Reacción #2358578

Ecuación de reacción

methyl 4,6-dichloropicolinate

2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Na2CO3

→

4,6-Dichloropicolinate

methyl 4-chloro-6-(4-(4-fluorophenoxy)phenyl)picolinate

Disolventes

dioxane

Condiciones de reacción

Tratamiento posterior

1. 1
   TemperaturaThe vessel was heated
2. 2
   Temperaturaat reflux under nitrogen overnight
3. 3
   TemperaturaAfter cooling
4. 4
   Otrothe reaction was partitioned between 100 mL EtOAc and 50 mL brine
5. 5
   Lavadowashed with additional brine
6. 6
   SecadoThe organics were dried over MgSO4
7. 7
   Filtraciónfiltered
8. 8
   Concentraciónconcentrated in vacuo
9. 9
   workup.DISSOLUTIONThe residue was dissolved in MeOH (150 mL)
10. 10
    workup.ADDITIONconcentrated H2SO4 (1.5 mL) was added
11. 11
    TemperaturaThe vessel was heated
12. 12
    Temperaturaat reflux under nitrogen overnight
13. 13
    TemperaturaAfter cooling the reaction
14. 14
    Otrowas quenched by addition of 10 g NaHCO3
15. 15
    OtroThe mixture was evaporated in vacuo
16. 16
    Otrothe residue partitioned between 100 mL EtOAc and 50 mL brine
17. 17
    LavadoThe organics were washed once with 50 mL brine
18. 18
    ExtracciónThe combined aqueous washes were extracted once with 50 mL EtOAc
19. 19
    SecadoThe combined organics were dried over MgSO4
20. 20
    Filtraciónfiltered
21. 21
    Concentraciónconcentrated in vacuo
22. 22
    OtroThe residue was chromatographed over silica gel eluting with 5-25% EtOAc in hexanes
23. 23
    OtroThe product fractions were isolated
24. 24
    Otroevaporated in vacuo

Procedimiento

4,6-Dichloropicolinate was synthesized according to the procedures described in WO 2006/053227. To a solution of the methyl 4,6-dichloropicolinate (2.52 g, 12.2 mmol) in dioxane (100 mL) was added 2-(4-(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.83 g, 12.2 mmol), 2M aqueous Na2CO3 solution (12.5 mL, 25 mmol) and PdCl2(dppf) (0.502 g, 0.62 mmol). The vessel was heated at reflux under nitrogen overnight. After cooling, the reaction was partitioned between 100 mL EtOAc and 50 mL brine and washed with additional brine. The organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in MeOH (150 mL) and concentrated H2SO4 (1.5 mL) was added. The vessel was heated at reflux under nitrogen overnight. After cooling the reaction was quenched by addition of 10 g NaHCO3. The mixture was evaporated in vacuo and the residue partitioned between 100 mL EtOAc and 50 mL brine. The organics were washed once with 50 mL brine. The combined aqueous washes were extracted once with 50 mL EtOAc. The combined organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with 5-25% EtOAc in hexanes. The product fractions were isolated and evaporated in vacuo to yield the product methyl 4-chloro-6-(4-(4-fluorophenoxy)phenyl)picolinate as a pale tan oil (1.426 g, 3.99 mmol, 33% yield, LC/MS: m/z=358.1 [M+H]+).

Fuente