Sodium hydride → 7-[2-Cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-7-hydroxy-3,5-dioxoheptanoic acid ethyl ester

HRID 1063480Notes

Reaction equation

HRID 1063480 reaction equation
[H-].[Na+].[CH2:3]([O:5][C:6](=[O:14])[CH2:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])[CH3:4].C([Li])CCC.[CH:20]1([C:23]2[C:32]([CH:33]=[O:34])=[C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCC.C1(C)C=CC=CC=1.C(O)(=O)C.O1CCCC1>[CH2:3]([O:5][C:6](=[O:14])[CH2:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH2:11][CH:33]([C:32]1[C:23]([CH:20]2[CH2:21][CH2:22]2)=[N:24][C:25]2[C:30]([C:31]=1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:34])[CH3:4]

Participants

10

Reactant 4

HCID 24758Sodium hydrideHCID 99479742-Cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxaldehydeHCID 11332732Ethyl 3,5-dioxohexanoateHCID 178418339Butyllithium

Product 1

HCID 234015247-[2-Cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-7-hydroxy-3,5-dioxoheptanoic acid ethyl esterYield 89.2%

Reagents, catalysts & solvents 5

HCID 176Acetic AcidSolventHCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent3×HCID 8058HexaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

In a mixture solution of 2.40 g of an oily 60% sodium hydride and 200 ml of tetrahydrofuran, a mixture solution of 10.3 g of 3,5-dioxohexanoic acid ethyl ester and 40 ml of tetrahydrofuran was dropped in 20 minutes while keeping an inner temperature at 2° C. or less. After allowing a reaction for 50 minutes at −10° C., 75 ml of a hexane solution of 1.6 M n-butyl lithium was dropped in 40 minutes with the inner temperature kept at −20 to −15° C., while allowing a reaction for 40 minutes at an inner temperature of 2° C. or less. In this case, furthermore, while keeping an inner temperature of −15° C. or less, a mixture of 11.7 g of 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-carbaldehyde and 80 ml of tetrahydrofuran was dropped in 40 minutes and was then reacted at 10° C. or less for 1 hour. Furthermore, while keeping an inner temperature of 5° C. or less, 14.4 ml of acetic acid and 40 ml of toluene were added in a reaction system, followed by washing with 100 ml of water and 100 ml of saturated brine in that order. After the solvent is distilled off, the residue thus obtained was added with 100 ml of hexane and 5 ml of ethyl acetate so as to be crystallized, followed by filtrating and drying it to obtain 16.6 g (yield: 89%) of 7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-7-hydroxy-3,5-dioxoheptanoic acid ethyl ester was obtained.

Workup

  1. customat 2° C. or less
  2. customa reaction for 50 minutes at −10° C.
  3. customkept at −20 to −15° C.
  4. customa reaction for 40 minutes at an inner temperature of 2° C. or less
  5. customan inner temperature of −15° C. or less
  6. additionwas dropped in 40 minutes
  7. customwas then reacted at 10° C. or less for 1 hour
  8. additionwere added in a reaction system
  9. washby washing with 100 ml of water and 100 ml of saturated brine in that order
  10. distillationAfter the solvent is distilled off
  11. customthe residue thus obtained
  12. customto be crystallized
  13. filtrationby filtrating
  14. customdrying it

Sources & evidence

ORD record
ord-4e27b616e8904b319854b858f450e394
Source dataset
uspto-grants-2005_11
Patent number
US06965031B2

Reaction notes

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