Sodium hydride → Methyl 6-[2-(2-tert-butoxycarbonylamino-4-methoxyphenyl)-3-oxo-3-thiophen-3-ylpropyl]pyridine-2-carboxylate

HRID 2409943Notes

Reaction equation

HRID 2409943 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:17][C:18](=[O:24])[C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1.[H-].[Na+].Cl[CH2:28][C:29]1[N:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>CN(C)C=O.O>[C:12]([O:11][C:10]([NH:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:17]([C:18](=[O:24])[C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)[CH2:28][C:29]1[N:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][CH:30]=1)=[O:16])([CH3:15])([CH3:13])[CH3:14]

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 53404482Methyl 6-(chloromethyl)pyridine-2-carboxylateHCID 69096725tert-Butyl [5-methoxy-2-(2-oxo-2-thiophen-3-ylethyl)phenyl]carbamate

Product 1

HCID 86703269Methyl 6-[2-(2-tert-butoxycarbonylamino-4-methoxyphenyl)-3-oxo-3-thiophen-3-ylpropyl]pyridine-2-carboxylateYield 78.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

Under an argon atmosphere, to a solution of tert-butyl [5-methoxy-2-(2-oxo-2-thiophen-3-ylethyl)phenyl]carbamate (1.87 g) in N,N-dimethylformamide (27 mL) was added sodium hydride (min. 55% in oil, 247 mg) in five divided portions under ice-cooling with stirring. This mixture was stirred for 70 minutes under ice-cooling. Then, methyl 6-chloromethylpyridine-2-carboxylate (999 mg) was added thereto in one portion, followed by stirring at 35° C. for 16 hours. To the reaction mixture were added a saturated aqueous ammonium chloride solution and water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (2.10 g). 1H-NMR (CDCl3) δ ppm: 1.60 (9H, s), 3.54 (1H, dd, J=10.2, 15.8 Hz), 3.61-3.75 (4H, m), 4.05 (3H, s), 5.40 (1H, dd, J=4.9, 10.2 Hz), 6.55 (1H, dd, J=2.8, 8.5 Hz), 7.00-7.12 (2H, m), 7.15-7.25 (2H, m), 7.50 (1H, dd, J=1.3, 5.0 Hz), 7.63 (1H, t, J=7.8 Hz), 7.89-7.95 (1H, m), 8.00-8.11 (2H, m).

Workup

  1. temperaturecooling
  2. stirringThis mixture was stirred for 70 minutes under ice-
  3. temperaturecooling
  4. stirringby stirring at 35° C. for 16 hours
  5. extractionfollowed by extraction with ethyl acetate
  6. washThe organic layer was washed with water and saturated brine successively
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane)

Sources & evidence

ORD record
ord-39b0784bc37949c085d5082262f5e03b
Source dataset
uspto-grants-2014_08
Patent number
US08815903B2

Reaction notes

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