Binap, (A+-)- → 3-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine

HRID 410358Notes

Reaction equation

HRID 410358 reaction equation
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.[C:47]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53][N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.Br[C:67]1[CH:95]=[CH:94][C:70]([CH2:71][N:72]2[C:76]3[CH:77]=[C:78]([CH3:81])[CH:79]=[CH:80][C:75]=3[N:74]([CH2:82][CH2:83][CH2:84][O:85][C:86]3[CH:91]=[CH:90][C:89]([F:92])=[CH:88][CH:87]=3)[C:73]2=[NH:93])=[CH:69][CH:68]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:47]1([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53][N:54]1[CH2:55][CH2:56][N:57]([C:67]2[CH:95]=[CH:94][C:70]([CH2:71][N:72]3[C:76]4[CH:77]=[C:78]([CH3:81])[CH:79]=[CH:80][C:75]=4[N:74]([CH2:82][CH2:83][CH2:84][O:85][C:86]4[CH:87]=[CH:88][C:89]([F:92])=[CH:90][CH:91]=4)[C:73]3=[NH:93])=[CH:69][CH:68]=2)[CH2:58][CH2:59]1

Participants

7

Reactant 4

HCID 634876Binap, (A+-)-HCID 183819371-Biphenyl-2-ylmethyl-piperazineHCID 23676156Sodium t-butoxideHCID 585649693-(4-Bromo-benzyl)-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydrobenzoimidazol-2-ylideneamine

Product 1

HCID 585649673-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydro-benzoimidazol-2-ylideneamineYield 11%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
130 °C

Procedure

3-(4-Bromo-benzyl)-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydrobenzoimidazol-2-ylideneamine, hydrobromide salt (20 mg, 0.036 mmol) was partitioned between aqueous NaOH and EtOAc. The organic phase was separated, dried (Na2SO4) and concentrated under reduced pressure to provide 3-(4-bromo-benzyl)-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydrobenzoimidazol-2-ylideneamine (0.036 mmol). To a degassed solution of Pd(OAc)2 (0.04 mg, 0.16 □mol) and BINAP (0.44 mg, 0.71 mmol) in toluene (8 ml) at 40° C. was added 1-biphenyl-2-ylmethyl-piperazine (18 mg, 0.071 mmol) followed by 3-(4-bromo-benzyl)-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydrobenzoimidazol-2-ylideneamine (0.036 mmol) and sodium t-butoxide (4.8 mg, 0.05 mmol). The suspension was then heated to 130° C. where it was maintained for 20 h. After this time, the mixture was filtered and then the filtrate was partitioned between H2O and EtOAc. The organic phase was separated and concentrated under reduced pressure to provide the crude product. Purification by preparative HPLC gave 3-[4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-1-[3-(4-fluoro-phenoxy)-propyl]-5-methyl-1,3-dihydro-benzoimidazol-2-ylideneamine (2.5 mg, 11%). HPLC-MS 640 [M+1]+, 320 (100%).

Workup

  1. temperaturewas maintained for 20 h
  2. filtrationAfter this time, the mixture was filtered
  3. customthe filtrate was partitioned between H2O and EtOAc
  4. customThe organic phase was separated
  5. concentrationconcentrated under reduced pressure
  6. customto provide the crude product
  7. customPurification by preparative HPLC

Sources & evidence

ORD record
ord-0acd23d7ee0a49cd964f7e9b55a36983
Source dataset
uspto-grants-2014_06
Patent number
US08759520B2

Reaction notes

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