Acetonitrile → 4-Amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)picolinonitrile

HRID 407174

Reaction equation

HRID 407174 reaction equation
[NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B2OCCCO2)=[C:16]([F:26])[C:15]=1[O:27][CH3:28].[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:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([O:27][CH3:28])[C:16]=2[F:26])[N:5]=[C:4]([C:10]#[N:11])[C:3]=1[Cl:12]

Participants

7

Reactant 4

HCID 6342AcetonitrileHCID 522689Potassium FluorideHCID 577824192-(4-Chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinaneHCID 71551457HCID 71551457, compound

Product 1

HCID 704956694-Amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)picolinonitrileYield 57.2%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
75 °C

Procedure

A mixture of 4-amino-3,6-dichloro-5-fluoropicolinonitrile (0.37 g, 1.80 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (0.549 g, 2.24 mmol) and KF (0.209 g, 3.59 mmol) was taken into acetonitrile (6.75 mL) and water (2.25 mL). The mixture was stirred and sparged with a nitrogen atmosphere. Pd(PPh3)2Cl2 (63mg, 0.1 mmol) was added, and the mixture was again sparged with nitrogen. The solution was then heated to 75° C. under nitrogen for 2 h. Upon cooling down, a precipitate formed and was collected by filtration, washed with water and dried under vacuum to give the product (0.34 g) as an off-white solid. The aqueous phase was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried, and concentrated. Purification by silica gel chromatography gave additional product (0.12 g) as a white solid. Total yield 78%. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (dd, J=8.5, 1.4 Hz, 1H), 7.45 (s, 2H), 7.33 (dd, J=8.5, 7.2 Hz, 1H), 3.94 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 152.97 (d, J=253.2 Hz), 145.73 (d, J=260.8 Hz), 143.82 (d, J=13.7 Hz), 141.83 (d, J=14.7 Hz), 138.45 (d, J=14.8 Hz), 133.93-132.79 (m), 128.93 (d, J=3.3 Hz), 127.74 (s), 126.37-125.10 (m), 122.08 (dd, J=13.6, 3.9 Hz), 119.34 (d, J=4.5 Hz), 114.99 (s), 61.61 (s); 19F NMR (376 MHz, DMSO-d6) δ −129.00 (dd, J=28.2, 7.0 Hz, 1F), −133.76 (d, J=28.2 Hz, 1F); ESIMS m/z 330.1 ([M+H]+).

Workup

  1. customsparged with a nitrogen atmosphere
  2. customthe mixture was again sparged with nitrogen
  3. temperatureUpon cooling down
  4. customa precipitate formed
  5. filtrationwas collected by filtration
  6. washwashed with water
  7. customdried under vacuum

Sources & evidence

ORD record
ord-e2a3054ad0674d5ab7f8b0a59adfa181
Source dataset
uspto-grants-2014_06
Patent number
US08754231B2

Linked notes

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