Potassium Carbonate → tert-butyl 2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

HRID 706438Notes

Reaction equation

HRID 706438 reaction equation
I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH2:30]1[C:33]2([CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH2:32][NH:31]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[OH-].[NH4+].[Cu]I>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([N:31]3[CH2:30][C:33]4([CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]4)[CH2:32]3)=[CH:3][C:4]=2[N:8]=[CH:7]1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 145742L-ProlineHCID 24820512tert-Butyl 2,7-diazaspiro[3.5]nonane-7-carboxylateHCID 1181141105-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole

Product 1

HCID 118114062tert-butyl 2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylateYield 72.4%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolventHCID 14923Ammonium HydroxideSolvent

Conditions

Temperature
120 °C

Procedure

To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.61 g, 1.22 mmol) in dimethyl sulfoxide (4 mL) was added tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (0.30 g, 1.34 mmol), copper(I) iodide (0.028 g, 0.15 mmol), potassium carbonate (0.41 g, 2.94 mmol), and L-proline (0.034 g, 0.29 mmol). The light yellow reaction mixture was heated to 120° C. After 16 h, the reaction mixture was allowed to cool to room temperature and was diluted with 3 N ammonium hydroxide solution (20 mL). The mixture was extracted with dichloromethane, resulting in a thick emulsion. The emulsion was filtered through Celite to remove any insoluble material. The organic phase was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute) afforded 0.53 g (72%) of tert-butyl 2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate.

Workup

  1. temperatureto cool to room temperature
  2. extractionThe mixture was extracted with dichloromethane
  3. customresulting in a thick emulsion
  4. filtrationThe emulsion was filtered through Celite
  5. customto remove any insoluble material
  6. washThe organic phase was washed with water, brine
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customChromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute)

Sources & evidence

ORD record
ord-ee7f1ef577bf40e791ac8393cc0a5f48
Source dataset
uspto-grants-2015_11
Patent number
US09174986B2

Reaction notes

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