4-Methylmorpholine → 2-(pyridin-3-yloxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

HRID 1046480Notes

Reaction equation

HRID 1046480 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH2:9][OH:10])[CH:2]=1.CN1CCOCC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:31]([CH:34]1[C:39]2[N:40]=[CH:41][NH:42][C:38]=2[CH2:37][CH2:36][N:35]1[C:43](OCC1SC=CN=1)=[O:44])([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:31]([CH:34]1[C:39]2[N:40]=[CH:41][NH:42][C:38]=2[CH2:37][CH2:36][N:35]1[C:43]([O:10][CH2:9][CH2:8][O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:44])([CH3:33])[CH3:32]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 81531DiisopropylethylamineHCID 821294-Nitrophenyl chloroformateHCID 219089972-(Pyridin-3-yloxy)ethan-1-olHCID 451109861,3-Thiazol-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

Product 1

HCID 451112742-(pyridin-3-yloxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylateYield 1.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

2-(3-Pyridyloxy)ethanol (0.62 g, 4.40 mmol) was dissolved in DCM (10.0 mL) at 0° C. and NMM (0.50 mL, 4.40 mmol) and 4-nitrophenyl chloroformate (0.90 g, 4.40 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. A solution of Intermediate 1 (0.35 g, 2.10 mmol) and DIPEA (1.10 g, 1.50 mL, 8.50 mmol) in DCM (20 mL) was added and the resulting solution was stirred for 3 d. The solvents were removed in vacuo, the residue was dissolved in MeOH (4 mL) and 1 M aq NaOH solution (4 mL) and the reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (60 mL), the organic layer was washed with 1 M aq Na2CO3 solution (5×40 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% and 10% MeOH in DCM (200 mL)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 0% to 40% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give 2-(pyridin-3-yloxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (7.4 mg, 1%) as a white solid.

Workup

  1. stirringthe resulting solution was stirred for 3 d
  2. customThe solvents were removed in vacuo
  3. dissolutionthe residue was dissolved in MeOH (4 mL)
  4. stirring1 M aq NaOH solution (4 mL) and the reaction mixture was stirred for 2 h
  5. concentrationconcentrated in vacuo
  6. dissolutionThe residue was dissolved in EtOAc (60 mL)
  7. washthe organic layer was washed with 1 M aq Na2CO3 solution (5×40 mL)
  8. dry with materialdried (MgSO4)
  9. customthe solvents were removed in vacuo
  10. customThe residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5% and 10% MeOH in DCM (200 mL))
  11. customYMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 0% to 40% (over 7 min)

Sources & evidence

ORD record
ord-ec570124c01c45b1bc1dfcbe15f0354b
Source dataset
uspto-grants-2013_10
Patent number
US08569338B2

Reaction notes

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