Potassium Fluoride → Methyl 4-acetamido-6-(4-amino-2,3,6-trifluorophenyl)-3-chloropicolinate

HRID 516552Notes

Reaction equation

HRID 516552 reaction equation
[C:1]([NH:4][C:5]1[CH:10]=[C:9]([Sn](C)(C)C)[N:8]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[C:6]=1[Cl:19])(=[O:3])[CH3:2].[F:20][C:21]1[C:27]([F:28])=[C:26](I)[C:25]([F:30])=[CH:24][C:22]=1[NH2:23].[F-].[K+]>CN(C=O)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.[Cu]I>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:26]2[C:25]([F:30])=[CH:24][C:22]([NH2:23])=[C:21]([F:20])[C:27]=2[F:28])[N:8]=[C:7]([C:15]([O:17][CH3:18])=[O:16])[C:6]=1[Cl:19])(=[O:3])[CH3:2]

Participants

7

Reactant 3

HCID 522689Potassium FluorideHCID 226773084-Acetylamino-3-chloro-6-trimethylstannylpyridine-2-carboxylic acid methyl esterHCID 462454002,3,5-Trifluoro-4-iodoaniline

Product 1

HCID 90408990Methyl 4-acetamido-6-(4-amino-2,3,6-trifluorophenyl)-3-chloropicolinateYield 53.2%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
20 °C

Procedure

A suspension of methyl 4-acetamido-3-chloro-6-(trimethylstannyl)picolinate (Head K) (0.502 g, 1.409 mmol, 1.0 eq), 2,3,5-trifluoro-4-iodoaniline (0.5 g, 1.831 mmol, 1.3 eq), bis(triphenylphosphine)palladium(II) chloride (0.098 g, 0.1401 mmol, 0.1 eq) and CuI (26 mg, 0.1401 mmol, 0.1 eq) in dry DMF (3 mL) was irradiated with microwave at 120° C. for 1 h. Reaction mixture was cooled to 20° C. and stirred with aqueous KF solution (20 mL) for 15 m and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anh. Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product was purified on silica gel (60-120) using a gradient from 0-30% EtOAc in hexanes yielded the title compound as a brown solid (280 mg, 44.8%): 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.32 (s, 1H), 6.51-6.46 (m, 1H), 6.22 (brs, 2H), 3.92 (s, 3H), 2.23 (s, 3H); ESIMS m/z 376 ([M+3H]+).

Workup

  1. customwas irradiated with microwave at 120° C. for 1 h
  2. customReaction mixture
  3. extractionextracted with ethyl acetate (3×100 mL)
  4. dry with materialThe combined organic layers were dried over anh. Na2SO4
  5. filtrationfiltered
  6. customevaporated to dryness under reduced pressure
  7. customThe crude product was purified on silica gel (60-120)

Sources & evidence

ORD record
ord-a75e2b2e113b410d9c2d6550f14073d8
Source dataset
uspto-grants-2015_08
Patent number
US09113629B2

Reaction notes

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