Acetonitrile → Methyl 4-amino-6-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-fluoro-3-methoxypicolinate

HRID 407232

Reaction equation

HRID 407232 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[O:14][CH3:15].[F:16][C:17]1[C:22]([F:23])=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[Si:33]([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+].CC#N>CCOC(C)=O.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:21]2[CH:20]=[CH:19][C:18]([Si:33]([CH3:34])([CH3:36])[CH3:35])=[C:17]([F:16])[C:22]=2[F:23])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]

Participants

8

Reactant 4

HCID 6342AcetonitrileHCID 10340Sodium CarbonateHCID 71150347(2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)trimethylsilaneHCID 86675409Methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate

Product 1

HCID 71150573Methyl 4-amino-6-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-fluoro-3-methoxypicolinateYield 75.5%

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
115 °C

Procedure

To a 20 mL microwave vial were added methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.80 g, 3.41 mmol), (2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)trimethylsilane (1.28 g, 4.09 mmol), sodium carbonate (Na2CO3; 0.36 g, 3.41 mmol), and PdCl2(PPh3)2 (0.24 g, 0.34 mmol). Subsequently, CH3CN (5.7 mL) and H2O (5.7 mL) were added, and the reaction vial was sealed and heated in a Biotage microwave to 115° C. for 20 min. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (2×2 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using a Teledyne ISCO purification system with a gradient eluent system of EtOAc and hexanes to yield methyl 4-amino-6-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-fluoro-3-methoxypicolinate (0.99 g, 75%) as a white solid: mp 123-125° C.; 1H NMR (400 MHz, CDCl3) δ 7.32 (ddd, J=7.6, 5.5, 1.1 Hz, 1H), 7.20 (ddd, J=7.7, 4.5, 1.4 Hz, 1H), 4.60 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 0.41-0.28 (m, 9H); 19F NMR (376 MHz, CDCl3) δ −127.39, −127.45, −127.46, −137.48, −137.56, −140.78, −140.85, −140.86, −140.92; ESIMS m/z 383.20 ([M−H]−).

Workup

  1. customthe reaction
  2. customvial was sealed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. customThe organic layer was separated
  5. extractionthe aqueous phase was extracted with EtOAc (2×2 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified
  10. customa Teledyne ISCO purification system with a gradient eluent system of EtOAc and hexanes

Sources & evidence

ORD record
ord-02c12041227a4f089b0cb4f9911c3f8a
Source dataset
uspto-grants-2014_06
Patent number
US08754229B2

Linked notes

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