Potassium Carbonate → methyl 3-(4-{5-[(pyridin-3-ylmethylamino)carbonyl]-1H-benzimidazol-1-yl}phenoxy)cyclobutanecarboxylate

HRID 2111804Notes

Reaction equation

HRID 2111804 reaction equation
[OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH:62]2[CH2:65][CH:64]([C:66]([O:68][CH3:69])=[O:67])[CH2:63]2)(=O)=O)=CC=1>CN(C=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][NH:19][C:17]([C:15]2[CH:14]=[CH:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH:62]5[CH2:65][CH:64]([C:66]([O:68][CH3:69])=[O:67])[CH2:63]5)=[CH:3][CH:4]=4)[CH:9]=[N:10][C:11]=3[CH:16]=2)=[O:18])[CH:22]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 2855718-Crown-6HCID 12815113Methyl 3-{[(4-methylbenzene)sulfonyl]oxy}cyclobutane-1-carboxylateHCID 690682371-(4-Hydroxyphenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide

Product 1

HCID 69063376methyl 3-(4-{5-[(pyridin-3-ylmethylamino)carbonyl]-1H-benzimidazol-1-yl}phenoxy)cyclobutanecarboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

Methyl 3-hydroxycyclobutanecarboxylate (671 mg, 5.16 mmol) was dissolved in CH2Cl2 (20 mL). Pyridine (0.63 mL, 7.73 mmol) was then added followed by p-toluenesulfonic anhydride (1.85 g, 5.67 mmol) and the reaction was stirred at rt for 14 h. The reaction was concentrated in vacuo, dissolved in ether, and washed with H2O, 2M HCl, 2M NaHCO3, brine, and dried over MgSO4. The solution was then filtered, and concentrated in vacuo to give methyl 3-{[(4-methylphenyl)sulfonyl]oxy}cyclobutanecarboxylate as a colorless oil, which was taken on crude. 1-(4-Hydroxyphenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (0.88 g, 2.56 mmol), 18-crown-6 (1.36 g, 5.13 mmol), and K2CO3 (0.71 g, 5.13 mmol) were dissolved in DMF (26 mL) in a 50 mL round bottom flask. The reaction was heated to 80° C. under N2 atmosphere upon which methyl 3-{[(4-methylphenyl)sulfonyl]oxy}cyclobutanecarboxylate was added drop-wise. After heating at 80° C. for 48 h, the reaction was cooled to rt, concentrated in vacuo, and purified using silica gel chromatography (5% methanol:CH2Cl2). To remove residual p-toluenesulfonic acid and 18-crown-6, the foamy white solid was washed with ethyl acetate. The combined organic washes were then washed with water and dried over MgSO4, filtered, and concentrated in vacuo to provide methyl 3-(4-{5-[(pyridin-3-ylmethylamino)carbonyl]-1H-benzimidazol-1-yl}phenoxy)cyclobutanecarboxylate as an off-white foamy solid (3:1 trans:cis isomers). MS (ES+): m/z 457 (100) [MH+].

Workup

  1. additionwas added drop-wise
  2. temperaturethe reaction was cooled to rt
  3. concentrationconcentrated in vacuo
  4. custompurified
  5. customTo remove residual p-toluenesulfonic acid and 18-crown-6
  6. washthe foamy white solid was washed with ethyl acetate
  7. washThe combined organic washes were then washed with water
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c2e15770a1a742648cf06476ec9c39b8
Source dataset
uspto-grants-2009_04
Patent number
US07521448B2

Reaction notes

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