Sodium hydride → HCID 22222496, compound

HRID 1794636Notes

Reaction equation

HRID 1794636 reaction equation
[H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:17])=[C:9]([F:16])[CH:10]=2)[N:5]=1.C(C1C(C)=C([O:31][C:32]([CH:34]2[CH2:36][CH2:35]2)=O)C2C(=CC(F)=C(F)C=2)N=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]=2F)[N:42]=1)C>CN(C)C=O.O>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([O:15][C:32]([CH:34]2[CH2:36][CH2:35]2)=[O:31])[C:11]2[C:6](=[CH:7][C:8]([Cl:17])=[C:9]([F:16])[CH:10]=2)[N:5]=1.[CH3:39][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[Cl:17])[N:42]=1

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 9857197HCID 9857197, compound2×HCID 22222485HCID 22222485, compound2×HCID 178432197HCID 178432197, compound

Product 2

HCID 22222496HCID 22222496, compoundHCID 22222498HCID 22222498, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

3-Chloro-4-fluoroaniline (5.0 g) and 4.9 g of ethyl-2-methyl acetoacetate were refluxed in toluene (50 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 mixture was allowed to stand for cooling, and the precipitate was then collected by filtration under the reduced pressure to give 1.7 g of a mixture of 2,3-dimethyl-4-hydroxy-6-fluoro-7-chloroquinoline with 2,3-dimethyl-4-hydroxy-5-chloro-6-fluoroquinoline. In 50 ml of dimethyl formamide was suspended 350 mg of 60% sodium hydride. Separately, the mixture of 2,3-dimethyl-4-hydroxy-6-fluoro-7-chloroquinoline with 2,3-dimethyl-4-hydroxy-5-chloro-6-fluoroquinoline (starting material 1) (1.7 g) was suspended in 30 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 940 μl of cyclopropanecarbonyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 13 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 480 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-6-fluoro-7-chloroquinoline (compound 26) and 350 mg of 2,3-dimethyl-4-cyclopropanecarbonyloxy-5-chloro-6-fluoro -quinoline (compound 27). 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 13 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-f092477bc79a4046823c7aa59d3cf5ce
Source dataset
uspto-grants-2006_04
Patent number
US07022855B2

Reaction notes

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