Patent EA-002622-B1 (EA)
Title: Method for preparing derivatives of the taxoid class
Inventor: DIDIER ERIC
IPC: C07D305/14
Filed: 1998-11-16
Abstract: 1. A process for direct one-step simultaneous alkylating of two hydroxyl functions at the 7-position and 10-position of desacetylbaccatin III or derivatives thereof esterified in position 13 of formula (V):   wherein A represents hydrogen, a side chain of formula (Ic):   wherein: G represents a hydroxyl protecting group; R1 represents: 1). a straight or branched alkyl radical containing 1 to 8 carbon atoms, a straight or branched alkenyl radical containing 2 to 8 carbon atoms, a straight or branched alkynyl radical containing 2 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl or α- or β-naphthyl radical, unsubstituted or substituted with one or more atoms or radicals chosen from halogen 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, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, or 2). a 5-membered aromatic heterocycle containing one or more hetero atoms, which may be identical or different, chosen from nitrogen, oxygen or sulphur atoms, said 5-membered aromatic heterocycle being unsubstituted or substituted with one or more of halogen atoms or alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, or alkoxycarbonyl radicals, 3). wherein when R1 is a substituted phenyl radical, a substituted α- or β-naphthyl radical, or a substituted aromatic heterocycle, the alkyl radical substituent or the alkyl portion of another radical substituent contains 1 to 4 carbon atoms, the alkenyl or alkynyl radical substituent contains 2 to 8 carbon atoms, and the aryl radical substituent is a phenyl or α- or β-naphthyl radical; R2 represents: 1) a benzoyl radical, unsubstituted or substituted with one or more atoms or radicals, which may be identical or different, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms or trifluoromethyl, thenoyl or furoyl radicals, or 2) a radical R'2 --C--CO--, wherein R'2 represents: an alkyl radical containing 1 to 8 carbon atoms, an 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 unsubstituted or substituted with one or more substituents chosen from halogen atoms and hydroxyl radicals, alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl part contains 1 to 4 carbon atoms, piperidino or morpholino radicals, 1-piperazinyl radicals (unsubstituted or substituted in position 4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenyl alkyl radical in which the alkyl part contains 1 to 4 carbon atoms), cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals (unsubstituted or substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms), cyano or carboxyl radicals or alkoxycarbonyl radicals in which the alkyl part contains 1 to 4 carbon atoms, a phenyl or α- or β-naphthyl radical, unsubstituted or substituted with one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms or a 5-membered aromatic heterocyclic radical preferably chosen from furyl and thienyl radicals, or a saturated heterocyclic radical containing 4 to 6 carbon atoms, unsubstituted or substituted with one or more alkyl radicals containing 1 to 4 carbon atoms;  or an oxazolidine of formula (Id):   wherein R3 and R4 represent hydrogen or alkyl, aryl, halo, alkoxy, arylalkyl, alkoxyaryl, haloalkyl or haloaryl radicals, or R3 and R4 together form a 4- to 7-membered ring; wherein an alkylating agent is selected from: an alkyl halide, and preferably, from an alkyl iodide (R1) alkyl sulphate, such as methylsulphate  oxonium salts such as a boric salt of a trialkyloxonium, in particular, trimethyloxonium tetrafluoroborate and use them in the presence of one or several anionization agents such as one or several strong bases in anhydrous medium. 2. The process according to claim 1, wherein the alkylating agent is methylsulphate or methyliodide, preferably methyliodide. 3. The process according to claim 1, wherein the base usable in anhydrous medium are selected from an alkali metal hydride, an alkali metal alkoxide, silver oxide, 1,8-bis(dimethylamino)naphthalene, an alkali metal amide mixed with an alkali metal t-butoxide, or an alkyllithium mixed with an alkali metal t-butoxide. 4. The process according to claim 3, wherein the alkali metal hydride is selected from sodium or potassium hydride, preferably from potassium hydrate. 5. The process according to claim 3, wherein the alkali metal alkoxide is potassium tert-butoxide. 6. The process according to claim 1, wherein the alkylating agent is methyliodide in the presence of potassium hydrate. 7. The process according to any of the preceding claim, wherein the reaction is carried out in an organic medium under reaction conditions wherein the organic medium is inert. 8. The process according to claims 4-6, wherein the solvent is selected from ethers. 9. The process according to claim 3, wherein the reaction is carried out in the presence of silver oxide, using the solvent selected from aromatic solvents and aprotic polar solvents. 10. The process according to claim 8, wherein tetrahydrofuran or dimethoxyethane are used as the solvent. 11. The process according to claim 1 or 3, wherein using a mixture of 1,8-bis(dimethylamino)-naphthalene, trimethyloxonium tetrafluoroborate, in ethyl acetate. 12. The process according to any of the preceding claim, wherein the anionization agent and the substrate are present in a molar ratio of at least about 2 and, preferably, from about 2 to about 20. 13. The process according to any of the preceding claim, wherein the alkylating agent and the substrate are present in a molar ratio of at least about 2 and, preferably, from about 2 to about 40. 14. The process according to any of the preceding claim, wherein the alkylation is carried out at a reaction temperature of from -30 degree C. to 80 degree C.