Potassium Carbonate → 1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazole

HRID 2178348Notes

Reaction equation

HRID 2178348 reaction equation
[F:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:16]([O:29][CH3:30])=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12](I)=[CH:13][C:8]=2[N:7]=[CH:6]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[OH-].[NH4+].[Cu]I>[F:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:16]([O:29][CH3:30])=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:13][C:8]=2[N:7]=[CH:6]1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 531671-MethylpiperazineHCID 145742L-ProlineHCID 1181140131-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-1H-benzo[d]imidazole

Product 1

HCID 1180098051-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazoleYield 32.3%

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 1-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-5-iodo-1H-benzo[d]imidazole (0.20 g, 0.39 mmol) in dimethyl sulfoxide (4 mL) was added 1-methylpiperazine (0.039 g, 0.39 mmol), copper(I) iodide (0.009 g, 0.046 mmol), potassium carbonate (0.19 g, 1.35 mmol), and L-proline (0.010 g, 0.092 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. The organic phase was washed with water (2×15 mL), brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute) provided 0.062 g of impure material. Subsequent re-purification via Prep-HPLC afforded 0.030 g (16%) of the product as a solid: 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=2.0 Hz, 1H), 7.88 (s, 1H), 7.65 (dd, J=8.5, 2.5 Hz, 1H) 7.33 (d, J=2.1 Hz, 1H), 7.29-7.22 (m, 2H), 7.07-6.99 (m, 1H), 6.78-6.69 (m, 2H), 6.56 (d, J=7.1 Hz, 1H), 5.30 (s, 2H), 5.00 (s, 2H), 3.94 (s, 3H), 3.69 (s, 3H), 3.25-3.18 (m, 4H), 2.71-2.59 (m, 4H), 2.39 (s, 3H) ppm; (M+1)=492.

Workup

  1. temperatureto cool to room temperature
  2. extractionThe mixture was extracted with dichloromethane
  3. washThe organic phase was washed with water (2×15 mL), brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customChromatographic purification (CombiFlash, 40 g SiO2 column, 1-5% methanol/dichloromethane elute)

Sources & evidence

ORD record
ord-72a7084a2fe84a6ba531c586752bd351
Source dataset
uspto-grants-2015_06
Patent number
US09067914B1

Reaction notes

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