Sodium hydride → (6S)-6-[(5-Chloro-2-pyrazinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine

HRID 1446080Notes

Reaction equation

HRID 1446080 reaction equation
[H-].[Na+].[N+:3]([C:6]1[N:7]=[C:8]2[N:13]([CH:14]=1)[CH2:12][C@H:11]([OH:15])[CH2:10][O:9]2)([O-:5])=[O:4].[Cl:16][C:17]1[CH:22]=[N:21][C:20]([CH2:23]I)=[CH:19][N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([CH2:23][O:15][C@@H:11]2[CH2:10][O:9][C:8]3=[N:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][N:13]3[CH2:12]2)=[N:21][CH:22]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 10130259(S)-2-nitro-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazin-6-olHCID 866357892-Chloro-5-(iodomethyl)pyrazine

Product 1

HCID 49852136(6S)-6-[(5-Chloro-2-pyrazinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazineYield 65%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

Triethylamine (4.17 mL, 3.0 mmol) and mesyl chloride (1.57 mL, 2.00 mmol) were added to a solution of (5-chloro-2-pyrazinyl)methanol (1.44 g, 10.0 mmol) in anhydrous THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 0.5 h then partitioned between EtOAc/water. The organic fraction was dried (MgSO4) and the solvent was removed under reduced pressure to give the crude mesylate. The mesylate was dissolved in acetone (40 mL), sodium iodide (7.5 g, 50 mmol) was added and the mixture was refluxed for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc/water. The residue was chromatographed on silica gel (DCM) to give 2-chloro-5-(iodomethyl)pyrazine. Sodium hydride (60% w/w, 0.36 g, 9.0 mmol) was added to a solution of (S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxa-zin-6-ol (0.93 g, 5.02 mmol) and 2-chloro-5-(iodomethyl)pyrazine (1.54 g, 6.05 mmol) in DMF (10 mL) at −78° C. The mixture was stirred at 0° C. for 1 h and then quenched with ice. EtOAc (200 mL) was added, the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with a gradient (0-5%) MeOH/EtOAc to give the title compound (1.015 g, 65%) as a white solid. APCI MS m/z 312.6 (M+H). 1H NMR (400 MHz, (CD3)2SO) δ 8.76 (d, J=1.4 Hz, 1H), 8.50 (d, J=1.4 Hz, 1H), 8.02 (s, 1H), 4.85 (d, J=13.7 Hz, 1H), 4.81 (d, J=13.7 Hz, 1H), 4.70 (td, J=12.1, 2.6 Hz, 1H), 4.49 (bd, J=12.0 Hz, 1H), 4.29-4.38 (m, 2H), 4.25 (dd, J=13.5, 3.3 Hz, 1H).

Workup

  1. customquenched with ice
  2. additionEtOAc (200 mL) was added
  3. dry with materialthe organic layer was dried (MgSO4)
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was chromatographed on silica gel
  6. washeluting with a gradient (0-5%) MeOH/EtOAc

Sources & evidence

ORD record
ord-933b93b416da43f1b24c041e2bb882c4
Source dataset
uspto-grants-2010_02
Patent number
US07666864B2

Reaction notes

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