Sodium hydride → HCID 58408394, compound

HRID 2383266Notes

Reaction equation

HRID 2383266 reaction equation
[H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][C@@H:6]([OH:9])[CH2:5]1.[CH:10]([CH:13]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH2:16][CH2:15][N:14]1[C:22](OCC(Cl)(Cl)Cl)=[O:23])([CH3:12])[CH3:11]>C1COCC1>[CH:10]([CH:13]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH2:16][CH2:15][N:14]1[C:22]([O:9][C@@H:6]1[CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]1)=[O:23])([CH3:12])[CH3:11]

Participants

5

Reactant 3

HCID 24758Sodium hydride2×HCID 69513321-Methyl-3-pyrrolidinol, (-)-2×HCID 451108382,2,2-Trichloroethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

Product 1

HCID 58408394HCID 58408394, compoundYield 2.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

NaH (0.19 g, 5.00 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL) at 0° C. and (R)-1-methylpyrrolidin-3-ol (0.47 mL, 4.00 mmol) was added. The suspension was stirred at 0° C. for 30 min and added to a solution of Intermediate 2 (1.33 g, 4.00 mmol) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and (R)-1-methylpyrrolidin-3-ol in THF were added after 18 and 26 h, respectively. After 44 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. 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%, 10% and 20% MeOH in DCM (200 mL)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 30% (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 (3R)-1-methylpyrrolidin-3-yl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo-[4,5-c]pyridine-5-carboxylate (32.3 mg, 2.7%) as a colourless gum.

Workup

  1. stirringthe reaction mixture was stirred at room temperature
  2. customAfter 44 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 2%, 4%, 5%, 10% and 20% MeOH in DCM (200 mL))
  9. customphase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 30% (over 12 min) to 100% (over 3 min) MeOH in water [1% formic acid])

Sources & evidence

ORD record
ord-994af0541e034f71b0c7ab286882610f
Source dataset
uspto-grants-2012_09
Patent number
US08263616B2

Reaction notes

Loading…