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   Synthesis Schemes
Drug Name
Palonosetron hydrochloride;RS-25259-197;Onicita;Onicit;Aloxi
Description of the Scheme
RS-25259-197 can be obtained by several related ways: 1) The condensation of naphthalene-1,8-dicarboxylic anhydride (I) or the corresponding imide (II) with quinuclidin-3(S)-amine (III) in refluxing isopropanol gives 2-[3(S)-quinuclidinyl]-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (IV), which by hydrogenation with H2 over PtO2 in ethanol yields 3-hydroxy-2-[3(S)-quinuclidinyl]-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquionlin-1-one (V). The dehydration of (V) with HCl in refluxing isopropanol affords the 2,4,5,6-tetrahydro compound (VI) (1), which is finally hydrogenated with H2 over Pd/C in acetic acid to yield a mixture of (S,S)- and (R,S)-diastereomers that is resolved by crystallization and chromatography. 2) The partial hydrogenation of anhydride (I) with H2 over Pd/C in hot acetic acid gives 3-acetoxy-5,6-dihydro-1H,4H-naphtho[1,8-cd]pyran-1-one (VIII), which is deacetylated by hydrogenation with H2 over Pd/C in ethyl acetate, yielding 5,6-dihydro-1H,4H-naphtho[1,8-cd]pyran-1-one (IX). Finally, this compound is condensed with the quinuclidine (III) by heating at 140 C and digestion with methanol to afford the hydroxy compound (V), already obtained. 3) The cyclization of N-[3(S)-quinuclidinyl]-5,6,7,8-tetrahydronaphthalene-2-carboxamide (X) by means of butyllithium and DMF gives the 2,4,5,6-tetrahydro compound (VI), already obtained.
Route of the Synthesis
Synthesisi Route of Palonosetron hydrochloride;RS-25259-197;Onicita;Onicit;Aloxi
Intermediate
1H,3H-benzo[de]isochromene-1,3-dione; 1,8-Naphthalic Anhydride (I)
1H-benz[de]isoquinoline-1,3(2H)-dione; 1H-benzo[de]isoquinoline-1,3(2H)-dione (II)
(3S)-1-azabicyclo[2.2.2]octan-3-amine; 1-aza-Bicyclo[2.2.2]oct-3-ylamine; (3S)-1-azabicyclo[2.2.2]oct-3-ylamine (III)
2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-1H-benzo[de]isoquinoline-1,3(2H)-dione (IV)
2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3-hydroxy-2,3,3a,4,5,6-hexahydro-1H-benzo[de]isoquinolin-1-one (V)
2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-1-one (VI)
2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-3a,4,5,6-tetrahydro-1H-benzo[de]isoquinoline-1,3(2H)-dione (VII)
1-oxo-5,6-dihydro-1H,4H-benzo[de]isochromen-3-yl acetate (VIII)
5,6-dihydro-1H,4H-benzo[de]isochromen-1-one (IX)
N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5,6,7,8-tetrahydro-1-naphthalenecarboxamide (X)
References1:
    Clark, R.D.; Miller, A.B.; Berger, J.; et al.; 2-(Quinuclidin-3-yl)pyrido[4,3-b]indol-1-ones and isoquinolin-1-ones.Potent conformationally restricted 5-HT3 receptor antagonists. J Med Chem 1993, 36, 18, 2645.
References2:
    Graul, A.; Castaer, J.; RS-25259-197. Drugs Fut 1996, 21, 9, 906.
References3:
    Berger, J.; Clark, R.D.; Eglen, R.M.; Smith, W.L.; Weinhardt, K.K. (Syntex (USA), Inc.); New tricyclic cpds. AU 9166963; EP 0430190; US 5202333 .
References4:
    Dvorak, C.A.; Kowalczyk, B.A. (F. Hoffmann-La Roche AG); Process for the preparation of 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro- -1H-benz[de]isoquinolin-1-one and intermediate product. WO 9601824 .
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