Diisobutylaluminum hydride → 1-ethyl-6-fluoro-3-(hydroxymethyl)-7,8-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one

HRID 525943Notes

Reaction equation

HRID 525943 reaction equation
[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:34])[C:5]([C:35](O)=[O:36])=[CH:4]1)[CH3:2].ClC(OCC(C)C)=O.CC(C[AlH]CC(C)C)C>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:34])[C:5]([CH2:35][OH:36])=[CH:4]1)[CH3:2]

Participants

6

Reactant 3

HCID 14487Diisobutylaluminum hydrideHCID 62365Isobutyl chloroformateHCID 867328111-Ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

Product 1

HCID 867328121-ethyl-6-fluoro-3-(hydroxymethyl)-7,8-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-oneYield 65.3%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (40 g, 79 mmol) in Tetrahydrofuran (THF) (300 mL) was added TEA (12.08 mL, 87 mmol) and isobutyl chloroformate (11.39 mL, 87 mmol). The resulting mixture was stirred at r.t. for 1 h. LCMS showed completion of the reaction. Then the mixture was cooled down to −78° C. and a solution of DIBAL-H (158 mL, 236 mmol) in toluene (1.5 M) was added. The mixture was stirred at the same temperature for 1.5 h, LCMS indicated completion of the reaction. The reaction was quenched with sat. NH4Cl (aq.), warmed up to r.t., concentrated, diluted with sat. NH4Cl and extracted with dichloromethane twice. The organic mixture was filtered through Celite to remove any solids. The combined organic solution was then washed with brine and dried over sodium sulfate, filtered and the resulting filtrate was concentrated in vacuo to afford 1-ethyl-6-fluoro-3-(hydroxymethyl)-7,8-bis((4-methoxybenzyl)oxy)quinolin-4(1H)-one (33 g, 51.5 mmol, 65.3% yield) as yellow solid, which was used in the next oxidation step without further purification. LCMS: (M+H)+: 494.3.

Workup

  1. customcompletion of the reaction
  2. temperatureThen the mixture was cooled down to −78° C.
  3. stirringThe mixture was stirred at the same temperature for 1.5 h
  4. customcompletion of the reaction
  5. customThe reaction was quenched with sat. NH4Cl (aq.)
  6. temperaturewarmed up to r.t.
  7. concentrationconcentrated
  8. additiondiluted with sat. NH4Cl
  9. extractionextracted with dichloromethane twice
  10. filtrationThe organic mixture was filtered through Celite
  11. customto remove any solids
  12. washThe combined organic solution was then washed with brine
  13. dry with materialdried over sodium sulfate
  14. filtrationfiltered
  15. concentrationthe resulting filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-4fd58227335d485cb6a9ff239f4a41d2
Source dataset
uspto-grants-2016_05
Patent number
US09340556B2

Reaction notes

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