4-Methylmorpholine → oxetan-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate

HRID 575902Notes

Reaction equation

HRID 575902 reaction equation
[OH:1][CH2:2][CH:3]1[CH2:6][CH2:5][O:4]1.CN1CCOCC1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.[CH:27]([CH:30]1[C:35]2[N:36]=[CH:37][NH:38][C:34]=2[CH2:33][CH2:32][N:31]1[C:39](OCC1SC=CN=1)=[O:40])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:27]([CH:30]1[C:35]2[N:36]=[CH:37][NH:38][C:34]=2[CH2:33][CH2:32][N:31]1[C:39]([O:1][CH2:2][CH:3]1[CH2:6][CH2:5][O:4]1)=[O:40])([CH3:29])[CH3:28]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 81531DiisopropylethylamineHCID 821294-Nitrophenyl chloroformateHCID 12284142(Oxetan-2-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 45111273oxetan-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylateYield 8.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

2-Hydroxymethyloxetane (0.71 g, 8.10 mmol) was dissolved in DCM (10 mL) at 0° C. and NMM (0.89 mL, 8.10 mmol) and 4-nitrophenyl chloroformate (1.63 g, 8.10 mmol) were added. The reaction mixture was stirred at room temperature for 5 h. A solution of Intermediate 1 (1.16 g, 3.90 mmol) and DIPEA (2.69 mL, 15.4 mmol) in DCM (20 mL) was added and the resulting solution was stirred for 18 h. The solvents were removed in vacuo, the residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (10 mL) and the reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (120 mL), the organic layer was washed with 1M 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)) and reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give oxetan-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (93.4 mg, 8.7%) as a white solid.

Workup

  1. stirringthe resulting solution was stirred for 18 h
  2. customThe solvents were removed in vacuo
  3. dissolutionthe residue was dissolved in MeOH (10 mL)
  4. stirring1 M aq NaOH solution (10 mL) and the reaction mixture was stirred for 2 h
  5. concentrationconcentrated in vacuo
  6. dissolutionThe residue was dissolved in EtOAc (120 mL)
  7. washthe organic layer was washed with 1M aq Na2CO3 solution (4×100 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% and 5% MeOH in DCM (200 mL))
  11. customYMC ODS-A 100×20 mm, 5 μm, 25 mL per min, gradient 20% to 100% (over 7 min)

Sources & evidence

ORD record
ord-a3c0ba6338a649bfbe28c522118768ef
Source dataset
uspto-grants-2015_05
Patent number
US09035066B2

Reaction notes

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