Triethylamine → 1-Tert-butoxycarbonyl-4-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]piperazine

HRID 1896051Notes

Reaction equation

HRID 1896051 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[C:39]([F:40])=[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])[C:39]([F:40])=[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 106791065,6-difluoro-1H-benzimidazole-2-thiol

Product 1

HCID 117110271-Tert-butoxycarbonyl-4-[2-(5,6-difluorobenzimidazol-2-ylthio)ethyl]piperazineYield 67.8%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1-tert-butoxycarbonyl-4-(2-hydroxyethyl)piperazine (7.40 g, 32.13 mmol) in THF (100 mL), triethylamine (4.36 g, 43.09 mmol), 4-dimethylaminopyridine (200 mg, 1.64 mmol) and methanesulfonyl chloride (7.40 g, 38.76 mmol) were successively added under ice cooling and stirring. The temperature of the reaction mixture was allowed to rise to room temperature, at which the reaction mixture was stirred for 50 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (200 mL). At room temperature, 5,6-difluoro-2-mercaptobenzimidazole (5.00 g, 26.86 mmol), potassium carbonate (8.64 g, 62.51 mmol) and 18-crown-6 (500 mg, 1.92 mmol) were successively added, followed by stirring at 80° C. for 90 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (silica gel: 200 g; developer: hexane:acetone=8:1→1:1). Crystallization was conducted from acetone-ethyl ether-hexane to obtain the title compound (7.26 g, yield: 680) as colorless crystals.

Workup

  1. customto rise to room temperature, at which
  2. stirringwas stirred for 50 minutes
  3. filtrationThe reaction mixture was filtered
  4. concentrationthe filtrate was concentrated under reduced pressure
  5. dissolutionThe residue was dissolved in DMF (200 mL)
  6. stirringby stirring at 80° C. for 90 minutes
  7. concentrationThe reaction mixture was concentrated under reduced pressure
  8. customthe residue was purified by column chromatography on silica gel (silica gel: 200 g; developer: hexane:acetone=8:1→1:1)
  9. customCrystallization

Sources & evidence

ORD record
ord-ea9b02149c3f4f47bcfd81c9110ca5e3
Source dataset
uspto-grants-2013_08
Patent number
US08518936B2

Reaction notes

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