Isopropanol → HCID 89943214, compound

HRID 541055Notes

Reaction equation

HRID 541055 reaction equation
Cl[C:2]1[C:7](Cl)=C(C2C=CC(OC)=CC=2)N=C(C(Cl)=O)[CH:3]=1.[F-].[K+].[F:22][C:23]1[C:28]([F:29])=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[N:26]=[C:25]([C:38](F)=[O:39])[CH:24]=1.C(N(CC)CC)C.C([OH:51])(C)C>S1(CCCC1)(=O)=O.O>[F:22][C:23]1[C:28]([F:29])=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[N:26]=[C:25]([C:38]([O:39][CH:2]([CH3:7])[CH3:3])=[O:51])[CH:24]=1

Participants

8

Reactant 5

HCID 3776IsopropanolHCID 8471TriethylamineHCID 522689Potassium Fluoride2×HCID 86709877HCID 86709877, compoundHCID 89942771HCID 89942771, compound

Product 1

HCID 89943214HCID 89943214, compoundYield 25%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31347SulfolaneSolvent

Conditions

Temperature
150 °C

Procedure

To a solution of 4,5-dichloro-6-(4-methoxyphenyl)picolinoyl chloride (2.5 g, 7.9 mmol) in sulfolane (40 mL, dried over 4 Å molecular sieves, 100 ppm of water) was added potassium fluoride (2.75 g, 47.4 mmol). The reaction mixture was heated at 150° C. for 24 h. Additional potassium fluoride (1.4 g, 24 mmol) was added, and reaction mixture was heated at 150° C. for an additional 24 h. Reaction mixture was analyzed by GC-MS and 19F NMR. Data for 4,5-difluoro-6-(4-methoxyphenyl)picolinoyl fluoride, GC-MS: m/z=267, 224, 176; 19F NMR (376 MHz, Tol) δ 16.94 (s), −124.65 (d, J=19.1 Hz), −141.23 (d, J=19.1 Hz). Reaction was allowed to cool to room temperature, and triethylamine (1.4 mL, 9.9 mmol) and isopropanol (0.9 mL, 11.9 mmol) were added. After stirring for 1.5 h, the reaction mixture was diluted with water (125 mL) and transferred to a reparatory funnel. The reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2×75 mL). The combined organic extracts were washed with water (3×75 mL) and saturated NaCl (75 mL) and concentrated under reduced pressure to provide a brown oil. The crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane→20% hexane/ethyl acetate) to provide 0.60 g (25% yield) of isopropyl 4,5-difluoro-6-(4-methoxyphenyl)picolinate as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.08-8.01 (m, 2H), 7.82 (dd, J=9.5, 5.2 Hz, 1H), 7.04-6.97 (m, 2H), 5.30 (hept, J=6.3 Hz, 1H), 3.86 (s, 3H), 1.42 (d, J=6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 162.93 (s), 161.22 (s), 156.68 (dd, J=263.5, 12.7 Hz), 147.70 (dd, J=267.9, 10.9 Hz), 146.61 (dd, J=286.4, 10.5 Hz), 145.18 (s), 130.53 (d, J=6.6 Hz), 126.43, 114.02 (s), 112.77 (d, J=16.1 Hz), 69.99 (s), 55.32 (s), 21.82 (s); 19F NMR (376 MHz, CDCl3) δ −125.81 (d, J=17.7 Hz), −145.30 (d, J=19.1 Hz); MS Calcd. for C16H15F2NO3: 307.10. Found: 307 (M+), 221, 206.

Workup

  1. customreaction mixture
  2. temperaturewas heated at 150° C. for an additional 24 h
  3. customReaction mixture
  4. customReaction
  5. temperatureto cool to room temperature
  6. customtransferred to a reparatory funnel
  7. extractionThe reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2×75 mL)
  8. washThe combined organic extracts were washed with water (3×75 mL) and saturated NaCl (75 mL)
  9. concentrationconcentrated under reduced pressure
  10. customto provide a brown oil
  11. customThe crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane→20% hexane/ethyl acetate)

Sources & evidence

ORD record
ord-3d4f602c129443929a9125b75302500d
Source dataset
uspto-grants-2014_10
Patent number
US08871943B2

Reaction notes

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