Potassium Carbonate → 1-[2-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-thiazol-4-ylmethyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine

HRID 410345Notes

Reaction equation

HRID 410345 reaction equation
Cl[C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([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:9]2=[NH:28])[N:6]=1.[C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.[Cu]I>[C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:36]1[CH2:37][CH2:38][N:39]([C:2]2[S:3][CH:4]=[C:5]([CH2:7][N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]([CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:9]3=[NH:28])[N:6]=2)[CH2:40][CH2:41]1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 183819371-Biphenyl-2-ylmethyl-piperazineHCID 585649551-(2-Chloro-thiazol-4-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine

Product 1

HCID 462404721-[2-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-thiazol-4-ylmethyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamineYield 8%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
190 °C

Procedure

To a solution of 1-(2-chloro-thiazol-4-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (30 mg, 0.072 mmol) in N-methylpyrrolidinone (2 ml) was added 1-biphenyl-2-ylmethyl-piperazine (18 mg, 0.072 mmol), CuI (14 mg, 0.072 mmol) and K2CO3 (15 mg, 0.11 mmol). The reaction was heated in a microwave at 190° C. for a total of 1.5 h. After this time, the suspension was cooled to rt and filtered through Celite®. The collected solids were washed with dichloromethane and then the combined filtrate and washings were washed with H2O. The aqueous phase was extracted with additional dichloromethane and the combined organic fractions were then washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC. The product was free-based by partitioning between a saturated solution of NaHCO3 and dichloromethane. The organic layer was then separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1-[2-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-thiazol-4-ylmethyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (3.6 mg, 8%). HPLC-MS 633 [M+1]+, 317 (100%).

Workup

  1. temperatureAfter this time, the suspension was cooled to rt
  2. filtrationfiltered through Celite®
  3. washThe collected solids were washed with dichloromethane
  4. washthe combined filtrate and washings were washed with H2O
  5. extractionThe aqueous phase was extracted with additional dichloromethane
  6. washthe combined organic fractions were then washed with brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated under reduced pressure
  10. customthe crude product was purified by preparative HPLC
  11. customby partitioning between a saturated solution of NaHCO3 and dichloromethane
  12. customThe organic layer was then separated
  13. dry with materialdried (Na2SO4)
  14. filtrationfiltered
  15. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-82e2ab4ea8e84eb888013b02f7f65b35
Source dataset
uspto-grants-2014_06
Patent number
US08759520B2

Reaction notes

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