Hydrochloric Acid → 2-Pyridinecarboxylic acid, 4,5-dichloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-

HRID 541046Notes

Reaction equation

HRID 541046 reaction equation
[Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[C:22]=1[O:31][CH3:32].Cl>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([O:31][CH3:32])[C:23]=2[F:30])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 129936922-Pyridinecarboxylic acid, 4,5,6-trichloro-HCID 441297064-Chloro-2-fluoro-3-methoxyphenylboronic acid

Product 1

HCID 867098682-Pyridinecarboxylic acid, 4,5-dichloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-Yield 58%

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent3×

Conditions

Temperature
50 °C

Procedure

To a 50 mL three-necked flask equipped with a stirring bar and a condenser were placed 4,5,6-trichloropicolinic acid (0.503 g, 90% purity, 2 mmol), triethylamine (0.607, 6 mmol), acetonitrile (5 g) and water (5 g). The mixture became a homogeneous solution which was sparged with nitrogen for 15 minutes. Bis(triphenylphosphine)palladium(II) dichloride (0.042 g, 0.06 mmol) was added and the mixture was heated to 50° C. In a one-necked flask were placed (4-chloro-2-fluoro-3-methoxyphenyl)-boronic acid (1.951 g, 22 wt % in methyl isobutyl ketone/dimethoxyethane, 2.1 mmol) and acetonitrile (2.5 g). The solution was sparged with nitrogen for 15 minutes, and then slowly added to trichloropicolinic acid solution by a syringe pump at 50° C. The total addition time was about two hours. The reaction mixture was stirred at 50° C. for three more hours. A sample was taken and analyzed by HPLC. The LC results indicated that the reaction was completed. The reaction mixture was allowed to cool to room temperature. To acidify the reaction mixture, hydrochloric acid (6 g, 1 N HCl in water) was added to the flask dropwise. The resulting slurry was stirred overnight. The mixture was filtered and a light brown solid was obtained. This crude product was stirred in acetonitrile at room temperature for 2 hours. After filtration and vacuum drying, the white product (0.44 g, 92% LC purity, 58% yield) was obtained. 1H NMR (400 MHz, THF-d8) δ 8.35 (s, 1H), 7.40 (dd, J=8.5, 1.7 Hz, 1H), 7.23 (dd, J=8.5, 6.9 Hz, 1H), 4.00 (d, J=1.3 Hz, 3H); 13C NMR (101 MHz, THF-d8) δ 163.62 (s), 154.81 (s), 153.03 (s), 152.31 (s), 147.36 (s), 144.64 (d, J=13.4 Hz), 143.70 (s), 133.21 (s), 129.55 (d, J=3.5 Hz), 126.34 (d, J=14.4 Hz), 125.71 (s), 125.41-125.01 (m), 60.91 (d, J=4.8 Hz); 19F NMR (376 MHz, THF-d8) δ+−128.96. ESI/LC/MS/PI (M+H)+=349.9559 (100%), 351.9531 (99.66%), 353.95 (33.59%).

Workup

  1. customTo a 50 mL three-necked flask equipped with a stirring bar and a condenser
  2. customwas sparged with nitrogen for 15 minutes
  3. customIn a one-necked flask were placed
  4. customThe solution was sparged with nitrogen for 15 minutes
  5. additionslowly added to trichloropicolinic acid solution by a syringe pump at 50° C
  6. additionThe total addition time
  7. customThe LC results
  8. temperatureto cool to room temperature
  9. additionwas added to the flask dropwise
  10. stirringThe resulting slurry was stirred overnight
  11. filtrationThe mixture was filtered
  12. customa light brown solid was obtained
  13. filtrationAfter filtration and vacuum
  14. customdrying
  15. customthe white product (0.44 g, 92% LC purity, 58% yield) was obtained

Sources & evidence

ORD record
ord-2b6dea0e5a3d4a7bafb46fa7509caf63
Source dataset
uspto-grants-2014_10
Patent number
US08871943B2

Reaction notes

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