Réaction #1994306

Équation de réaction

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

Rendement 57.1%

Solvants

THF

Conditions de réaction

Traitement

1. 1
   TempératureThe solution was cooled in an ice bath
2. 2
   Autrequenched by addition of a saturated aqueous ammonium chloride (NH4Cl) solution (200 mL)
3. 3
   AutreThe organic layer was separated
4. 4
   Extractionthe aqueous layer was extracted with ether (2×100 mL)
5. 5
   LavageThe combined organic extracts were washed with H2O
6. 6
   SéchageThe solution was dried (MgSO4)
7. 7
   Autreevaporated 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
    ExtractionThe reaction mixture was extracted with ether
11. 11
    LavageThe ether extracts were washed with H2O
12. 12
    Séchagedried (MgSO4)
13. 13
    Autreevaporated to a yellow oil
14. 14
    AutreThe crude product was purified by silica gel chromatography (hexane-EtOAc gradient)
15. 15
    Autreto give a yellow oil
16. 16
    AutreThe oil was crystallized from MeOH

Mode opératoire

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.

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