Ethyl 2-chloroacetoacetate → Ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate

HRID 2401623Notes

Reaction equation

HRID 2401623 reaction equation
[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.Cl[CH:19]([C:25]([CH3:27])=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:25]([CH3:27])[N:12]=2)[CH:9]=[CH:10][CH:11]=1

Participants

4

Reactant 2

HCID 11858Ethyl 2-chloroacetoacetateHCID 102634983-(2,6-Difluoro-benzyloxy)-pyridin-2-ylamine

Product 1

HCID 86717871Ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylateYield 41.6%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

170 g of 3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 1A; 719 mmol, 1 equivalent) were initially charged in 3800 ml of ethanol, and 151 g of powdered molecular sieve 3 Å and 623 g of ethyl 2-chloroacetoacetate (3.6 mol, 5 equivalents) were added. The mixture was heated at reflux for 24 h and then filtered off through kieselguhr and concentrated under reduced pressure. After standing for a relatively long time (48 h) at RT a solid precipitated out. It was filtered off, stirred three times with a little isopropanol and then filtered off each time and finally washed with diethyl ether. This gave 60.8 g (23.4% of theory) of the title compound. The combined mother liquor of the filtration steps was chromatographed on silica gel using cyclohexane/diethyl ether as mobile phase, and this gave a further 46.5 g (18.2% of theory; total yield: 41.6% of theory) of the title compound.

Workup

  1. temperatureThe mixture was heated
  2. temperatureat reflux for 24 h
  3. filtrationfiltered off through kieselguhr
  4. concentrationconcentrated under reduced pressure
  5. customAfter standing for a relatively long time (48 h) at RT
  6. customprecipitated out
  7. filtrationIt was filtered off
  8. filtrationfiltered off each time
  9. washfinally washed with diethyl ether
  10. filtrationThe combined mother liquor of the filtration steps
  11. customwas chromatographed on silica gel

Sources & evidence

ORD record
ord-913dc2f9c1ae436ab3a2a174b12cc783
Source dataset
uspto-grants-2014_08
Patent number
US08796305B2

Reaction notes

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