Acetonitrile → Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate

HRID 1913904Notes

Reaction equation

HRID 1913904 reaction equation
[NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OCCCO2)=[C:18]([F:28])[C:17]=1[O:29][CH3:30].[F-].[K+].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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([O:29][CH3:30])[C:18]=2[F:28])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 522689Potassium FluorideHCID 22677265Methyl 4-amino-3,6-dichloro-5-fluoropicolinateHCID 577824192-(4-Chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane

Product 1

HCID 57412076Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinateYield 76%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
70 °C

Procedure

A 250 mL three-neck flask with a reflux condenser, a nitrogen inlet and a thermocouple was charged with methyl 4-amino-3,6-dichloro-5-fluoropicolinate (9.965 g, 41.7 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (12.74 g, 52.1 mmol) and KF (4.84 g, 83 mmol). Acetonitrile (78 mL) and water (26 mL) were added. The reaction mixture was purged with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2; 1.477 g, 2.10 mmol, 5 mol %) was added, and the solution was heated to 70° C. under nitrogen for 2 h. Upon cooling to room temperature, a precipitate formed which was filtered and washed with water. The precipitate was dissolved in EtOAc (ca 500 mL) and washed with water and then brine. The organic layer was dried (MgSO4) and the solvent was removed using a rotary evaporator to give an orange solid, which was dried in vacuum oven at 50° C. (11.46 g, 76% yield): mp 169-170.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 164.85 (s), 153.11 (d, J=252.5 Hz), 146.29 (s), 144.52 (d, J=4.3 Hz), 143.74 (s), 142.75 (dd, J=227.1, 14.0 Hz), 136.38 (d, J=13.4 Hz), 128.58 (d, J=3.2 Hz), 125.87 (s), 125.54 (d, J=3.5 Hz), 122.89 (dd, J=13.8, 4.0 Hz), 113.01 (d, J=3.0 Hz), 61.61 (d, J=4.2 Hz), 52.70 (s); ESIMS m/z 364 ([M+H]+). Anal. Calcd for C14H10Cl2F2N2O3: C, 46.30; H, 2.78; N, 7.71. Found: C, 46.60; H, 2.68; N, 7.51.

Workup

  1. customThe reaction mixture was purged with nitrogen
  2. temperatureUpon cooling to room temperature
  3. customa precipitate formed which
  4. filtrationwas filtered
  5. washwashed with water
  6. dissolutionThe precipitate was dissolved in EtOAc (ca 500 mL)
  7. washwashed with water
  8. dry with materialThe organic layer was dried (MgSO4)
  9. customthe solvent was removed
  10. customa rotary evaporator
  11. customto give an orange solid, which
  12. customwas dried in vacuum oven at 50° C. (11.46 g, 76% yield)

Sources & evidence

ORD record
ord-d9367efa7fc342a59ccc525edc27ab4b
Source dataset
uspto-grants-2013_12
Patent number
US08609853B2

Reaction notes

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