Imidazole → tert-butyl (R)-1-(4-(cyclohexylcarbamoyl)phenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate

HRID 1096651Notes

Reaction equation

HRID 1096651 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]3[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]4[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[CH:41]1([NH2:47])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1.N12CCCN=C1CCCCC2.N1C=CN=C1.C1C[O:67][CH2:66]C1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:41]1([NH:47][C:66]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:10][C:11]([N:13]3[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]4[N:23]([CH2:24][CH2:25][CH2:26][O:27][CH3:28])[C:22]5[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=5[N:20]=4)[CH2:14]3)=[O:12])=[CH:6][CH:7]=2)=[O:67])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1

Participants

7

Reactant 5

HCID 795ImidazoleHCID 7965CyclohexylamineHCID 8028TetrahydrofuranHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 66791560tert-butyl (R)-1-(4-bromophenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate

Product 1

HCID 66791757tert-butyl (R)-1-(4-(cyclohexylcarbamoyl)phenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamateYield 39%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
150 °C

Procedure

tert-Butyl (R)-1-(4-bromophenyl)-4-((R)-3-(1-(3-methoxypropyl)-11−1-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (6A) (as prepared in Example 6, Step A) (0.098 mmol, 0.060 g) was added to a 5 mL microwave vessel equipped for stirring. Cyclohexanamine (0.293 moles, 0.034 mL), palladium(II) acetate (0.01 mmol, 0.002 g), Mo(CO)6 (0.098 mmol, 0.026 g), 1,8 diazabicyclo[5.4.0]undec-7-ene (0.293 mmol, 0.044 mL), imidazole (0.049 mmol, 0.003 g), and THF (2 mL) were then added. The flask was sealed and heated to 150° C. for 15 min in the microwave. The reaction mixture was filtered over celite and the solid rinsed with THF (20 mL). The filtrate was collected and concentrated in-vacuo. This crude oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative LC/MS (20-80% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-butyl (R)-1-(4-(cyclohexylcarbamoyl)phenyl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (98A) as a clear colored oil (0.039 mmol, 0.025 g, 39% yield). ESI-MS: 660.4 m/z (M+H)+.

Workup

  1. customequipped
  2. customThe flask was sealed
  3. filtrationThe reaction mixture was filtered over celite
  4. washthe solid rinsed with THF (20 mL)
  5. customThe filtrate was collected
  6. concentrationconcentrated in-vacuo
  7. dissolutionThis crude oil was re-dissolved in methanol (3 mL)
  8. filtrationfiltered
  9. custompurified by preparative LC/MS (20-80% CH3CN in H2O)
  10. customThe resultant fractions were collected
  11. customthe solvent was removed in-vacuo

Sources & evidence

ORD record
ord-e96b6fcd2fe348d2ab68b77a9f4ef005
Source dataset
uspto-grants-2012_03
Patent number
US08138168B1

Reaction notes

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