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US 6,486,320 B2Granted
Preparation of camptothecin and of its derivatives
AssigneeAventis Pharma S.A.
InventorsStefanie Leue, Stéphanie Garçon, Andrew-Elliot Greene, Yves Génisson, Patrick Léon
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Abstract
The present invention relates to a novel process for preparation of camptothecin and of its derivatives by convergent synthesis starting from a 3-(aminomethyl)quinoline derivative and 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid and to the intermediates obtained.
Claims45
Process for the preparation of camptothecin, or of at least one derivative of formula (I):
- wherein R1, R2, and R3 each represent an identical or different group chosen from:
- hydrogen,
- a hydroxyl group,
- a halogen atom, chosen from fluorine, chlorine, bromine, or iodine,
- a linear or branched alkoxy group comprising 1 to 4 carbon atoms,
- a linear or branched alkylthio group comprising 1 to 4 carbon atoms,
- a (C1-C4)alkylamino group, optionally substituted by one or more C1-C4 alkyl groups,
- an aralkyl group, optionally substituted by a C1-C4 alkyl group, wherein said aryl group is optionally a heterocycle with 1 to 3 heteroatoms chosen from oxygen, sulfur, and nitrogen, and
- an arylcarbonyloxy group, wherein said aryl group is optionally a mono- or polycyclic heterocycle with 1 to 3 heteroatoms chosen from oxygen, sulfur, and nitrogen;
- comprising condensing a 3-(aminomethyl)quinoline derivative and a 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid or acid derivative, followed by an ethynylation stage, and optionally by at least one of a hydrolysis stage, a double cyclization stage, a dehydrogenation, and a deprotection/dealkoxycarbonylation.
7 more elements
A compound of formula:
- wherein R1, R2, R3 each represent an identical or different group chosen from:
- hydrogen,
- a hydroxyl group,
- a halogen atom, chosen from fluorine, chlorine, bromine, or iodine,
- a linear or branched alkoxy group comprising 1 to 4 carbon atoms,
- a linear or branched alkylthio group comprising 1 to 4 carbon atoms,
- a (C1-C4)alkylamino group, optionally substituted by one or more C1-C4 alkyl groups,
- an aralkyl group, optionally substituted by a C1-C4 alkyl group, wherein said aryl group are optionally a heterocycle with 1 to 3 heteroatoms chosen from oxygen, sulfur, and nitrogen, and
- an arylcarbonyloxy group, wherein said aryl group is optionally a mono- or polycyclic heterocycle with 1 to 3 heteroatoms chosen from oxygen, sulfur, and nitrogen;
- wherein Y is a leaving group, and G1 is hydrogen or a protective group for an hydroxyl functional group.
7 more elements
A compound of formula (V)
- wherein R1, R2, and R3 each represent an identical or different group chosen from:
- hydrogen,
- a hydroxyl group,
- a halogen atom chosen from fluorine, chlorine, bromine, or iodine,
- a linear or branched alkoxy group comprising 1 to 4 carbon atoms,
- a linear or branched alkylthio group comprising 1 to 4 carbon atoms,
- a (C1-C4)alkylamino group, optionally substituted by one or more C1-C4 alkyl groups,
- an aralkyl group, optionally substituted by a C1-C4 alkyl group, wherein said aryl group is optionally a heterocycle with 1 to 3 heteroatoms chosen from oxygen, sulfur, and nitrogen,
- an arylcarbonyloxy group, wherein said aryl group is optionally a mono- or polycyclic heteroatoms with 1 to 3 heteroatoms chosen from oxygen, sulfur, and nitrogen,
- G1 is hydrogen or a protective group for a hydroxyl group, and Alk is a C1-C4 alkyl group optionally substituted by at least one aryl or heteroaryl group.
7 more elements
A compound of formula
- wherein R1, R2, and R3 each represent an identical or different group chosen from:
- hydrogen,
- a hydroxyl group,
- a halogen atom chosen from fluorine, chlorine, bromine or iodine,
- a linear or branched alkoxy group comprising 1 to 4 carbon atoms,
- a linear or branched alkylthio group comprising 1 to 4 carbon atoms,
- a (C1-C4)alkylamino group, optionally substituted by one or more C1-C4 alkyl groups,
- an aralkyl group, optionally substituted by a C1-C4 alkyl group, wherein said aryl group is optionally a heterocycle with 1 to3 heteroatoms chosen from oxygen, sulfur, and nitrogen, and
- an arylcarbonyloxy group, wherein said aryl group is optionally a mono- or polycyclic heterocycle with 1 to 3 heteroatoms chosen from oxygen, sulfur, and nitrogen;
- G1 is hydrogen or a protective group for an alcohol functional group;
- and Alk is a C1 -C4 alkyl group optionally substituted by at least one aryl or heteroaryl group.
8 more elements
Dependencies are inferred from the claim text.