Triethylamine → 1-Tert-butoxycarbonyl-4-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazine

HRID 1354258Notes

Reaction equation

HRID 1354258 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[F:29][C:30]1[CH:39]=[CH:38][C:33]2[N:34]=[C:35]([SH:37])[NH:36][C:32]=2[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:37][C:35]2[NH:36][C:32]3[CH:31]=[C:30]([F:29])[CH:39]=[CH:38][C:33]=3[N:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

9

Reactant 6

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 2855718-Crown-6HCID 31297Methanesulfonyl chlorideHCID 735736Tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylateHCID 34348856-fluoro-1H-benzimidazole-2-thiol

Product 1

HCID 231161621-Tert-butoxycarbonyl-4-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazineYield 73.4%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

1-tert-Butoxycarbonyl-4-(2-hydroxyethyl)piperazine (6.00 g, 26.05 mmol) was dissolved in THF (36 mL), and triethylamine (3.43 g, 33.90 mmol) and 4-dimethylaminopyridine (159 mg, 1.30 mmol) were added thereto. Under cooling with ice, a solution of methanesulfonyl chloride (3.58 g, 31.25 mmol) in THF (9 mL) was added dropwise to the mixture. The resultant mixture was stirred for one hour and then filtrated, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (90 mL). While the solution was stirred at room temperature, 5-fluoro-2-mercaptobenzimidazole (4.82 g, 28.66 mmol), potassium carbonate (5.40 g, 39.07 mmol), and 18-crown-6 (688 mg, 2.60 mmol) were sequentially added to the solution, and the resultant mixture was stirred for two hours at 80° C. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (silica gel 150 g, hexane:ethyl acetate=2:1 to 1:1 to 1:2), to thereby yield 1-tert-butoxycarbonyl-4-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazine (7.28 g, yield 73%).

Workup

  1. temperatureUnder cooling with ice
  2. filtrationfiltrated
  3. concentrationthe filtrate was concentrated under reduced pressure
  4. dissolutionThe residue was dissolved in DMF (90 mL)
  5. concentrationThe reaction mixture was concentrated under reduced pressure, and water
  6. additionwas added to the residue
  7. extractionfollowed by extraction with ethyl acetate
  8. washThe organic layer was washed with water and saturated brine
  9. dry with materialdried over sodium sulfate anhydrate
  10. concentrationfollowed by concentration under reduced pressure
  11. customThe residue was purified through silica gel column chromatography (silica gel 150 g, hexane:ethyl acetate=2:1 to 1:1 to 1:2)

Sources & evidence

ORD record
ord-cfa2cef59d3c46ebb15fc6b6f0725007
Source dataset
uspto-grants-2007_05
Patent number
US07223764B2

Reaction notes

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