Sodium hydride → HCID 45111275, compound

HRID 2383269Notes

Reaction equation

HRID 2383269 reaction equation
[F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:25]([CH:28]1[C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH2:31][CH2:30][N:29]1[C:37](OCC1SC=CN=1)=[O:38])([CH3:27])[CH3:26]>C1COCC1>[CH:25]([CH:28]1[C:33]2[N:34]=[CH:35][NH:36][C:32]=2[CH2:31][CH2:30][N:29]1[C:37]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])=[O:38])([CH3:27])[CH3:26]

Participants

6

Reactant 4

HCID 24758Sodium hydride2×HCID 821294-Nitrophenyl chloroformate2×HCID 2558542-(2,2,2-Trifluoroethoxy)ethan-1-ol2×HCID 451109861,3-Thiazol-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

Product 1

HCID 45111275HCID 45111275, compoundYield 0.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

2-(2,2,2-Trifluoroethoxy)ethanol (0.57 mL, 3.60 mmol) was dissolved in THF (5 mL), NaH (146 mg, 60% dispersion in mineral oil, 3.60 mmol) was added and the reaction mixture was stirred for 10 min. 4-Nitrophenyl chloroformate (726 mg, 3.60 mmol) was added and the reaction mixture was stirred for 16 h. Intermediate 1 (297 mg, 1.80 mmol) was dissolved in THF (5 mL) and added to the reaction mixture which was stirred at room temperature. Three additional such portions of NaH, 2-(2,2,2-trifluoroethoxy)ethanol and 4-nitrophenyl chloroformate in THF were added after 8, 24 and 32 h, respectively. After 104 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (6 mL) and stirred for 1.5 h. The solvents were removed in vacuo and the residue dissolved in EtOAc (100 mL). The organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water to give 2-(2,2,2-trifluoroethoxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (3 mg, 0.5%) as a pale yellow gum.

Workup

  1. stirringthe reaction mixture was stirred for 16 h
  2. additionadded to the reaction mixture which
  3. stirringwas stirred at room temperature
  4. customAfter 104 h the reaction mixture was quenched with water (10 mL)
  5. customthe solvents were removed in vacuo
  6. dissolutionThe residue was dissolved in MeOH (10 mL)
  7. stirring1 M aq NaOH solution (6 mL) and stirred for 1.5 h
  8. customThe solvents were removed in vacuo
  9. dissolutionthe residue dissolved in EtOAc (100 mL)
  10. washThe organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL)
  11. dry with materialdried (MgSO4)
  12. customthe solvents were removed in vacuo
  13. customThe residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water

Sources & evidence

ORD record
ord-c0c41bdbc83d486690286321e678146b
Source dataset
uspto-grants-2012_09
Patent number
US08263616B2

Reaction notes

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