Acetic Acid → 1-{4-[4-(4-Chloro-benzyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine

HRID 410349Notes

Reaction equation

HRID 410349 reaction equation
[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br.[F:16][C:17]1[CH:45]=[CH:44][C:20]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]([CH2:34][C:35]3[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=3)[C:26]2=[NH:43])=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:39][C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:27]4[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[N:25]([CH2:24][CH2:23][CH2:22][O:21][C:20]5[CH:19]=[CH:18][C:17]([F:16])=[CH:45][CH:44]=5)[C:26]4=[NH:43])=[CH:42][CH:41]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 1348264-ChlorobenzylpiperazineHCID 5003444Sodium cyanoborohydrideHCID 867624844-{3-[3-(4-Fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzaldehyde hydrobromide salt

Product 1

HCID 585649581-{4-[4-(4-Chloro-benzyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamineYield 11.7%

Reagents, catalysts & solvents 2

HCID 962WaterCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
55 °C

Procedure

To a solution of 1-(4-chloro-benzyl)-piperazine (70 mg, 0.33 mmol) in THF (10 ml) was added 4-{3-[3-(4-fluoro-phenoxy)-propyl]-2-imino-2,3-dihydro-benzoimidazol-1-ylmethyl}-benzaldehyde, hydrobromide salt (0.20 g, 0.41 mmol), sodium cyanoborohydride (31 mg, 0.49 mmol), H2O (1 drop) and glacial acetic acid (0.068 ml). The reaction was warmed to 55° C. where it was maintained for 6 h. After this time, the mixture was cooled to rt and stirred for 16 h. The mixture was concentrated under reduced pressure and then partitioned between 1N HCl and EtOAc. The organic layer was removed and the aqueous phase was made basic using 10% K2CO3. The basic aqueous phase was extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with MeOH/dichloromethane provided 1-{4-[4-(4-chloro-benzyl)-piperazin-1-ylmethyl]-benzyl}-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (23 mg, 11%). HPLC-MS 598 [M+1]+, 300.

Workup

  1. temperaturewas maintained for 6 h
  2. temperatureAfter this time, the mixture was cooled to rt
  3. concentrationThe mixture was concentrated under reduced pressure
  4. custompartitioned between 1N HCl and EtOAc
  5. customThe organic layer was removed
  6. extractionThe basic aqueous phase was extracted with EtOAc
  7. dry with materialThe organic layer was dried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customPurification by chromatography on silica eluting with MeOH/dichloromethane

Sources & evidence

ORD record
ord-9d2adc9871bb4de7b303e4a4e5b3bdcf
Source dataset
uspto-grants-2014_06
Patent number
US08759520B2

Reaction notes

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