反応 #1994306

反応方程式

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

収率 57.1%

溶媒

THF

反応条件

後処理

1. 1
   温度The solution was cooled in an ice bath
2. 2
   その他quenched by addition of a saturated aqueous ammonium chloride (NH4Cl) solution (200 mL)
3. 3
   その他The organic layer was separated
4. 4
   抽出the aqueous layer was extracted with ether (2×100 mL)
5. 5
   洗浄The combined organic extracts were washed with H2O
6. 6
   乾燥The solution was dried (MgSO4)
7. 7
   その他evaporated 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
    抽出The reaction mixture was extracted with ether
11. 11
    洗浄The ether extracts were washed with H2O
12. 12
    乾燥dried (MgSO4)
13. 13
    その他evaporated to a yellow oil
14. 14
    その他The crude product was purified by silica gel chromatography (hexane-EtOAc gradient)
15. 15
    その他to give a yellow oil
16. 16
    その他The oil was crystallized from MeOH

実験手順

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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