Sodium hydride → (5-chloropyridin-2-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

HRID 575894Notes

Reaction equation

HRID 575894 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1.[CH:12]([CH:15]1[C:20]2[N:21]=[CH:22][NH:23][C:19]=2[CH2:18][CH2:17][N:16]1[C:24](OCC(Cl)(Cl)Cl)=[O:25])([CH3:14])[CH3:13]>C1COCC1>[CH:12]([CH:15]1[C:20]2[N:21]=[CH:22][NH:23][C:19]=2[CH2:18][CH2:17][N:16]1[C:24]([O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][N:8]=1)=[O:25])([CH3:14])[CH3:13]

Participants

5

Reactant 3

HCID 24758Sodium hydride2×HCID 20537893(5-Chloropyridin-2-yl)methanol2×HCID 451108382,2,2-Trichloroethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

Product 1

HCID 58408390(5-chloropyridin-2-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylateYield 1.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

NaH (80.0 mg, 2.00 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL), the suspension was cooled to 0° C. and 5-chloropyridine-2-methanol (0.29 g, 2.00 mmol) was added. The suspension was stirred at 0° C. for 30 min then added to a solution of Intermediate 2 (0.65 g, 2.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and 5-chloropyridine-2-methanol in THF were added after 2 and 3 d, respectively. After 4 d the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The solvents were removed in vacuo and the residue was dissolved in EtOAc (100 mL) washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5% and 10% MeOH in DCM (200 mL each)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 20% to 80% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 to give (5-chloropyridin-2-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (7.91 mg, 1.2%) as a white solid.

Workup

  1. stirringthe reaction mixture was stirred at room temperature
  2. customAfter 4 d the reaction mixture was quenched with water (10 mL)
  3. customthe solvents were removed in vacuo
  4. customThe solvents were removed in vacuo
  5. dissolutionthe residue was dissolved in EtOAc (100 mL)
  6. washwashed with 1 M aq Na2CO3 solution (4×100 mL)
  7. dry with materialdried (MgSO4)
  8. customthe solvents were removed in vacuo
  9. customThe residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5% and 10% MeOH in DCM (200 mL each))
  10. customphase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 20% to 80% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid))

Sources & evidence

ORD record
ord-8a0fee44494b42548c315650661c8f5f
Source dataset
uspto-grants-2015_05
Patent number
US09035066B2

Reaction notes

Loading…