Reaktion #219646

Reaktionsgleichung

1-(2-Aminoethyl)-piperidine

Acetic acid

(S)-Dimethyl 2-((3,7-dichloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate

thionyl chloride

potassium carbonate

→

title compound

Ausbeute 51.0%

(S)-methyl 2-(1,4-dichloro-8-oxo-9-(2-(piperidin-1-yl)ethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate

Ausbeute 51.0%

Lösungsmittel

acetonitrile

Reaktionsbedingungen

Aufarbeitung

1. 1
   EinengenMixture was concentrated by roto-vap
2. 2
   workup.DISSOLUTIONResidue was dissolved in ethyl acetate
3. 3
   WaschenMixture was washed twice with aqueous sodium bicarbonate
4. 4
   Filtrationfiltered
5. 5
   Einengenconcentrated to dryness
6. 6
   TemperaturMixture was warmed
7. 7
   Temperaturto reflux
8. 8
   workup.STIRRINGwith stirring for 1 hour
9. 9
   TemperaturMixture was cooled to room temperature
10. 10
    Filtrationfiltered over celite
11. 11
    EinengenFiltrate was concentrated by roto-vap
12. 12
    workup.DISSOLUTIONResidue was dissolved in toluene (15 mL)
13. 13
    SonstigeReaction
14. 14
    Temperaturwas warmed
15. 15
    Temperaturto reflux
16. 16
    workup.STIRRINGwith stirring for 16 hours
17. 17
    TemperaturMixture was cooled to room temperature
18. 18
    Einengenconcentrated by roto-vap
19. 19
    WaschenMixture was washed twice with aqueous sodium bicarbonate
20. 20
    Filtrationfiltered
21. 21
    Einengenconcentrated to dryness
22. 22
    WaschenSilica gel chromatography eluting 2M ammonia in methanol-dichloromethane

Vorschrift

(S)-Dimethyl 2-((3,7-dichloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (990 mg, 2.64 mmol) was dissolved in thionyl chloride (2.0 M in dichloromethane) (20 mL, 40.0 mmol). Mixture stirred at room temperature for 3 hours. Mixture was concentrated by roto-vap. Residue was dissolved in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate. Organics were dried MgSO4, filtered and then concentrated to dryness. A portion of the residue (460 mg, 1.169 mmol) was dissolved in acetonitrile (15 mL). 1-(2-Aminoethyl)-piperidine (600 μl, 4.21 mmol) was added to the mixture followed by potassium carbonate (200 mg, 1.447 mmol). Mixture was warmed to reflux and held with stirring for 1 hour. Mixture was cooled to room temperature and then filtered over celite. Filtrate was concentrated by roto-vap. Residue was dissolved in toluene (15 mL). Acetic acid (1.0 mL, 17.47 mmol) was added to the mixture. Reaction was warmed to reflux and held with stirring for 16 hours. Mixture was cooled to room temperature and then concentrated by roto-vap. Residue was suspended in ethyl acetate. Mixture was washed twice with aqueous sodium bicarbonate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Silica gel chromatography eluting 2M ammonia in methanol-dichloromethane afforded the title compound as amber oil in 51% yield. (M+H)+=453.0, 455.0.

Quelle