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

HRID 1624059Notes

Reaction equation

HRID 1624059 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 4A; 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 resulting reaction mixture was heated under reflux for 24 h and then filtered off through kieselguhr and concentrated under reduced pressure. After relatively long standing (48 h) at RT, a solid precipitated out. This solid was filtered off, three times suspended in a little isopropanol and in each case filtered off again 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. This gave a further 46.5 g (18.2% of theory; total yield: 41.6% of theory) of the title compound.

Workup

  1. customThe resulting reaction mixture
  2. temperaturewas heated
  3. temperatureunder reflux for 24 h
  4. filtrationfiltered off through kieselguhr
  5. concentrationconcentrated under reduced pressure
  6. customAfter relatively long standing (48 h) at RT, a solid precipitated out
  7. filtrationThis solid was filtered off
  8. filtrationfiltered off again
  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-f63ff118bd9f4bfd97cc7bd8591dbec6
Source dataset
uspto-grants-2014_07
Patent number
US08778964B2

Reaction notes

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