Benzimidazole → HCID 59326866, compound

HRID 410277Notes

Reaction equation

HRID 410277 reaction equation
[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.C(OC(C)C)(OC(C)C)OC(C)C.C([O:25][C:26]([C:28]1[CH:53]=[CH:52][C:31]([O:32][C:33]2[C:38]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:30][CH:29]=1)=O)C.C([N-]C(C)C)(C)C.[Li+]>C1(C)C=CC=CC=1.C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:26]([C:28]1[CH:29]=[CH:30][C:31]([O:32][C:33]2[C:38]([CH:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:43][CH2:44]3)=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:52][CH:53]=1)=[O:25]

Participants

7

Reactant 4

HCID 5798BenzimidazoleHCID 78191Propane, 2,2',2''-[methylidynetris(oxy)]tris-HCID 2724682Lithium diisopropylamideHCID 59326865Tert-butyl 4-(2-(4-(ethoxycarbonyl)phenoxy)pyridin-3-YL)piperidine-1-carboxylate

Product 1

HCID 59326866HCID 59326866, compound

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of benzimidazole (0.351 g, 2.97 mmol) and triisopropyl orthoformate (3.9 mL, 17.61 mmol) in toluene (25 mL) was heated in a 100 mL round bottom flask equipped with a Dean-Stark trap and reflux condenser under an atmosphere of nitrogen. After 1 h the solvent was removed in vacuo. The residue was dissolved in THF (8 mL) and to the solution was added a solution of tert-butyl 4-(2-(4-(ethoxycarbonyl)phenoxy)pyridin-3-yl)piperidine-1-carboxylate (1.07 g, 2.509 mmol) in THF (8 mL). The mixture was cooled (−78° C.) and lithium diisopropylamide (2.0M solution in heptane/THF/ethylbenzene, 1.80 mL, 3.60 mmol) was added dropwise resulting in a reddish solution. After 2 h the reaction was quenched with saturated NH4Cl and allowed to warm to rt. The mixture was partitioned between EtOAc/saturated NaHCO3. The organic layer was washed with brine and dried over Na2SO4. The solution was filtered and the filtrate was evaporated onto silica gel and purified by flash chromatography (Isco, (120 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 499.1 (M+1). IC50 (uM) +++++.

Workup

  1. temperaturewas heated in a 100 mL round bottom flask
  2. customequipped with a Dean-Stark trap
  3. temperaturereflux condenser under an atmosphere of nitrogen
  4. customAfter 1 h the solvent was removed in vacuo
  5. dissolutionThe residue was dissolved in THF (8 mL) and to the solution
  6. additionwas added dropwise
  7. customresulting in a reddish solution
  8. customAfter 2 h the reaction was quenched with saturated NH4Cl
  9. customThe mixture was partitioned between EtOAc/saturated NaHCO3
  10. washThe organic layer was washed with brine
  11. dry with materialdried over Na2SO4
  12. filtrationThe solution was filtered
  13. customthe filtrate was evaporated onto silica gel
  14. custompurified by flash chromatography (Isco, (120 gram))
  15. washeluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97)
  16. customto give a white amorphous solid

Sources & evidence

ORD record
ord-f47c03a2673a48b4b90c6879ad9a5605
Source dataset
uspto-grants-2014_06
Patent number
US08759532B2

Reaction notes

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