Hydrochloric Acid → Panobinostat Carboxylic Acid Methyl Ester Hydrochloride

HRID 43287

Reaktionsgleichung

Reaktionsgleichung von HRID 43287
[CH3:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH2:6].[CH3:14][O:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1.[BH4-].[Na+].[ClH:30].[H][H]>CO.O>[ClH:30].[CH3:14][O:15][C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH:6][CH2:5][CH2:4][C:3]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:13][C:2]=2[CH3:1])=[CH:23][CH:24]=1

Komponenten

8

Edukt 5

HCID 313Hydrochloric Acid2×HCID 759492-Methyl-1H-indole-3-ethylamineHCID 4311764Sodium borohydrideHCID 11008713methyl (2E)-3-(4-formylphenyl)prop-2-enoateHCID 178418361HCID 178418361, Verbindung

Produkt 1

HCID 23652684Panobinostat Carboxylic Acid Methyl Ester Hydrochloride

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 962WaterLösungsmittel

Reaktionsbedingungen

Temperatur
22.5 °C

Versuchsvorschrift

2-Methyltryptamine (50 g, 287 mmole) and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester (54.6 g, 287 mmole) are suspended in methanol (514 g). The solution is stirred for 1 hour at 20-25° C., to allow the formation of the imine intermediate. The solution is cooled to −15° C. within ca. 20 minutes. Sodium borohydride (5.43 g, 143.5 mmole) is added in several portions during ca. 1 hour while maintaining the temperature at −15° C. to −10° C. The reaction mixture is stirred for additional 30 minutes at this temperature and the temperature is raised to 20-25° C. within ca. 25 minutes. The reaction mixture is stirred for 30 minutes at 20-25° C. and water (80 g) is slowly added while maintaining the temperature at 20-25° C. An aqueous solution of hydrochloric acid (70.5 g concentrated HCl in 50 g of water) is slowly added to the reaction mixture such that the temperature is maintained at 20-25° C. and the hydrogen gas evolution can be controlled. The addition needs ca. 1 hour in this case. A second portion of aqueous hydrochloric acid solution (70.5 g concentrated HCl in 50 g water) is added within 30 minutes and the temperature is raised to 65° C. within 30 minutes. The suspension is stirred for 30 minutes at 65° C. and the temperature is lowered to −15° C. within 45 minutes. After 10 minutes stirring at −15° C., the temperature is raised again to 65° C. and the suspension is stirred for 30 minutes at this temperature. Finally, the suspension is cooled to −15° C. within 45 minutes and stirring is continued for additional 30 minutes at this temperature. The product is isolated by filtration and the wet filter cake is washed with pre-cooled (−15° C.) methanol (2×150 g). The wet product is dried at 50° C. under reduced pressure to obtain pure (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-acrylic acid methyl ester hydrochloride salt as product. The product has usually >99 area % purity according to HPLC. IR, NMR and HR-MS confirmed the proposed structure. Melting point: decomposition starting at 251-252° C.

Aufarbeitung

  1. temperatureThe solution is cooled to −15° C. within ca. 20 minutes
  2. temperaturewhile maintaining the temperature at −15° C. to −10° C
  3. stirringThe reaction mixture is stirred for additional 30 minutes at this temperature
  4. temperaturethe temperature is raised to 20-25° C. within ca. 25 minutes
  5. stirringThe reaction mixture is stirred for 30 minutes at 20-25° C.
  6. temperaturewhile maintaining the temperature at 20-25° C
  7. temperatureis maintained at 20-25° C.
  8. additionThe addition
  9. waitneeds ca. 1 hour in this case
  10. temperaturethe temperature is raised to 65° C. within 30 minutes
  11. stirringThe suspension is stirred for 30 minutes at 65° C.
  12. waitthe temperature is lowered to −15° C. within 45 minutes
  13. stirringAfter 10 minutes stirring at −15° C.
  14. temperaturethe temperature is raised again to 65° C.
  15. stirringthe suspension is stirred for 30 minutes at this temperature
  16. temperatureFinally, the suspension is cooled to −15° C. within 45 minutes
  17. stirringstirring
  18. waitis continued for additional 30 minutes at this temperature
  19. customThe product is isolated by filtration
  20. washthe wet filter cake is washed
  21. temperaturewith pre-cooled (−15° C.) methanol (2×150 g)
  22. customThe wet product is dried at 50° C. under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-515130eb6ab5446b8930fa231a98d79a
Quelldatensatz
uspto-grants-2013_09
Patentnummer
US08536346B2

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