Water → 5-(4-fluorophenyl)-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amine

HRID 706512Notes

Reaction equation

HRID 706512 reaction equation
I[C:2]1[CH:31]=[CH:30][C:5]2[N:6]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[CH3:11])[C:7]([NH2:9])=[N:8][C:4]=2[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:31]=[CH:30][C:5]3[N:6]([CH:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]5[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)=[C:14]([O:28][CH3:29])[CH:13]=4)[CH3:11])[C:7]([NH2:9])=[N:8][C:4]=3[CH:3]=2)=[CH:35][CH:34]=1

Participants

7

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 2856454-Fluorophenylboronic acidHCID 1181140505-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amine

Product 1

HCID 1180098365-(4-fluorophenyl)-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amineYield 152.9%

Reagents, catalysts & solvents 2

HCID 54751079XPhos PalladacycleCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a stirred solution of 5-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amine (Example 3-45-6) (0.195 g, 0.37 mmol), 4-fluorophenylboronic acid (0.064 g, 0.46 mmol), and potassium phosphate tribasic (0.413 g, 1.91 mmol) in tetrahydrofuran (5 mL)/water (4 mL) was added 2nd generation XPhos precatalyst (0.015 g, 0.018 mmol). The yellow solution was degassed under vacuum/backfilled with nitrogen (×3). The mixture was heated to 60° C. After 90 min, the mixture was treated with an additional portion of boronic acid (0.030 g) and precatalyst (0.014 g), and the temperature was increased to 75° C. After a total reaction time of 150 min, the brown mixture was allowed to cool to room temperature and was diluted with water (30 mL). The mixture was extracted with dichloromethane (3×25 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 0.282 g of a brown oil. Chromatographic purification (CombiFlash, 12 g SiO2 gold column, 1-5% 2M ammonia in methanol/dichloromethane elute) afforded 0.142 g (78%) of the product as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=2.4, 0.8 Hz, 1H), 7.68 (dd, J=8.4, 2.5 Hz, 1H), 7.62-7.52 (m, 3H), 7.23 (dd, J=8.4, 1.7 Hz, 1H), 7.17-7.06 (m, 3H), 6.96-6.88 (m, 2H), 6.81-6.79 (m, 1H), 6.78-6.74 (m, 1H), 5.58 (q, J=7.0 Hz, 1H), 5.05 (s, 2H), 4.49 (s, 2H), 3.93 (s, 3H), 3.76 (s, 3H), 1.88 (d, J=7.0 Hz, 3H) ppm; (M+1)=499.

Workup

  1. customThe yellow solution was degassed under vacuum/backfilled with nitrogen (×3)
  2. additionthe mixture was treated with an additional portion of boronic acid (0.030 g) and precatalyst (0.014 g)
  3. temperaturethe temperature was increased to 75° C
  4. customAfter a total reaction time of 150 min
  5. temperatureto cool to room temperature
  6. additionwas diluted with water (30 mL)
  7. extractionThe mixture was extracted with dichloromethane (3×25 mL)
  8. dry with materialThe combined organic phases were dried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-41e243a3799d4ad1a1712d727ca07f9f
Source dataset
uspto-grants-2015_11
Patent number
US09174986B2

Reaction notes

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