Aventis Pharma S.a.

Stefanie Leue

Andrew-Elliot Greene

Yves G&eacute;nisson

Yves Genisson

Khalid Mekouar

St&eacute;phanie Gar&ccedil;on

Patrick L&eacute;on

The invention concerns the preparation of nothapodytine or camptothecin derivatives which consists in causing 4-ethyl 2methyl hepta-2,4-dienoic acid act on a 3-aminomethyl 2-bromo quinoline derivative (III) wherein R and R are H or R is a halogen atom or alkyl, R is a O&mdash;CO&mdash;X radical as defined for the camptothecin derivatives; or R and R are defined for the known camptothecin derivatives or represent protected radicals or radicals easily convertible into the radicals R and R , to obtain the quinoline derivative (IV); adding to the resulting quinoline derivative (2-methoxy carbonyl vinyl) tributyltin in the presence of a complex of palladium and triphenylarsin to obtain the quinoline derivative (V); cyclizing the resulting quinoline derivative to obtain the tetracyclic derivative (VI); then in subjecting said derivative to an ozonolysis followed by treatment with dimethyl sulphide to obtain the tetracyclic derivative (VII); saponification followed by decarboxylation in oxidising conditions of the resulting tetracyclic derivative to obtain the nothopodytine derivative (VIII); then optionally transforming the resulting derivative into a camptothecin derivative or into a mappicine derivative.

Preparation of camptothecin and nothapodytine derivatives

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.

Preparation of camptothecin and of its derivatives

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Chantilly, France

Stefanie Leue