Sodium hydride → pyrazin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

HRID 575895Notes

Reaction equation

HRID 575895 reaction equation
[H-].[Na+].[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][OH:10].[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23](OCC(Cl)(Cl)Cl)=[O:24])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23]([O:10][CH2:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][N:3]=1)=[O:24])([CH3:13])[CH3:12]

Participants

5

Reactant 3

HCID 24758Sodium hydride2×HCID 201734Pyrazinemethanol2×HCID 451108382,2,2-Trichloroethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

Product 1

HCID 45110980pyrazin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylateYield 10.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

NaH (0.22 g, 5.60 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL), cooled to 0° C. and pyrazin-2-yl methanol (0.49 mL, 5.00 mmol) was added. The suspension was stirred at 0° C. for 30 min and then added to a solution of Intermediate 2 (0.66 g, 2.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. An additional such portion of NaH and pyrazin-2-yl methanol in THF was added after 18 h. After 2 d the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo. The residue was dissolved in EtOAc (120 mL) and the organic layer was washed with 1 M aq Na2CO3 solution (6×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 100% (over 12 min) then 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 in DCM to give pyrazin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (62.9 mg, 10.4%) as a white solid.

Workup

  1. stirringthe reaction mixture was stirred at room temperature
  2. customAfter 2 d the reaction mixture was quenched with water (10 mL)
  3. customthe solvents were removed in vacuo
  4. dissolutionThe residue was dissolved in MeOH (10 mL)
  5. stirring1 M aq NaOH solution (10 mL) and the reaction mixture was stirred at room temperature for 2 h
  6. concentrationthen concentrated in vacuo
  7. dissolutionThe residue was dissolved in EtOAc (120 mL)
  8. washthe organic layer was washed with 1 M aq Na2CO3 solution (6×100 mL)
  9. dry with materialdried (MgSO4)
  10. customthe solvents were removed in vacuo
  11. customThe residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 100% (over 12 min)
  12. custom100% (over 3 min) MeOH in water (1% formic acid)

Sources & evidence

ORD record
ord-59d6fa085e354e9ebe5c0bff73e1e934
Source dataset
uspto-grants-2015_05
Patent number
US09035066B2

Reaction notes

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