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

HRID 889654Notes

Reaction equation

HRID 889654 reaction equation
C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].[Cl-].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Zn+])=[C:27]([F:32])[C:26]=1[O:33][CH3:34]>C1COCC1>[C:17]1([O:16][C:14]([N:6]2[CH:7]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([O:33][CH3:34])[C:27]=3[F:32])[CH2:8][C:3](=[O:2])[CH:4]=[C:5]2[C:9]([O:11][CH3:12])=[O:10])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1

Participants

5

Reactant 3

HCID 15891Phenyl chloroformateHCID 1519345Methyl 4-methoxypyridine-2-carboxylateHCID 178492964HCID 178492964, compound

Product 1

HCID 596121126-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-5,6-dihydro-4H-pyridine-1,2-dicarboxylic acid 2-methyl ester 1-phenyl esterYield 57.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

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.

Workup

  1. temperatureThe solution was cooled in an ice bath
  2. customquenched by addition of a saturated aqueous ammonium chloride (NH4Cl) solution (200 mL)
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with ether (2×100 mL)
  5. washThe combined organic extracts were washed with H2O
  6. dry with materialThe solution was dried (MgSO4)
  7. customevaporated to a bright yellow liquid which
  8. dissolutionwas dissolved in THF (250 mL)
  9. stirringThe reaction mixture was stirred at room temperature for 2 d
  10. extractionThe reaction mixture was extracted with ether
  11. washThe ether extracts were washed with H2O
  12. dry with materialdried (MgSO4)
  13. customevaporated to a yellow oil
  14. customThe crude product was purified by silica gel chromatography (hexane-EtOAc gradient)
  15. customto give a yellow oil
  16. customThe oil was crystallized from MeOH

Sources & evidence

ORD record
ord-a135a5605e3c424c9dd8889837b1d2c2
Source dataset
uspto-grants-2012_08
Patent number
US08252938B2

Reaction notes

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