Ethanol → Ethyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(difluoromethoxy)picolinate

HRID 407220Notes

Reaction equation

HRID 407220 reaction equation
Cl[C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[C:6]([NH2:12])[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:3]=1.C(N([CH2:28][CH3:29])CC)C.[C]=[O:31].C[CH2:33][OH:34]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:12][C:6]1[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:3]=[C:2]([C:33]([O:34][CH2:28][CH3:29])=[O:31])[C:7]=1[O:8][CH:9]([F:11])[F:10]

Participants

6

Reactant 4

HCID 702EthanolHCID 8471TriethylamineHCID 866754052-Chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(difluoromethoxy)pyridin-4-amineHCID 178418416HCID 178418416, compound

Product 1

HCID 71150498Ethyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(difluoromethoxy)picolinateYield 35.7%

Reagents, catalysts & solvents 1

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst

Conditions

Temperature
105 °C

Procedure

2-Chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-(difluoromethoxy)pyridin-4-amine (0.2 g, 0.566 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) ((C17H14P)2Fe·PdCl2; 0.041 g, 0.057 mmol), and triethylamine (Et3N, 0.158 mL, 1.133 mmol) were combined in EtOH (5 mL) in a 45 mL bomb reactor. The bomb reactor was pressurized to 400 pounds per square inch (psi) with carbon monoxide (CO) and the reaction was heated at 105° C. for 40 h. The reaction mixture was then filtered through a small plug of silica gel utilizing EtOAc as the eluent. The filtrate was concentrated, and the product was purified by column chromatography (SiO2, hexane/EtOAc gradient) to yield the title compound as a white solid (79 mg, 35.7%): 1H NMR (300 MHz, CDCl3) δ 7.66 (dd, J=8.6, 7.7 Hz, 1H), 7.28-7.24 (m, 1H), 7.22 (d, J=1.7 Hz, 1H), 6.72 (t, J=75.1 Hz, 1H), 4.73 (s, 2H), 4.46 (q, J=7.1 Hz, 2H), 3.97 (d, J=0.8 Hz, 3H), 1.42 (t, J=7.2 Hz, 3H); ESIMS m/z 391 ([M+H]+), 389 ([M−H]−); 19F NMR (376 MHz, CDCl3) δ −79.74, −132.19.

Workup

  1. filtrationThe reaction mixture was then filtered through a small plug of silica gel
  2. concentrationThe filtrate was concentrated
  3. customthe product was purified by column chromatography (SiO2, hexane/EtOAc gradient)

Sources & evidence

ORD record
ord-d0b4a627a330406184dd08df5527f2b2
Source dataset
uspto-grants-2014_06
Patent number
US08754229B2

Reaction notes

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