Cesium fluoride → 4-Acetylamino-3-chloro-6-(2-fluoro-3-methoxy-4-trifluoromethylphenyl)pyridine-2-carboxylic acid methyl ester

HRID 2249390Notes

Reaction equation

HRID 2249390 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7](Cl)[N:6]=1)=[O:4].[F:17][C:18]1[C:23]([O:24][CH3:25])=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=[CH:20][C:19]=1[Sn](C)(C)C.[F-].[Cs+].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:19]2[CH:20]=[CH:21][C:22]([C:26]([F:28])([F:29])[F:27])=[C:23]([O:24][CH3:25])[C:18]=2[F:17])[N:6]=1)=[O:4]

Participants

7

Reactant 4

HCID 25953Cesium fluorideHCID 821241,4-Bis(diphenylphosphino)butaneHCID 22677481Methyl 4-acetamido-3,6-dichloropyridine-2-carboxylateHCID 68810358(2-Fluoro-3-methoxy-4-trifluoromethylphenyl)trimethyl stannane

Product 1

HCID 688110344-Acetylamino-3-chloro-6-(2-fluoro-3-methoxy-4-trifluoromethylphenyl)pyridine-2-carboxylic acid methyl esterYield 10%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6342AcetonitrileSolvent

Procedure

In an oven dried, nitrogen flushed 100 mL 3 neck flask equipped with a condenser and a magnetic stirbar was dissolved methyl-4-acetamido-3,6-dichloropyridine-2-carboxylate (1.2 g, 4.6 mmol) and (2-fluoro-3-methoxy-4-trifluoromethylphenyl)trimethyl stannane (1.7 g, 4.6 mmol) in acetonitrile (15 mL) and the resulting solution was de-aerated with a purge of nitrogen for 15 minutes. Cesium fluoride (2.1 g, 13.9 mmol), 1,4-bis(diphenylphosphino)butane (0.2 g, 0.46 mmol) and palladium acetate (0.1 g, 0.46 mmol) were added and the head space of the reaction was purged with nitrogen as the reaction was heated to reflux with stirring. The reaction was then stirred under an open nitrogen atmosphere for 5 hours by which time TLC (hexane:ethyl acetate/1:2) indicated complete consumption of starting material. The cooled reaction was filtered through celite with ethyl acetate and the filtrate concentrated and purified by flash silica gel chromatography (hexanes:ethyl acetate/2:1) to give 4-acetylamino-3-chloro-6-(2-fluoro-3-methoxy-4-trifluoromethylphenyl)pyridine-2-carboxylic acid methyl ester (0.19 g, 0.46 mmol) as an oil: 1H NMR (CDCl3): δ 9.03 (d, 1H), 8.02 (bs, 1H), 7.68 (bt, 1H), 7.42 (bd, 1H), 4.03 (d, 3H), 4.01 (s, 3H), 2.33 (s, 3H).

Workup

  1. customIn an oven dried
  2. customnitrogen flushed 100 mL 3 neck flask
  3. customequipped with a condenser
  4. customa purge of nitrogen for 15 minutes
  5. customthe head space of the reaction was purged with nitrogen as the reaction
  6. temperaturewas heated
  7. temperatureto reflux
  8. stirringThe reaction was then stirred under an open nitrogen atmosphere for 5 hours by which time TLC (hexane:ethyl acetate/1:2)
  9. customconsumption of starting material
  10. customThe cooled reaction
  11. filtrationwas filtered through celite with ethyl acetate
  12. concentrationthe filtrate concentrated
  13. custompurified by flash silica gel chromatography (hexanes:ethyl acetate/2:1)

Sources & evidence

ORD record
ord-223796424bda409c81c6565a912d7188
Source dataset
uspto-grants-2008_01
Patent number
US07314849B2

Reaction notes

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