Cesium carbonate → 3-(4-{4-[2-(4-Chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-5-fluoro-1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine

HRID 410359Notes

Reaction equation

HRID 410359 reaction equation
Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=3[N:9]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:8]2=[NH:28])=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[Cl:77][C:78]1[CH:83]=[CH:82][C:81]([C:84]2[CH2:89][CH2:88][C:87]([CH3:91])([CH3:90])[CH2:86][C:85]=2[CH2:92][N:93]2[CH2:98][CH2:97][NH:96][CH2:95][CH2:94]2)=[CH:80][CH:79]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:77][C:78]1[CH:83]=[CH:82][C:81]([C:84]2[CH2:89][CH2:88][C:87]([CH3:90])([CH3:91])[CH2:86][C:85]=2[CH2:92][N:93]2[CH2:94][CH2:95][N:96]([C:2]3[CH:30]=[CH:29][C:5]([CH2:6][N:7]4[C:11]5[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=5[N:9]([CH2:17][CH2:18][CH2:19][O:20][C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=5)[C:8]4=[NH:28])=[CH:4][CH:3]=3)[CH2:97][CH2:98]2)=[CH:80][CH:79]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 462408813-(4-Bromo-benzyl)-5-fluoro-1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamineHCID 585649441-((4'-Chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine

Product 1

HCID 585649723-(4-{4-[2-(4-Chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-5-fluoro-1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamineYield 45%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent2×

Conditions

Temperature
95 °C

Procedure

To a degassed solution of 3-(4-bromo-benzyl)-5-fluoro-1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (0.060 g, 0.11 mmol) in toluene (2 ml) at rt under nitrogen was added Pd(OAc)2 (0.9 mg, 4.0 μmol) and BINAP (4.7 mg, 7.6 μmol). Nitrogen was bubbled through the mixture for 10 min before a degassed solution of 1-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazine (49 mg, 0.15 mmol) in toluene (1 ml) was introduced. After 5 min Cs2CO3 (0.41 g, 1.27 mmol) was added. During all additions nitrogen was continuously bubbled through the reaction. Once the additions were completed the reaction vessel was sealed and then heated to 95° C. where it was maintained for 18 h. After this time, the reaction was cooled to rt and filtered through Celite® and the collected solids were washed with dichloromethane. The combined filtrate and washings were concentrated under reduced pressure and the crude product was purified by preparative HPLC. The purified product was partitioned between a saturated solution of NaHCO3 and dichloromethane and the organic phase was separated. The aqueous layer was extracted with additional dichloromethane and then the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 3-(4-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-5-fluoro-1-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (34 mg, 45%). HPLC-MS 710 [M+1]+, 348.

Workup

  1. additionwas introduced
  2. customDuring all additions nitrogen was continuously bubbled through the reaction
  3. customwas sealed
  4. temperaturewas maintained for 18 h
  5. temperatureAfter this time, the reaction was cooled to rt
  6. filtrationfiltered through Celite®
  7. washthe collected solids were washed with dichloromethane
  8. concentrationThe combined filtrate and washings were concentrated under reduced pressure
  9. customthe crude product was purified by preparative HPLC
  10. customThe purified product was partitioned between a saturated solution of NaHCO3 and dichloromethane
  11. customthe organic phase was separated
  12. extractionThe aqueous layer was extracted with additional dichloromethane
  13. washthe combined organic fractions were washed with brine
  14. dry with materialdried (Na2SO4)
  15. filtrationfiltered
  16. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-c36bc4a3dd64483c8cf65e98ff53e4a1
Source dataset
uspto-grants-2014_06
Patent number
US08759520B2

Reaction notes

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