Piconol → pyridin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

HRID 575891Notes

Reaction equation

HRID 575891 reaction equation
[H-].[Na+].[N:3]1[CH:8]=[CH:7][CH: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]=[CH:6][CH:7]=[CH:8][N:3]=1)=[O:24])([CH3:13])[CH3:12]

Participants

5

Reactant 3

HCID 11474Piconol2×HCID 24758Sodium hydride2×HCID 451108382,2,2-Trichloroethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

Product 1

HCID 45110841pyridin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylateYield 14.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

NaH (0.22 g, 5.0 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (15 mL), the suspension was cooled to 0° C. and 2-pyridylmethanol (0.55 g, 5.0 mmol) was added. The suspension was stirred at 0° C. for 1 h and added to a stirred 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. Two additional such portions of NaH and 2-pyridylmethanol in THF were added after 18 and 36 h, respectively. After 54 h the reaction mixture was quenched with water (10 mL), 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 1%, 2% and 5% MeOH in DCM (200 mL each)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 70% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 in DCM to give pyridin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (86.4 mg, 14.4%) as a white solid.

Workup

  1. stirringthe reaction mixture was stirred at room temperature
  2. customAfter 54 h the reaction mixture was quenched with water (10 mL)
  3. customthe solvents were removed in vacuo
  4. dissolutionthe residue was dissolved in EtOAc (100 mL)
  5. washwashed with 1 M aq Na2CO3 solution (4×100 mL)
  6. dry with materialdried (MgSO4)
  7. customthe solvents were removed in vacuo
  8. customThe residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 1%, 2% and 5% MeOH in DCM (200 mL each))
  9. customphase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 0% to 70% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid))

Sources & evidence

ORD record
ord-b8836171d2cb4a2eb4be175272bb1482
Source dataset
uspto-grants-2015_05
Patent number
US09035066B2

Reaction notes

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