Process for preparing taxane derivatives

Details Process for preparing taxane derivatives Process for preparing taxane derivatives

1995-04-04

1997-06-10

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549510, C07D41302, C07D26304

Patent

active

056377231

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION OF THE INVENTION

This application is a 35 U.S.C. 371 National Stage filing of PCT/FR93/00968 published as WO 94/07878 on Apr. 14, 1994.
The present invention relates to a new process for preparing taxane derivatives of general formula: ##STR2## which possess noteworthy antileukaemic and antitumor properties.
In the general formula (I): R represents a hydrogen atom or an acetyl radical, R.sub.1 represents a benzoyl radical or a radical R.sub.2 --O--CO-- in which R.sub.2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or nitrogenous heterocyclic radical, and Ar represents an aryl radical.
More especially, R represents a hydrogen atom or an acetyl radical and R.sub.1 represents a benzoyl radical or a radical R.sub.2 --O--CO-- in which R.sub.2 represents: alkenyl radical containing 2 to 8 carbon atoms, an alkynyl radical containing 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or a bicycloalkyl radical containing 7 to 10 carbon atoms, these radicals being optionally substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinyl radicals (optionally substituted at position 4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains i to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl, cyano or carboxyl radicals or alkyloxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, radicals chosen from alkyl radicals containing 1 to 4 carbon atoms or alkyloxy radicals containing 1 to 4 carbon atoms, radical optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, on the understanding that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals can be optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, and Ar represents a phenyl or .alpha.- or .beta.-naphthyl radical optionally substituted with one or more atoms or radicals chosen from halogen (fluorine, chlorine, bromine, iodine) atoms and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano and trifluoromethyl radicals, on the understanding that the alkyl radicals and alkyl portions of the other radicals contain 1 to 4 carbon atoms, and that the alkenyl and alkynyl radicals contain 3 to 8 carbon atoms and the aryl radicals are phenyl or .alpha.- or .beta.-naphthyl radicals.
Of very special importance are the products of general formula (I) in which R represents a hydrogen atom or an acetyl radical, R.sub.1 represents a benzoyl or t-butoxycarbonylamino radical and Ar represents a phenyl radical.
The products of general formula (I) in which R.sub.1 represents a benzoyl radical correspond to taxol and to 10-deacetyltaxol, and the products of general formula (I) in which R.sub.1 represents a t-butoxycarbonyl radical correspond to those which form the subject of European Patent 0,253,738.
According to the process which is described in International Application PCT W0 92/09,589, the derivatives of general formula (I) may be obtained by: ##STR3## in which Ar is defined as above, Boc represents a t-butoxycarbonyl radical and R'.sub.2 and R'.sub.3, which may be identical or different, represent an alkyl radical containing 1 to 4 carbon atoms optionally substituted with one or more aryl radicals, or an aryl radical, or alternatively R'.sub.2 and R'.sub.3, together with the carbon atom to which they are linked, form a 4- to 7-membered ring, with protected 10-deacetylbaccatin III or baccatin III of general formula

REFERENCES:
patent: 5440056 (1995-08-01), Klein et al.
patent: 5476954 (1995-12-01), Bourzat et al.

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