Ethyl 2-amino-6-chloropyridine-4-carboxylate → Ethyl 5-chloro-3-{(4,4-difluorocyclohexyl)methyl}-2-(trifluoromethyl)imidazo[1,2-a]pyridine-7-carboxylate

HRID 1468285Notes

Reaction equation

HRID 1468285 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:13])[N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH:15]([CH2:22][CH:23]1[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]1)[C:16](=O)[C:17]([F:20])([F:19])[F:18].C(=O)([O-])O.[Na+]>C(O)CCC>[Cl:13][C:11]1[N:12]2[C:15]([CH2:22][CH:23]3[CH2:24][CH2:25][C:26]([F:29])([F:30])[CH2:27][CH2:28]3)=[C:16]([C:17]([F:18])([F:20])[F:19])[N:1]=[C:2]2[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=1

Participants

5

Reactant 3

HCID 269587Ethyl 2-amino-6-chloropyridine-4-carboxylateHCID 516892Sodium BicarbonateHCID 867100943-Bromo-4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one

Product 1

HCID 86710093Ethyl 5-chloro-3-{(4,4-difluorocyclohexyl)methyl}-2-(trifluoromethyl)imidazo[1,2-a]pyridine-7-carboxylateYield 5.7%

Reagents, catalysts & solvents 1

HCID 2631-ButanolSolvent

Conditions

Temperature
130 °C

Procedure

Ethyl 2-amino-6-chloroisonicotinate (510 mg, 2.54 mmol) obtained in step 1 was suspended in n-butanol (5.08 mL), and the suspension was stirred overnight at 130° C. after adding 3-bromo-4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (821 mg, 2.54 mmol) obtained in step 2 of Example 36, and molecular sieve 4A (510 mg). The reaction mixture was allowed to cool to room temperature, and, after adding a sodium hydrogen carbonate aqueous solution, the mixture was filtered through Celite (registered trademark), and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→2/1), amino silica gel column chromatography (hexane/ethyl acetate=20/1→9/1), and preparative thin-layer chromatography (hexane/ethyl acetate=9/1) to give ethyl 5-chloro-3-{(4,4-difluorocyclohexyl)methyl}-2-(trifluoromethyl)imidazo[1,2-a]pyridine-7-carboxylate (62.0 mg, yield 5.7%).

Workup

  1. temperatureto cool to room temperature
  2. filtrationthe mixture was filtered through Celite (registered trademark)
  3. extractionextracted with ethyl acetate
  4. washThe organic layer was washed with water and saturated brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. customThe solvent was then evaporated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→2/1), amino silica gel column chromatography (hexane/ethyl acetate=20/1→9/1)

Sources & evidence

ORD record
ord-a2635ec1ac4742288e5d9ed749d0812c
Source dataset
uspto-grants-2015_04
Patent number
US09000186B2

Reaction notes

Loading…