Sodium hydride → HCID 58408395, compound

HRID 2383265Notes

Reaction equation

HRID 2383265 reaction equation
[H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]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@@H:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH3:3])=[O:24])([CH3:13])[CH3:12]

Participants

5

Reactant 3

HCID 24758Sodium hydride2×HCID 643492(2S)-1-Methyl-2-pyrrolidinemethanolHCID 451108382,2,2-Trichloroethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

Product 1

HCID 58408395HCID 58408395, compoundYield 4.3%

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 (S)—N-methylpyrrolidine-2-methanol (0.47 mL, 4.80 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. An additional such portion of NaH and N-methylpyrrolidine methanol in THF was added after 8 h. After 18 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 60% (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 [(2S)-1-methylpyrrolidin-2-yl]methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (52.1 mg, 4.2%) as a colourless gum.

Workup

  1. stirringthe reaction mixture was stirred at room temperature
  2. customAfter 18 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 60% (over 12 min) to 100% (over 3 min) MeOH in water [1% formic acid])

Sources & evidence

ORD record
ord-8842003c1efe4d24bdc5e9c4479ded17
Source dataset
uspto-grants-2012_09
Patent number
US08263616B2

Reaction notes

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