Reacción #1994306

Ecuación de reacción

Methyl 4-methoxypicolinate

phenyl chloroformate

(4-chloro-2-fluoro-3-methoxyphenyl)zinc(II) chloride

→

6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-5,6-dihydro-4H-pyridine-1,2-dicarboxylic acid 2-methyl ester 1-phenyl ester

Rendimiento 57.1%

Disolventes

THF

Condiciones de reacción

Tratamiento posterior

1. 1
   TemperaturaThe solution was cooled in an ice bath
2. 2
   Otroquenched by addition of a saturated aqueous ammonium chloride (NH4Cl) solution (200 mL)
3. 3
   OtroThe organic layer was separated
4. 4
   Extracciónthe aqueous layer was extracted with ether (2×100 mL)
5. 5
   LavadoThe combined organic extracts were washed with H2O
6. 6
   SecadoThe solution was dried (MgSO4)
7. 7
   Otroevaporated to a bright yellow liquid which
8. 8
   workup.DISSOLUTIONwas dissolved in THF (250 mL)
9. 9
   workup.STIRRINGThe reaction mixture was stirred at room temperature for 2 d
10. 10
    ExtracciónThe reaction mixture was extracted with ether
11. 11
    LavadoThe ether extracts were washed with H2O
12. 12
    Secadodried (MgSO4)
13. 13
    Otroevaporated to a yellow oil
14. 14
    OtroThe crude product was purified by silica gel chromatography (hexane-EtOAc gradient)
15. 15
    Otroto give a yellow oil
16. 16
    OtroThe oil was crystallized from MeOH

Procedimiento

Methyl 4-methoxypicolinate (11.92 g, 0.0713 mol) was dissolved in anhydrous THF (300 mL) under N2. The solution was cooled in an ice bath. Neat phenyl chloroformate (10.5 mL, 0.0837 mol) was added. After 45 min the stock solution of (4-chloro-2-fluoro-3-methoxyphenyl)zinc(II) chloride (1.19 M in THF, 76.0 mL, 0.0904 mol) was added dropwise over 1 h. The solution was stirred at room temperature for 3 days (d) and then quenched by addition of a saturated aqueous ammonium chloride (NH4Cl) solution (200 mL). The organic layer was separated, and the aqueous layer was extracted with ether (2×100 mL). The combined organic extracts were washed with H2O and then brine. The solution was dried (MgSO4) and evaporated to a bright yellow liquid which was dissolved in THF (250 mL) and 1 M HCl (250 mL). The reaction mixture was stirred at room temperature for 2 d and then neutralized with saturated NaHCO3 solution. The reaction mixture was extracted with ether. The ether extracts were washed with H2O followed by brine, then dried (MgSO4) and evaporated to a yellow oil. The crude product was purified by silica gel chromatography (hexane-EtOAc gradient) to give a yellow oil. The oil was crystallized from MeOH to give 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-5,6-dihydro-4H-pyridine-1,2-dicarboxylic acid 2-methyl ester 1-phenyl ester (15; 17.67 g, 57%) as a white solid: mp 112-114° C.; 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 2H), 7.27 (m, 1H), 7.14 (m, 4H), 6.22 (d, J=6.6 Hz, 1H, H6), 5.90 (d, J=1.2 Hz, 1H, H3), 3.97 (d, JF-H=0.9 Hz, 3H, OMe), 3.87 (s, 3H, CO2Me), 3.30 (dd, J=6.6, 17.4 Hz, 1H, H5a), 3.05 (d, J=18 Hz, 1H, H5b); 13C{1H} NMR (75.4 MHz, CDCl3) δ 191.7 (C4), 163.8 (CO2Me), 153.9 (d, JF-C=250 Hz, C2′), 151.0, 150.3, 145.0, 144.8, 129.6 (meta Ph), 128.8 (d, JF-C=3 Hz, C4′), 126.5 (para Ph), 125.2 (d, JF-C=3 Hz, C5′), 124.5 (d, JF-C=12 Hz, C1′), 121.0 (d, JF-C=4 Hz, C6′), 120.9 (ortho Ph), 114.5 (C3), 61.6 (d, JF-C=5 Hz, OMe), 53.8, 53.4, 41.6; Anal. Calcd for C21H17ClFNO6: C, 58.14; H, 3.95; N, 3.23. Found: C, 57.82; H, 3.90; N, 3.18.

Fuente