Sodium hydride → HCID 22222501, compound

HRID 1794631Notes

Reaction equation

HRID 1794631 reaction equation
[H-].[Na+].CC1C(C)=C(O)C2C(=CC(F)=C(F)C=2)N=1.[CH2:18]([C:20]1[C:29]([CH3:30])=[C:28]([O:31][C:32]([CH:34]2[CH2:36][CH2:35]2)=[O:33])[C:27]2[C:22](=[CH:23][C:24]([F:38])=[C:25]([F:37])[CH:26]=2)[N:21]=1)C.[CH2:39]([C:41]1[C:50]([CH3:51])=[C:49]([O:52][C:53]([CH:55]2[CH2:57][CH2:56]2)=[O:54])[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([F:59])[C:47]=2[F:58])[N:42]=1)C>O1CCCC1.O>[CH3:18][C:20]1[C:29]([CH3:30])=[C:28]([O:31][C:32]([CH:34]2[CH2:35][CH2:36]2)=[O:33])[C:27]2[C:22](=[CH:23][C:24]([F:38])=[C:25]([F:37])[CH:26]=2)[N:21]=1.[CH3:39][C:41]1[C:50]([CH3:51])=[C:49]([O:52][C:53]([CH:55]2[CH2:56][CH2:57]2)=[O:54])[C:48]2[C:43](=[CH:44][CH:45]=[C:46]([F:59])[C:47]=2[F:58])[N:42]=1

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 9857197HCID 9857197, compound2×HCID 22222485HCID 22222485, compound3×HCID 178432237HCID 178432237, compound

Product 2

HCID 22222501HCID 22222501, compoundHCID 22222520HCID 22222520, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

3,4-Difluoroaniline (5.16 g) and 5.76 g of ethyl-2-methyl acetoacetate were refluxed in toluene (80 ml) in the presence of 0.3 ml of boron trifluoride etherate for 3 hr. The reaction mixture was 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 4.0 g of a mixture of 2,3-dimethyl-4-hydroxy-6,7-difluoroquinoline with 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline. In 10 ml of tetrahydrofuran was suspended 230 mg of 60% sodium hydride. The mixture of 2,3-dimethyl-4-hydroxy-6,7-difluoroquinoline with 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) (1 g) was suspended in 20 ml of tetrahydrofuran, and this suspension of starting material 1 was added dropwise to the above suspension under ice cooling. The reaction mixture was stirred for one hr. Cyclopropanecarbonyl chloride (starting material 2) (600 mg) was then added thereto, and the mixture was stirred at room temperature for 15 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 (200 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 890 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-6,7-difluoroquinoline (compound 15) and 90.6 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-5,6-difluoroquinoline (compound 16). 1H-NMR data are shown in Table 3.

Workup

  1. additionwas added dropwise to the above suspension under ice cooling
  2. stirringthe mixture was stirred at room temperature for 15 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(200 ml; elution solvent=n-hexane-ethyl acetate (10:1))

Sources & evidence

ORD record
ord-914b98fc00b1488ea284a26efe684689
Source dataset
uspto-grants-2006_04
Patent number
US07022855B2

Reaction notes

Loading…