N-(8-Amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide → Exatecan intermediate 9

HRID 1267598Notes

Reaction equation

HRID 1267598 reaction equation
[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([F:16])[C:11]=2[CH3:15])[C:6]1=O)(=[O:3])[CH3:2].[CH2:19]([C@:21]1([OH:37])[C:33]2[CH:32]=[C:31]3[N:27]([CH2:28][CH2:29][C:30]3=O)[C:26](=[O:35])[C:25]=2[CH2:24][O:23][C:22]1=[O:36])[CH3:20]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]1[C:6]2=[C:29]3[CH2:28][N:27]4[C:31](=[CH:32][C:33]5[C@:21]([CH2:19][CH3:20])([OH:37])[C:22](=[O:36])[O:23][CH2:24][C:25]=5[C:26]4=[O:35])[C:30]3=[N:17][C:8]3[CH:9]=[C:10]([F:16])[C:11]([CH3:15])=[C:12]([C:7]=32)[CH2:13][CH2:14]1)(=[O:3])[CH3:2]

Participants

5

Reactant 2

HCID 10220585N-(8-Amino-6-fluoro-5-methyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetamideHCID 10220900(4S)-4-Ethyl-7,8-dihydro-4-hydroxy-1H-pyrano(3,4-f)indolizine-3,6,10(4H)-trione

Product 1

HCID 12067229Exatecan intermediate 9Yield 91.4%

Reagents, catalysts & solvents 2

HCID 466102Benzenesulfonic acid, 4-methyl-, compd. with pyridine (1:1)Catalyst3×HCID 1140TolueneSolvent

Procedure

To 2.00 g of 2-acetylamino-8-amino-6-fluoro-5-methyl-1-tetralone and 2.10 g of (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione, 250 ml of toluene and then 0.1 g of pyridinium p-toluenesulfonate were added, followed by heating under reflux for 3 hours. The mixture was added with 0.1 g of pyridinium p-toluenesulfonate, followed by heating under reflux for 2.5 hours. The mixture was then added with 0.1 g of pyridinium p-toluenesulfonate, followed by heating under reflux for 38 hours. The reaction mixture was cooled. The solvent was then removed under reduced pressure. To a crystalline residue, acetone was added and the crystals so precipitated were collected by filtration, whereby 3.48 g of the title compound were obtained. Melting point: 225-235° C. (decomposed)

Workup

  1. temperatureby heating
  2. temperatureunder reflux for 3 hours
  3. temperatureby heating
  4. temperatureunder reflux for 2.5 hours
  5. temperatureby heating
  6. temperatureunder reflux for 38 hours
  7. temperatureThe reaction mixture was cooled
  8. customThe solvent was then removed under reduced pressure
  9. additionTo a crystalline residue, acetone was added
  10. customthe crystals so precipitated
  11. filtrationwere collected by filtration

Sources & evidence

ORD record
ord-afa6013fc3a445d6b44faef9759a4c76
Source dataset
uspto-grants-2003_04
Patent number
US06552197B2

Reaction notes

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