US5580998A
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Process for preparing taxoids
Assignee: Aventis Pharma SA
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Filing: 1995-06-07
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Granted: 1996-12-03
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Expires: 2015-06-07
Abstract
Abstract The invention relates to a process for preparing taxoids of formula I herein that includes comprising the steps of esterifying a baccatin III derivative of the formula VI herein, treating the compound obtained in acidic medium, and optionally removing a protecting group to give the desired taxoid product.
Inventors
- 👤 Herv e Bouchard
- 👤 Jean-Dominique Bourzat
- 👤 Alain Commercon
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-08 06:49
CPC Classifications
C; C07; C07D; C07D305/00; C07D305/14; A; A61; A61K; A61K31/00; A61K31/33; A61K31/335; A61P; A61P35/00; Y; Y02; Y02P; Y02P20/00; Y02P20/50; Y02P20/55
Claims Analysis
Total Claims: 30
Claim 1
Independent Claim
175 words
A process for preparing a taxoid of formula I: ##STR27## in which R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical, R 1 represents a benzoyl radical or a radical R 2 --O --CO in which R 2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical, comprising the steps of esterifying a compound of formula VI: ##STR28## in which G 1 represents a hydrogen atom, an acetyl, alkyl, or alkoxyacetyl radical or a hydroxy-protecting group, with a free acid of the formula XXVI: ##STR29## in which Ar and R 1 are as defined above, and G 3 represents a hydroxy-protecting group, or of an activated derivative of this acid, to give a compound of the formula XXVII: ##STR30## in which Ar, R 1 , G 1 and G 3 are as defined above, replacing the protecting group G 3 with hydrogen, and when G 1 represents a protecting group, removing said G 1 protecting group to give a product of formula I.
Claim 2
Dependent Claim
175 words
A process for preparing a taxoid of formula I: ##STR27## in which R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical, R 1 represents a benzoyl radical or a radical R 2 --O --CO in which R 2 represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Ar represents an aryl radical, comprising the steps of esterifying a compound of formula VI: ##STR28## in which G 1 represents a hydrogen atom, an acetyl, alkyl, or alkoxyacetyl radical or a hydroxy-protecting group, with a free acid of the formula XXVI: ##STR29## in which Ar and R 1 are as defined above, and G 3 represents a hydroxy-protecting group, or of an activated derivative of this acid, to give a compound of the formula XXVII: ##STR30## in which Ar, R 1 , G 1 and G 3 are as defined above, replacing the protecting group G 3 with hydrogen, and when G 1 represents a protecting group, removing said G 1 protecting group to give a product of formula I.
Claim 3
Dependent Claim
17 words
The process of claim 1, wherein the G 1 protecting group is replaced by a hydrogen atom.
Claim 4
Dependent Claim
55 words
The process of claim 1, wherein the esterifying step further comprises using a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from -10° to 90° C.
Claim 5
Dependent Claim
62 words
The process of claim 1, wherein the free acid of esterifying step is in an anhydride form, and wherein the esterifying step is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0° to 90° C.
Claim 6
Dependent Claim
73 words
The process of claim 1, wherein the free acid of the esterifying step is in a halide form or an anhydride form with an aliphatic or aromatic acid, and wherein esterifying step is carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0° to 80° C.
Claim 7
Dependent Claim
17 words
The process of claim 5, wherein the anhydride form of the free acid is prepared in situ.
Claim 8
Dependent Claim
83 words
The process of claim 1, wherein G 1 and G 3 represent a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical and each is replaced a hydrogen atom by treating with zinc or zinc combined with copper in the presence of acetic acid at a temperature ranging from 30° to 60° C. or by treating with an inorganic or organic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester in the presence of zinc or zinc combined with copper.
Claim 9
Dependent Claim
125 words
The process of claim 1, wherein G 3 represents a silylated radical or an acetal residue and is replaced with hydrogen by treating in acidic medium in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or aqueous hydrofluoric acid at a temperature ranging from 0° to 40° C., followed by the replacement of the protecting group G 1 with hydrogen by treating with zinc or zinc combined with copper in the presence of acetic acid at a temperature ranging from 30° to 60° C. or by treating with an inorganic or organic acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester in the presence of zinc or zinc combined with copper.
Claim 10
Dependent Claim
52 words
The process of claim 1, wherein G 1 represents an alkoxyacetyl radical and is replaced with a hydrogen atom by treating in an alkaline medium using ammonia in aqueous-alcoholic medium at a temperature of about 20° C. or by treating with zinc halide in methanol at a temperature of about 20° C.
Claim 11
Dependent Claim
17 words
The process of claim 7, wherein the organic acid is selected from hydrochloric acid and acetic acid.
Claim 12
Dependent Claim
19 words
The process of claim 7, wherein the aliphatic ester is selected from ethyl acetate, isopropyl acetate, and n-butyl acetate.
Claim 13
Dependent Claim
17 words
The process of claim 8, wherein the organic acid is selected from hydrochloric acid and acetic acid.
Claim 14
Dependent Claim
19 words
The process of claim 8, wherein the aliphatic ester is selected from ethyl acetate, isopropyl acetate, and n-butyl acetate.
Claim 15
Dependent Claim
32 words
The process of claim 1, wherein when G 3 represents a radical --CH 2 --Ph and is replaced by a hydrogen atom using hydrogenolysis after replacing the protecting group G 1 .
Claim 16
Dependent Claim
161 words
The process for preparing a taxiod of formula I: ##STR31## in which R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical, R 1 represents a radical R 2 --O--CO-- in which R 2 represents an alkyl radical, and Ar represents an aryl radical, comprising the steps of esterifying a compound of formula VI: ##STR32## in which G 1 represents a hydrogen atom, an acetyl, alkyl, or alkoxyacetyl radical or a hydroxy-protecting group, with a free acid of the formula XXVI: ##STR33## in which Ar and R 1 are as defined above, and G 3 represents a hydroxy-protecting group, or an activated derivative of this acid, to give a compound of the formula XXVII: ##STR34## in which Ar, R 1 , G 1 and G 3 are as defined above, replacing the protecting group G 3 with hydrogen, and when G 1 represents a protecting group, removing said G 1 protecting group to give a product of formula I.
Claim 17
Dependent Claim
161 words
The process for preparing a taxiod of formula I: ##STR31## in which R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical, R 1 represents a radical R 2 --O--CO-- in which R 2 represents an alkyl radical, and Ar represents an aryl radical, comprising the steps of esterifying a compound of formula VI: ##STR32## in which G 1 represents a hydrogen atom, an acetyl, alkyl, or alkoxyacetyl radical or a hydroxy-protecting group, with a free acid of the formula XXVI: ##STR33## in which Ar and R 1 are as defined above, and G 3 represents a hydroxy-protecting group, or an activated derivative of this acid, to give a compound of the formula XXVII: ##STR34## in which Ar, R 1 , G 1 and G 3 are as defined above, replacing the protecting group G 3 with hydrogen, and when G 1 represents a protecting group, removing said G 1 protecting group to give a product of formula I.
Claim 18
Dependent Claim
17 words
The process of claim 15, wherein the G 1 protecting group is replaced by a hydrogen atom.
Claim 19
Dependent Claim
55 words
The process of claim 15, wherein the esterifying step further comprises using a condensing agent chosen from carbodiimides and reactive carbonates and an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, ketones, esters, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from -10° to 90° C.
Claim 20
Dependent Claim
62 words
The process of claim 15, wherein the free acid of esterifying step is in an anhydride form, and wherein the esterifying step is carried out in the presence of an activating agent chosen from aminopyridines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0° to 90° C.
Claim 21
Dependent Claim
74 words
The process of claim 15, wherein the free acid of the esterifying step is in a halide form or an anhydride form with an aliphatic or aromatic acid, and wherein the esterifying step is carried out in the presence of a base chosen from tertiary aliphatic amines in an organic solvent chosen from ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0° to 80° C.
Claim 22
Dependent Claim
17 words
The process of claim 19, wherein the anhydride form of the free acid is prepared in situ.
Claim 23
Dependent Claim
84 words
The process of claim 15, wherein G 1 and G 3 represent a 2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonyl radical and each is replaced with a hydrogen atom by treating with zinc or zinc combined with copper in the presence of acetic acid at a temperature ranging from 30° to 60° C. or by treating with an inorganic or organic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester in the presence of zinc or zinc combined with copper.
Claim 24
Dependent Claim
125 words
The process of claim 15, wherein G 3 represents a silylated radical or an acetal residue and is replaced with hydrogen by treating in acidic medium in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or aqueous hydrofluoric acid at a temperature ranging from 0° to 40° C., followed by the replacement of the protecting group G 1 with hydrogen by treating with zinc or zinc combined with copper in the presence of acetic acid at a temperature ranging from 30° to 60° C. or by treating with an inorganic or organic acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester in the presence of zinc or zinc combined with copper.
Claim 25
Dependent Claim
52 words
The process of claim 15, wherein G 1 represents an alkoxyacetyl radical and is replaced with a hydrogen atom by treating in an alkaline medium using ammonia in aqueous-alcoholic medium at a temperature of about 20° C. or by treating with zinc halide in methanol at a temperature of about 20° C.
Claim 26
Dependent Claim
17 words
The process of claim 21, wherein the organic acid is selected from hydrochloric acid and acetic acid.
Claim 27
Dependent Claim
19 words
The process of claim 21, wherein the aliphatic ester is selected from ethyl acetate, isopropyl acetate, and n-butyl acetate.
Claim 28
Dependent Claim
17 words
The process of claim 22, wherein the organic acid is selected from hydrochloric acid and acetic acid.
Claim 29
Dependent Claim
19 words
The process of claim 22, wherein the aliphatic ester is selected from ethyl acetate, isopropyl acetate, and n-butyl acetate.
Claim 30
Dependent Claim
32 words
The process of claim 15, wherein when G 3 represents a radical --CH 2 --Ph and is replaced by a hydrogen atom using hydrogenolysis after replacing the protecting group G 1 .
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1999-12-03 | 2000-06-03 | 2000-12-03 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2003-12-03 | 2004-06-03 | 2004-12-03 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2007-12-03 | 2008-06-03 | 2008-12-03 | $7700.00 | Window Closed / Lapsed |