1,3,3-Trimethyl-6-azabicyclo(3.2.1)octane → Ethyl 8-fluoro-4-methyl-1-oxo-9-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-1,4-dihydrobenzo[f] [1,7]naphthyridine-2-carboxylate

HRID 413045Notes

Reaction equation

HRID 413045 reaction equation
[F:1][C:2]1[C:22](F)=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1.[CH3:24][C:25]12[CH2:32][CH:29]([NH:30][CH2:31]1)[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]2>CS(C)=O>[F:1][C:2]1[C:22]([N:30]2[CH2:31][C:25]3([CH3:24])[CH2:32][CH:29]2[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1

Participants

4

Reactant 2

HCID 1037871,3,3-Trimethyl-6-azabicyclo(3.2.1)octaneHCID 18523355Ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate

Product 1

HCID 18523295Ethyl 8-fluoro-4-methyl-1-oxo-9-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-1,4-dihydrobenzo[f] [1,7]naphthyridine-2-carboxylateYield 31.7%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
90 °C

Procedure

A suspension of 2 g of ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 2.6 g of 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane in 50 cm3 of dimethyl sulphoxide was heated, with stirring, at a temperature of 90° C. for 12 days. After cooling to 20° C., the mixture was poured into 200 cm3 of ice-cold water. The medium was extracted 3 times with 200 cm3 of dichloromethane, and the organic extracts were washed 3 times with 100 cm3 of water, and dried over sodium sulphate. After filtration and concentration under reduced pressure (5.2 kPa), the compound obtained was purified by chromatography on 160 g of silica gel (0.06-0.20 mm). Elution was carried out with 3 liters of a dichloromethane-ethanol mixture (97-3 by volume), collecting 200 cm3 fractions. The fractions between 1.65 and 3 liters were concentrated to dryness under reduced pressure (5.2 kPa). 0.9 g of ethyl 8-fluoro-4-methyl-1-oxo-9-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of yellow crystals, which melted at 187° C.

Workup

  1. temperaturewas heated
  2. temperatureAfter cooling to 20° C.
  3. extractionThe medium was extracted 3 times with 200 cm3 of dichloromethane
  4. washthe organic extracts were washed 3 times with 100 cm3 of water
  5. dry with materialdried over sodium sulphate
  6. filtrationAfter filtration and concentration under reduced pressure (5.2 kPa)
  7. customthe compound obtained
  8. customwas purified by chromatography on 160 g of silica gel (0.06-0.20 mm)
  9. washElution
  10. customcollecting 200 cm3 fractions
  11. concentrationThe fractions between 1.65 and 3 liters were concentrated to dryness under reduced pressure (5.2 kPa)

Sources & evidence

ORD record
ord-433c4b383b2b46a3bc3504c914469148
Source dataset
uspto-grants-2003_05
Patent number
US06566362B2

Reaction notes

Loading…