Hydrochloric Acid → 6-Methyl-4-(morpholinomethyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile

HRID 593867Notes

Reaction equation

HRID 593867 reaction equation
[O-]CC.[Na+].[C:5]([CH2:7][C:8]([NH2:10])=[O:9])#[N:6].[N:11]1([CH2:17][C:18]#[C:19][C:20](=O)[CH3:21])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.Cl>CCO>[CH3:21][C:20]1[NH:10][C:8](=[O:9])[C:7]([C:5]#[N:6])=[C:18]([CH2:17][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:19]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 7898CyanoacetamideHCID 2723922Sodium ethoxideHCID 674677495-(Morpholin-4-yl)pent-3-yn-2-one

Product 1

HCID 674663986-Methyl-4-(morpholinomethyl)-2-oxo-1,2-dihydropyridine-3-carbonitrileYield 32.3%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent3×

Procedure

To a stirred solution of 21 wt % sodium ethoxide in EtOH (4.2 g, 12.96 mmol) in EtOH (30 mL) was added 2-cyanoacetamide (1.1 g, 13.08 mmol). The reaction was stirred for 15 min. then a solution of 5-(4-morpholinyl)-3-pentyn-2-one (2.0 g, 11.96 mmol) in EtOH was added to the reaction in one portion. (The reaction quickly turned dark red.) The reaction was stirred overnight at RT, neutralized with 6N HCl (2.17 mL, 13.02 mmol) and evaporated to dryness under vacuum. Dried under vacuum overnight. The remaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL), filtered from insoluble material, washed with (9:1) CH2Cl2, MeOH, and the filtrate evaporated to dryness under vacuum. The dark solid was triturated with a solution of (1:1) EtOAc in hexanes, filtered, washed with (1:1) EtOAc in hexanes, and dried under vacuum to give a brown solid (removed a lot of fast running non-polar impurities). The crude product was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 15% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness, triturated with hexanes and dried under vacuum to give the product 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.90 g, 3.86 mmol, 32.3% yield) as a light tan solid.

Workup

  1. custom(The reaction quickly turned dark red
  2. stirring) The reaction was stirred overnight at RT
  3. customevaporated to dryness under vacuum
  4. customDried under vacuum overnight
  5. customThe remaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL)
  6. filtrationfiltered from insoluble material
  7. washwashed with (9:1) CH2Cl2, MeOH
  8. customthe filtrate evaporated to dryness under vacuum
  9. customThe dark solid was triturated with a solution of (1:1) EtOAc in hexanes
  10. filtrationfiltered
  11. washwashed with (1:1) EtOAc in hexanes
  12. customdried under vacuum
  13. customto give a brown solid (
  14. customremoved a lot
  15. customThe crude product was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 15% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2)
  16. customevaporated to dryness
  17. customtriturated with hexanes
  18. customdried under vacuum

Sources & evidence

ORD record
ord-133a30d1b3ba459fb4dd9b744bdea6fc
Source dataset
uspto-grants-2016_01
Patent number
US09242962B2

Reaction notes

Loading…