4-Methylmorpholine → (5-methylisoxazol-3-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

HRID 575899Notes

Reaction equation

HRID 575899 reaction equation
[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][OH:8])[CH:3]=1.CN1CCOCC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:29]([CH:32]1[C:37]2[N:38]=[CH:39][NH:40][C:36]=2[CH2:35][CH2:34][N:33]1[C:41](OCC1SC=CN=1)=[O:42])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:29]([CH:32]1[C:37]2[N:38]=[CH:39][NH:40][C:36]=2[CH2:35][CH2:34][N:33]1[C:41]([O:8][CH2:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:42])([CH3:31])[CH3:30]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 81531DiisopropylethylamineHCID 821294-Nitrophenyl chloroformateHCID 2736567(5-Methyl-1,2-oxazol-3-yl)methanolHCID 451109861,3-Thiazol-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

Product 1

HCID 58408392(5-methylisoxazol-3-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylateYield 9.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

5-Methylisoxazole-3-methanol (1.64 g, 14.5 mmol) was dissolved in DCM (10 mL) at 0° C. and NMM (1.47 g, 1.40 mL, 14.5 mmol) and 4-nitrophenyl chloroformate (2.93 g, 14.5 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. A solution of Intermediate 1 (1.87 g, 3.60 mmol) in DCM (20 mL) and DIPEA (1.87 g, 2.52 mL, 14.5 mmol) was added and the resulting solution was stirred for 3 d and concentrated in vacuo. The residue was dissolved in MeOH (8 mL) and 1 M aq NaOH solution (6 mL) and the reaction mixture was stirred for 18 h and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and the organic layer was washed with 1 M aq Na2CO3 solution (6×100 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL per min, gradient 0% to 20% (over 5 min) to 90% (over 40 min) MeOH in water) and reverse phase HPLC (YMC ODS-A 150×20 mm, 5 μm, 25 mL per min, gradient 40% to 80% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give (5-methylisoxazol-3-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (107 mg, 9.7%) as a colourless gum.

Workup

  1. stirringthe resulting solution was stirred for 3 d
  2. concentrationconcentrated in vacuo
  3. dissolutionThe residue was dissolved in MeOH (8 mL)
  4. stirring1 M aq NaOH solution (6 mL) and the reaction mixture was stirred for 18 h
  5. concentrationconcentrated in vacuo
  6. dissolutionThe residue was dissolved in EtOAc (100 mL)
  7. washthe organic layer was washed with 1 M aq Na2CO3 solution (6×100 mL)
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×26 mm (100 g), 30 mL per min, gradient 0% to 20% (over 5 min) to 90% (over 40 min) MeOH in water)
  11. customYMC ODS-A 150×20 mm, 5 μm, 25 mL per min, gradient 40% to 80% (over 7 min)

Sources & evidence

ORD record
ord-468b27d639e44445b594e69f65f93d77
Source dataset
uspto-grants-2015_05
Patent number
US09035066B2

Reaction notes

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