HRID 2405852 reaction equation
[CH3:1][O:2][C:3]([C:5]1([NH:10][C:11]([CH:13]2[CH2:17][CH:16]([OH:18])[CH2:15][N:14]2[C:19](=[O:34])[CH:20]([NH:25][C:26]([O:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:27])[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:12])[CH2:7][CH:6]1[CH:8]=[CH2:9])=[O:4].C1N=CN([C:40]([N:42]2[CH:46]=N[CH:44]=[CH:43]2)=[O:41])C=1.[F:47][C:48]1C=[CH:55][CH:54]=[C:53]2[C:49]=1CNC2>C(Cl)Cl>[CH:29]1([O:28][C:26]([NH:25][CH:20]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]([N:14]2[CH:13]([C:11](=[O:12])[NH:10][C:5]3([C:3]([O:2][CH3:1])=[O:4])[CH2:7][CH:6]3[CH:8]=[CH2:9])[CH2:17][CH:16]([O:18][C:40]([N:42]3[CH2:43][C:44]4[C:55](=[CH:54][CH:53]=[CH:49][C:48]=4[F:47])[CH2:46]3)=[O:41])[CH2:15]2)=[O:34])=[O:27])[CH2:30][CH2:31][CH2:32][CH2:33]1

Participants

5

Reactant 3

HCID 682631,1'-CarbonyldiimidazoleHCID 147958674-fluoro-2,3-dihydro-1H-isoindoleHCID 68616309HCID 68616309, compound

Product 1

HCID 68799027HCID 68799027, compoundYield 79%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

1-{[1-(2-Cyclopentyloxycarbonylamino-3,3-dimethyl-butyryl)-4-hydroxy-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid methyl ester (530 mg, 1.11 mmol) was dissolved in CH2Cl2 (11 mL) and treated with CDI (234 mg, 1.44 mmol). After stirring overnight at room temperature, 4-fluoro-2,3-dihydro-1H-isoindole (762 mg, 5.56 mmol) was added and the reaction mixture was stirred overnight. The reaction was then diluted with CH2Cl2 and sequentially washed with 1N HCl, saturated aqueous NaHCO3, H2O and saturated aqueous NaCl. The organic phase was then dried over sodium sulfate. After removal of solvent, the crude product was purified by column chromatography on silica (40→60% EtOAc/Hexanes) to provide 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid 1-(2-cyclopentyloxycarbonylamino-3,3-dimethyl-butyryl)-5-(1-methoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester (563 mg, 79% yield). 1H NMR (CDCl3, 300 MHz) δ 7.77 (bd, 1H), 6.92-7.27 (m, 3H), 5.75 (m, 1H), 5.29 (m, 2H), 5.15 (m, 2H), 4.55-4.85 (m, 5H), 4.26 (m, 2H), 3.70 (m, 1H), 3.67 (s, 3H), 2.82 (m, 1H), 2.56 (m, 1H), 2.10 (m, 1H), 1.87 (m, 1H), 1.40-1.65 (m, 5H), 1.02 (s, 9H). LCMS found 643.3 [M+H]+.

Workup

  1. stirringthe reaction mixture was stirred overnight
  2. washsequentially washed with 1N HCl, saturated aqueous NaHCO3, H2O and saturated aqueous NaCl
  3. dry with materialThe organic phase was then dried over sodium sulfate
  4. customAfter removal of solvent
  5. customthe crude product was purified by column chromatography on silica (40→60% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-d8d432c439994aa18e62f3345f61e687
Source dataset
uspto-grants-2014_08
Patent number
US08809267B2

Reaction notes

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