Sodium hydride → HCID 9965565, compound

HRID 1794633Notes

Reaction equation

HRID 1794633 reaction equation
[H-].[Na+].[CH2:3]([C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][C:9]([Cl:18])=[C:10]([F:17])[CH:11]=2)[N:6]=1)[CH3:4].C(C1C(C)=[C:29]([O:32]C(C2CC2)=O)[C:28]2C(=CC(F)=C(F)C=2)N=1)C.[CH2:40]([C:42]1[C:51]([CH3:52])=[C:50]([O:53][C:54]([CH:56]2CC2)=[O:55])[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([F:60])[C:48]=2F)[N:43]=1)[CH3:41]>O1CCCC1.O>[CH2:3]([C:5]1[C:14]([CH3:15])=[C:13]([O:16][C:29](=[O:32])[CH3:28])[C:12]2[C:7](=[CH:8][C:9]([Cl:18])=[C:10]([F:17])[CH:11]=2)[N:6]=1)[CH3:4].[CH2:40]([C:42]1[C:51]([CH3:52])=[C:50]([O:53][C:54](=[O:55])[CH3:56])[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([F:60])[C:48]=2[Cl:18])[N:43]=1)[CH3:41]

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 9857197HCID 9857197, compound2×HCID 22222485HCID 22222485, compound2×HCID 178437472HCID 178437472, compound

Product 2

HCID 9965565HCID 9965565, compoundHCID 22222484HCID 22222484, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

3-Chloro-4-fluoroaniline (2.91 g) and 3.16 g of ethyl-2-methylpropionyl acetate were refluxed in toluene (60 ml) in the presence of 0.3 ml of boron trifluoride etherate for 3 hr. The reaction mixture was then washed with a saturated sodium hydrogencarbonate solution and saturated brine and was dried over anhydrous sodium sulfate, and the solvent was then removed by evaporation. The resultant intermediate was refluxed in diphenyl ether for 30 min. The reaction solution was allowed to stand for cooling, and the precipitate was then collected by filtration under the reduced pressure to give 820 mg of a mixture of 2-ethyl-3-methyl-4-hydroxy-6-fluoro-7-chloroquinoline with 2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline. In 10 ml of tetrahydrofuran was suspended 90.3 mg of 60% sodium hydride. The mixture of 2-ethyl-3-methyl-4-hydroxy-6-fluoro-7-chloroquinoline with 2-ethyl-3-methyl-4-hydroxy-5-chloro-6-fluoroquinoline (starting material 1) (400 mg) was suspended in 10 ml of tetrahydrofuran, and this suspension was added dropwise to the above suspension under ice cooling. The mixture was stirred for one hr. Acetyl chloride (starting material 2) (180 μl) was then added thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 17.5 mg of 2-ethyl-3-methyl-4-acetyloxy-6-fluoro-7-chloroquinoline (compound 18) and 44.6 mg of 2-ethyl-3-methyl-4-acetyloxy-5-chloro-6-fluoroquinoline (compound 19). 1H-NMR data are shown in Table 3.

Workup

  1. additionthis suspension was added dropwise to the above suspension under ice cooling
  2. stirringthe mixture was stirred at room temperature for 3 hr
  3. extractionthe mixture was extracted with ethyl acetate
  4. washThe ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine
  5. dry with materialwas then dried over anhydrous sodium sulfate
  6. customThe solvent was then removed by evaporation under the reduced pressure
  7. customThe crude product thus obtained
  8. customwas purified on Wako Gel
  9. wash(100 ml; elution solvent=n-hexane-ethyl acetate (10:1))

Sources & evidence

ORD record
ord-19d7daff51d44ac89f4a50c68fcfdcdf
Source dataset
uspto-grants-2006_04
Patent number
US07022855B2

Reaction notes

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