Sodium hydride → (3S)-tetrahydro-furan-3-yl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

HRID 575897Notes

Reaction equation

HRID 575897 reaction equation
[H-].[Na+].[OH:3][C@H:4]1[CH2:8][CH2:7][O:6][CH2:5]1.[CH:9]([CH:12]1[C:17]2[N:18]=[CH:19][NH:20][C:16]=2[CH2:15][CH2:14][N:13]1[C:21](OCC(Cl)(Cl)Cl)=[O:22])([CH3:11])[CH3:10]>C1COCC1>[CH:9]([CH:12]1[C:17]2[N:18]=[CH:19][NH:20][C:16]=2[CH2:15][CH2:14][N:13]1[C:21]([O:3][C@H:4]1[CH2:8][CH2:7][O:6][CH2:5]1)=[O:22])([CH3:11])[CH3:10]

Participants

5

Reactant 3

HCID 24758Sodium hydride2×HCID 2733227(S)-(+)-3-Hydroxytetrahydrofuran2×HCID 451108382,2,2-Trichloroethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

Product 1

HCID 67372017(3S)-tetrahydro-furan-3-yl 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 (0.40 g, 10.0 mmol, 60% dispersion in mineral oil) was suspended in anhydrous THF (20 mL), cooled to 0° C. and (S)-3-hydroxytetrahydrofuran (0.88 g, 0.68 mL, 10.0 mmol) was added. The suspension was stirred at 0° C. for 30 min then added to a solution of Intermediate 2 (3.30 g, 10.0 mmol, 70% pure) in THF (60 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and (S)-3-hydroxytetrahydrofuran in THF were added after 5 and 29 h, respectively. After 2 d 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% and 5% MeOH in DCM (200 mL each)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 30% to 60% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give (3S)-tetrahydro-furan-3-yl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (34.8 mg, 1.1%) 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 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% and 5% MeOH in DCM (200 mL each))
  9. customYMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 30% to 60% (over 7 min)

Sources & evidence

ORD record
ord-5a8a5202dcb44a75bd8c7da295ffa197
Source dataset
uspto-grants-2015_05
Patent number
US09035066B2

Reaction notes

Loading…