Citric Acid → Bis(1,1-dimethylethyl) {3-[(3-chloro-5-cyanophenyl)oxy]-2-fluoro-4-nitrophenyl}propanedioate

HRID 1874778Notes

Reaction equation

HRID 1874778 reaction equation
[H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][C:28]2[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[C:30](F)[C:29]=2[F:38])[CH:26]=1)[C:22]#[N:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.C1COCC1>[Cl:18][C:19]1[CH:26]=[C:25]([O:27][C:28]2[C:29]([F:38])=[C:30]([CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:31]=[CH:32][C:33]=2[N+:34]([O-:36])=[O:35])[CH:24]=[C:21]([C:22]#[N:23])[CH:20]=1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 24758Sodium hydrideHCID 68324Di-tert-butyl malonateHCID 25158671HCID 25158671, compound

Product 1

HCID 59451518Bis(1,1-dimethylethyl) {3-[(3-chloro-5-cyanophenyl)oxy]-2-fluoro-4-nitrophenyl}propanedioate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% dispersion in oil, 2.16 g, 54.1 mmol) was added to anhydrous THF (50 mL) and cooled to 0° C. under nitrogen. Di-tert-butyl malonate (4.65 g, 24.8 mmol) was added dropwise and the reaction mixture was stirred 15 min and allowed to warm to RT. The reaction was cooled to 0° C. and 3-chloro-5-[(2,3-difluoro-6-nitrophenyl)oxy]benzonitrile (7.0 g, 22.5 mmol) was added dropwise in a minimal amount of THF. The reaction was allowed to warm to RT and stirred for 3 h then 10% aqueous citric acid (50 ml) and EtOAc (50 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with brine, dried over Na2SO4, filtered and evaporated to afford the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): 6 ppm 8.13 (dd, 1H), 7.84 (d, 1H), 7.65 (dd, 1H), 7.59-7.61 (m, 1H), 7.56-7.59 (m, 1H), 5.10 (s, 1H), 1.40 (s, 18H). MS: m/z 507.2 (M+1).

Workup

  1. temperatureto warm to RT
  2. temperatureThe reaction was cooled to 0° C.
  3. temperatureto warm to RT
  4. stirringstirred for 3 h
  5. customThe layers were separated
  6. extractionthe aqueous layer was extracted with EtOAc (2×50 mL)
  7. washwashed with brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. customevaporated

Sources & evidence

ORD record
ord-5ad20c59915747048c89e785f05d61a1
Source dataset
uspto-grants-2012_11
Patent number
US08304419B2

Reaction notes

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