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

HRID 2275754Notes

Reaction equation

HRID 2275754 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%

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 reaction mixture was heated at reflux for 24 h and then filtered off through silica gel and concentrated under reduced pressure. The mixture was kept at RT for 48 h, and the solid formed was filtered off. The solid was then stirred three times with a little isopropanol and then filtered off and washed with diethyl ether. This gave 60.8 g (23% of theory) of the title compound. The combined filtrates of the filtration steps were concentrated and the residue was chromatographed on silica gel using cyclohexane/diethyl ether as mobile phase. This gave a further 46.5 g (18% of theory; total yield: 41% of theory) of the title compound.

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux for 24 h
  3. filtrationfiltered off through silica gel
  4. concentrationconcentrated under reduced pressure
  5. customthe solid formed
  6. filtrationwas filtered off
  7. filtrationfiltered off
  8. washwashed with diethyl ether
  9. filtrationThe combined filtrates of the filtration steps
  10. concentrationwere concentrated
  11. customthe residue was chromatographed on silica gel

Sources & evidence

ORD record
ord-82901139c5ee4079bef7d647350e0011
Source dataset
uspto-grants-2015_09
Patent number
US09126998B2

Reaction notes

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