Pyridine → 6-Chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrile

HRID 1255666Notes

Reaction equation

HRID 1255666 reaction equation
[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])[N:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([N:11]([CH2:13][CH2:14][O:15][CH3:16])[CH3:12])[N:3]=1

Participants

6

Reactant 4

HCID 1049PyridineHCID 14798Sodium HydroxideHCID 24813Phosphorus oxychlorideHCID 57968952HCID 57968952, compound

Product 1

HCID 866364246-Chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinonitrileYield 90%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
55 °C

Procedure

To a solution of 6-chloro-2-[(2-methoxy-ethyl)-methyl-amino]-nicotinamide (3) (14 g, 58 mmol) in acetonitrile (anhydrous, 360 mL) were added pyridine (37.5 mL, 463.8 mmol) and POCl3 (21.2 mL, 232 mmol). The reaction was heated at 55° C. for 3 hours. After cooling to room temperature, NaOH solution (10% aq.) was slowly added till pH 9. The solution was extracted with EtOAc (3×200 mL). The combined organic layer was dried over MgSO4, filtered, and evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 5%-30% EtOAc/hexanes gradient, to afford 11.6 g (90% yield) of the desired product. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=7.4 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 3.87 (t, J=5.3 Hz, 2H), 3.64 (t, J=5.3 Hz, 2H), 3.38 (s, 3H), 3.36 (s, 3H).

Workup

  1. temperatureAfter cooling to room temperature
  2. extractionThe solution was extracted with EtOAc (3×200 mL)
  3. dry with materialThe combined organic layer was dried over MgSO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customPurification
  7. washeluting with 5%-30% EtOAc/hexanes gradient

Sources & evidence

ORD record
ord-d040c12153324d75a97173dacbce72a6
Source dataset
uspto-grants-2013_06
Patent number
US08461135B2

Reaction notes

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