1,4-Dioxane → HCID 58936501, compound

HRID 855771Notes

Reaction equation

HRID 855771 reaction equation
[C:1]([O:5][C:6]1[C:13]([F:14])=[CH:12][C:9]([C:10]#[N:11])=[C:8](F)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O1CCOCC1>CCOCC>[CH3:17][O:18][C:19](=[O:28])[CH:20]([C:8]1[C:9]([C:10]#[N:11])=[CH:12][C:13]([F:14])=[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:7]=1)[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]

Participants

5

Reactant 3

HCID 312751,4-DioxaneHCID 58936498HCID 58936498, compoundHCID 86608633HCID 86608633, compound

Product 1

HCID 58936501HCID 58936501, compound

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
95 °C

Procedure

A thick mixture of 6-tert-butoxy-2,5-difluoro-nicotinonitrile (18.22 g, 85.9 mmol), as prepared in Example 1b, malonic acid tert-butyl ester methyl ester sodium salt (34.49 g, 176 mmol), as prepared in the previous step, and dioxane (110 mL) was stirred under argon at 95° C. (oil bath) for 14 h. The resulting homogeneous dark amber solution was allowed to cool to rt, diluted with ether (150 mL), and washed with a solution of 1.0 M NaH2PO4 (200 mL) containing 2.0 M citric acid (40 mL). The aqueous layer was back-extracted with ether (1×100 mL), the organic layers were combined, washed with 4 M NaCl (1×100 mL), dried (Na2SO4), and concentrated under reduced pressure. Malonic acid tert-butyl ester methyl ester was largely removed from the residue by high vacuum at 95° C. for 1 h to afford the title compound as a clear, dark brown viscous oil (32.37 g, approx. 100% crude yield). 1H-NMR (300 MHz, CDCl3) δ 7.48 (d, 1H), 5.06 (s, 1H), 3.80 (s, 3H), 1.62 (s, 9H), 1.47 (s, 9H).

Workup

  1. temperatureto cool to rt
  2. washwashed with a solution of 1.0 M NaH2PO4 (200 mL)
  3. additioncontaining 2.0 M citric acid (40 mL)
  4. extractionThe aqueous layer was back-extracted with ether (1×100 mL)
  5. washwashed with 4 M NaCl (1×100 mL)
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated under reduced pressure
  8. customMalonic acid tert-butyl ester methyl ester was largely removed from the residue by high vacuum at 95° C. for 1 h

Sources & evidence

ORD record
ord-845071af4def49cab19189ff280f9486
Source dataset
uspto-grants-2007_08
Patent number
US07262210B2

Reaction notes

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