Sarcosine → 4-Chloro-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehyde

HRID 1021876Notes

Reaction equation

HRID 1021876 reaction equation
C(=O)([O-])[O-].[K+].[K+].[CH:7]1[C:12]2=[C:13]3[N:18]([CH:19]=[C:11]2[C:10](=[O:20])[NH:9][N:8]=1)[CH2:17][CH2:16][CH2:15][CH2:14]3.Br[C:22]1[N:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:23]=1[CH:24]=[O:25].N(CC(O)=O)C>[Cu]Br.O1CCOCC1>[Cl:30][C:26]1[C:23]([CH:24]=[O:25])=[C:22]([N:9]2[C:10](=[O:20])[C:11]3=[CH:19][N:18]4[C:13]([CH2:14][CH2:15][CH2:16][CH2:17]4)=[C:12]3[CH:7]=[N:8]2)[N:29]=[CH:28][CH:27]=1

Participants

7

Reactant 4

HCID 1088SarcosineHCID 11430Potassium CarbonateHCID 866839142-Bromo-4-chloropyridine-3-carbaldehydeHCID 866843517,8,9,10-Tetrahydropyridazino[4,5-a]indolizin-4(3H)-one

Product 1

HCID 866843524-Chloro-2-(4-oxo-7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-3(4H)-yl)nicotinaldehydeYield 30%

Reagents, catalysts & solvents 2

HCID 24593copper(I) bromideCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
95 °C

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (50 mL), potassium carbonate (1.5 g, 10.6 mmol), 7,8,9,10-tetrahydropyridazino[4,5-a]indolizin-4(3H)-one 192b (1.0 g, 5.3 mmol), and 2-bromo-4-chloronicotinaldehyde (3.5 g, 15.9 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, copper(I) bromide (75.0 mg, 0.53 mmol) and sarcosine (47.0 mg, 0.53 mmol) were added, and the reaction mixture was heated at 95° C. for 12 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between methylene chloride (60 mL) and water (40 mL). The aqueous layer was separated and extracted with methylene chloride (3×70 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 10:1 ethyl acetate/petroleum ether to afford 192c as a brown solid (521 mg, 30%). MS-ESI: [M+H]+ 329.2.

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter bubbling nitrogen through the resulting mixture for 30 minutes
  3. temperatureAfter this time the reaction was cooled to room temperature
  4. filtrationfiltered
  5. customThe filtrate was partitioned between methylene chloride (60 mL) and water (40 mL)
  6. customThe aqueous layer was separated
  7. extractionextracted with methylene chloride (3×70 mL)
  8. washThe combined organic layer was washed with brine (30 mL)
  9. dry with materialdried over sodium sulfate
  10. customThe drying agent was removed by filtration
  11. concentrationthe filtrate was concentrated under reduced pressure
  12. customThe residue was purified by silica-gel column chromatography
  13. washeluting with 10:1 ethyl acetate/petroleum ether

Sources & evidence

ORD record
ord-750faed55604419a9220f531b6b73955
Source dataset
uspto-grants-2014_05
Patent number
US08716274B2

Reaction notes

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