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

HRID 2401634Notes

Reaction equation

HRID 2401634 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:20]([C:26]([CH3:28])=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:12]([F:18])=[CH:13][CH:14]=[CH:15][C:16]=2[F:17])[C:5]2[N:6]([C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:26]([CH3:28])[N:8]=2)[CH:7]=1

Participants

4

Reactant 2

HCID 11858Ethyl 2-chloroacetoacetateHCID 211114885-Bromo-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine

Product 1

HCID 86717880Ethyl 6-bromo-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

24 g of 5-bromo-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 17A; 76.2 mmol; 1 equivalent) were initially charged in 400 ml of ethanol, 16 g of powdered molecular sieve 3 Å and 52.7 ml of ethyl 2-chloroacetoacetate (380.8 mmol; 5 equivalents) were added and the mixture was heated at reflux overnight. A further 8 g of molecular sieve were added, and the mixture was heated at reflux for a further 24 h. The reaction mixture was concentrated and the residue was taken up in dichloromethane and chromatographed on silica gel (dichloromethane/methanol 20:1 as mobile phase). The product-containing fractions were concentrated and the residue was stirred with 100 ml of diethyl ether for 30 min, and the product was filtered off, washed with a little diethyl ether and dried. This gave 15 g (45% of theory) of the title compound.

Workup

  1. temperaturethe mixture was heated
  2. temperatureat reflux overnight
  3. additionA further 8 g of molecular sieve were added
  4. temperaturethe mixture was heated
  5. temperatureat reflux for a further 24 h
  6. concentrationThe reaction mixture was concentrated
  7. customchromatographed on silica gel (dichloromethane/methanol 20:1 as mobile phase)
  8. concentrationThe product-containing fractions were concentrated
  9. filtrationthe product was filtered off
  10. washwashed with a little diethyl ether
  11. customdried

Sources & evidence

ORD record
ord-71e719f63e4d4c1d97901e75d7273ec3
Source dataset
uspto-grants-2014_08
Patent number
US08796305B2

Reaction notes

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