Cesium fluoride → 4-Acetylamino-3-chloro-6-(2,4-difluoro-3-methylphenyl)-pyridine-2-carboxylic acid methyl ester

HRID 1782616Notes

Reaction equation

HRID 1782616 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[C:3]=1[F:10].[CH3:11][O:12][C:13]([C:15]1[C:20]([Cl:21])=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[CH:18]=[C:17]([Sn](C)(C)C)[N:16]=1)=[O:14].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][O:12][C:13]([C:15]1[C:20]([Cl:21])=[C:19]([NH:22][C:23](=[O:25])[CH3:24])[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH3:9])[C:3]=2[F:10])[N:16]=1)=[O:14]

Participants

7

Reactant 4

HCID 25953Cesium fluorideHCID 821241,4-Bis(diphenylphosphino)butaneHCID 112872263-Bromo-2,6-difluorotolueneHCID 226773084-Acetylamino-3-chloro-6-trimethylstannylpyridine-2-carboxylic acid methyl ester

Product 1

HCID 685975834-Acetylamino-3-chloro-6-(2,4-difluoro-3-methylphenyl)-pyridine-2-carboxylic acid methyl esterYield 20%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6342AcetonitrileSolvent

Procedure

A solution of 1-bromo-2,4-difluoro-3-methylbenzene (2.10 g, 0.09 mol), 4-acetylamino-3-chloro-6-trimethylstannylpyridine-2-carboxylic acid methyl ester (4.00 g, 0.01 mol), 1,4-bis(diphenylphosphino)butane (0.140 g, 0.0003 mol) and cesium fluoride (4.5 g, 0.03 mol) in acetonitrile (100 mL) was degassed with nitrogen. Palladium acetate (0.70 g, 0.0003 mol) was added the solution heated to reflux for 2 hours. The reaction mixture was filtered through celite and the filtrate diluted with water (200 mL) and then extracted with ethyl acetate (2×150 mL). The combined organic phases were dried and concentrated and the residual solid was purified by chromatography (50% ethyl acetate in hexanes) to give 4-acetylamino-3-chloro-6-(2,4-difluoro-3-methylphenyl)-pyridine-2-carboxylic acid methyl ester (0.800 g, 0.002 mol): mp 152-153° C.

Workup

  1. temperatureheated
  2. temperatureto reflux for 2 hours
  3. filtrationThe reaction mixture was filtered through celite
  4. additionthe filtrate diluted with water (200 mL)
  5. extractionextracted with ethyl acetate (2×150 mL)
  6. customThe combined organic phases were dried
  7. concentrationconcentrated
  8. customthe residual solid was purified by chromatography (50% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-100bc78c6db840f1b52b9e256a480b2c
Source dataset
uspto-grants-2009_03
Patent number
US07498468B2

Reaction notes

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