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

HRID 2275770Notes

Reaction equation

HRID 2275770 reaction equation
Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:11][C:12]1[CH:13]=[C:14]([O:19][CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:15]([NH2:18])=[N:16][CH:17]=1>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:19][CH2:20][C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:15]2[N:16]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N:18]=2)[CH:17]=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

16 g of powdered molecular sieve 3 Å and 52.7 ml of ethyl 2-chloroacetoacetate (380.8 mmol; 5 equivalents) were added to 24 g of 5-bromo-3-[(2,6-difluorobenzyl)oxy]pyridine-2-amine (Example 17A; 76.2 mmol; 1 equivalent) in 400 ml of ethanol, 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 under reduced pressure 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. The product was then 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 under reduced pressure
  7. customchromatographed on silica gel (dichloromethane/methanol 20:1 as mobile phase)
  8. concentrationThe product-containing fractions were concentrated
  9. filtrationThe product was then filtered off
  10. washwashed with a little diethyl ether
  11. customdried

Sources & evidence

ORD record
ord-a4e52e71c3b84cd9a14b9cf962b8bd4f
Source dataset
uspto-grants-2015_09
Patent number
US09126998B2

Reaction notes

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