2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 3-(3-{3-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid ethyl ester

HRID 410363Notes

Reaction equation

HRID 410363 reaction equation
[CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=3)[C:16]2=[NH:32])[CH:6]=1)[CH3:2].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:74]1([C:87]2[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=2)[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=1[CH2:80][N:81]1[CH2:86][CH2:85][NH:84][CH2:83][CH2:82]1>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N:84]4[CH2:85][CH2:86][N:81]([CH2:80][C:75]5[CH:76]=[CH:77][CH:78]=[CH:79][C:74]=5[C:87]5[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=5)[CH2:82][CH2:83]4)=[CH:27][CH:26]=3)[C:16]2=[NH:32])[CH:6]=1)[CH3:2]

Participants

8

Reactant 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 183819371-Biphenyl-2-ylmethyl-piperazineHCID 23676156Sodium t-butoxideHCID 585649753-(3-{3-(4-Bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid ethyl ester

Product 1

HCID 585649503-(3-{3-[4-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid ethyl esterYield 6.2%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
120 °C

Procedure

To a mixture of 3-{3-[3-(4-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid ethyl ester (0.50 g, 0.99 mmol), sodium tert-butoxide (0.26 g, 2.67 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (33 mg, 0.07 mmol) and Pd(OAc)2 (22 mg, 0.10 mmol) at rt was added a degassed solution of 1-biphenyl-2-ylmethyl-piperazine (0.25 g, 0.99 mmol) in toluene (15 ml) and tert-butanol (3 ml). The reaction was heated to 120° C. where it was maintained fro 3 d. After this time, the reaction was cooled to rt and concentrated under reduced pressure. The material that remained was partitioned between H2O and EtOAc and the organic phase was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with EtOAc/hexane provided 3-(3-{3-[4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid ethyl ester (42 mg, 6%). HPLC-MS 680 [M+1]+, 341.

Workup

  1. temperaturewas maintained fro 3 d
  2. temperatureAfter this time, the reaction was cooled to rt
  3. concentrationconcentrated under reduced pressure
  4. customThe material that remained was partitioned between H2O and EtOAc
  5. customthe organic phase was separated
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customPurification by chromatography on silica eluting with EtOAc/hexane

Sources & evidence

ORD record
ord-f4898e43b09d4c29aff8a98cca58806b
Source dataset
uspto-grants-2014_06
Patent number
US08759520B2

Reaction notes

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